volume 16 - volume 1 -number 3number 1 may - september 1997...
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Volume 1 - Number 1 May - September 1997
Volume 16 - Number 3 March 2012
The PDF version of the Atlas of Genetics and Cytogenetics in Oncology and Haematology is a reissue of the original articles published in collaboration with
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Atlas of Genetics and Cytogenetics in Oncology and Haematology
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Scope
The Atlas of Genetics and Cytogenetics in Oncology and Haematology is a peer reviewed on-line journal in
open access, devoted to genes, cytogenetics, and clinical entities in cancer, and cancer-prone diseases.
It presents structured review articles ("cards") on genes, leukaemias, solid tumours, cancer-prone diseases, more
traditional review articles on these and also on surrounding topics ("deep insights"), case reports in hematology,
and educational items in the various related topics for students in Medicine and in Sciences.
Editorial correspondance
Jean-Loup Huret Genetics, Department of Medical Information,
University Hospital
F-86021 Poitiers, France
tel +33 5 49 44 45 46 or +33 5 49 45 47 67
[email protected] or [email protected]
Staff Mohammad Ahmad, Mélanie Arsaban, Marie-Christine Jacquemot-Perbal, Maureen Labarussias, Vanessa Le
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Philippe Dessen is the Database Director, and Alain Bernheim the Chairman of the on-line version (Gustave
Roussy Institute – Villejuif – France).
The Atlas of Genetics and Cytogenetics in Oncology and Haematology (ISSN 1768-3262) is published 12 times
a year by ARMGHM, a non profit organisation, and by the INstitute for Scientific and Technical Information of
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Atlas Genet Cytogenet Oncol Haematol. 2012; 16(3)
Atlas of Genetics and Cytogenetics in Oncology and Haematology
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Atlas of Genetics and Cytogenetics in Oncology and Haematology
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Atlas of Genetics and Cytogenetics in Oncology and Haematology
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Editor
Jean-Loup Huret
(Poitiers, France)
Editorial Board
Sreeparna Banerjee (Ankara, Turkey) Solid Tumours Section
Alessandro Beghini (Milan, Italy) Genes Section
Anne von Bergh (Rotterdam, The Netherlands) Genes / Leukaemia Sections
Judith Bovée (Leiden, The Netherlands) Solid Tumours Section
Vasantha Brito-Babapulle (London, UK) Leukaemia Section
Charles Buys (Groningen, The Netherlands) Deep Insights Section
Anne Marie Capodano (Marseille, France) Solid Tumours Section
Fei Chen (Morgantown, West Virginia) Genes / Deep Insights Sections
Antonio Cuneo (Ferrara, Italy) Leukaemia Section
Paola Dal Cin (Boston, Massachussetts) Genes / Solid Tumours Section
Louis Dallaire (Montreal, Canada) Education Section
Brigitte Debuire (Villejuif, France) Deep Insights Section
François Desangles (Paris, France) Leukaemia / Solid Tumours Sections
Enric Domingo-Villanueva (London, UK) Solid Tumours Section
Ayse Erson (Ankara, Turkey) Solid Tumours Section
Richard Gatti (Los Angeles, California) Cancer-Prone Diseases / Deep Insights Sections
Ad Geurts van Kessel (Nijmegen, The Netherlands) Cancer-Prone Diseases Section
Oskar Haas (Vienna, Austria) Genes / Leukaemia Sections
Anne Hagemeijer (Leuven, Belgium) Deep Insights Section
Nyla Heerema (Colombus, Ohio) Leukaemia Section
Jim Heighway (Liverpool, UK) Genes / Deep Insights Sections
Sakari Knuutila (Helsinki, Finland) Deep Insights Section
Lidia Larizza (Milano, Italy) Solid Tumours Section
Lisa Lee-Jones (Newcastle, UK) Solid Tumours Section
Edmond Ma (Hong Kong, China) Leukaemia Section
Roderick McLeod (Braunschweig, Germany) Deep Insights / Education Sections
Cristina Mecucci (Perugia, Italy) Genes / Leukaemia Sections
Yasmin Mehraein (Homburg, Germany) Cancer-Prone Diseases Section
Fredrik Mertens (Lund, Sweden) Solid Tumours Section
Konstantin Miller (Hannover, Germany) Education Section
Felix Mitelman (Lund, Sweden) Deep Insights Section
Hossain Mossafa (Cergy Pontoise, France) Leukaemia Section
Stefan Nagel (Braunschweig, Germany) Deep Insights / Education Sections
Florence Pedeutour (Nice, France) Genes / Solid Tumours Sections
Elizabeth Petty (Ann Harbor, Michigan) Deep Insights Section
Susana Raimondi (Memphis, Tennesse) Genes / Leukaemia Section
Mariano Rocchi (Bari, Italy) Genes Section
Alain Sarasin (Villejuif, France) Cancer-Prone Diseases Section
Albert Schinzel (Schwerzenbach, Switzerland) Education Section
Clelia Storlazzi (Bari, Italy) Genes Section
Sabine Strehl (Vienna, Austria) Genes / Leukaemia Sections
Nancy Uhrhammer (Clermont Ferrand, France) Genes / Cancer-Prone Diseases Sections
Dan Van Dyke (Rochester, Minnesota) Education Section
Roberta Vanni (Montserrato, Italy) Solid Tumours Section
Franck Viguié (Paris, France) Leukaemia Section
José Luis Vizmanos (Pamplona, Spain) Leukaemia Section
Thomas Wan (Hong Kong, China) Genes / Leukaemia Sections
Atlas Genet Cytogenet Oncol Haematol. 2012; 16(3)
Atlas of Genetics and Cytogenetics in Oncology and Haematology
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Volume 16, Number 3, March 2012
Table of contents
Editorial
Why breast cancer and prostate cancer are so frequent? A new genetic mechanism, involving hormones and viruses 185 Jean-Loup Huret
Gene Section
CUX1 (cut-like homeobox 1) 189 Benjamin Kühnemuth, Patrick Michl
DNAJA3 (DnaJ (Hsp40) homolog, subfamily A, member 3) 194 June L Traicoff, Stephen M Hewitt, Joon-Yong Chung
MYEOV (myeloma overexpressed (in a subset of t(11;14) positive multiple myelomas)) 203 Jérôme Moreaux
PCNA (proliferating cell nuclear antigen) 206 Ivaylo Stoimenov, Thomas Helleday
RASSF5 (Ras association (RalGDS/AF-6) domain family member 5) 210 Lee Schmidt, Geoffrey J Clark
RGS17 (regulator of G-protein signaling 17) 214 Chenguang Li, Lei Wang, Yihua Sun, Haiquan Chen
SLC39A1 (solute carrier family 39 (zinc transporter), member 1) 216 Renty B Franklin, Leslie C Costello
CBX7 (chromobox homolog 7) 218 Ana O'Loghlen, Jesus Gil
RPRM (reprimo, TP53 dependent G2 arrest mediator candidate) 221 Alejandro H Corvalan, Veronica A Torres
VMP1 (vacuole membrane protein 1) 223 Alejandro Ropolo, Andrea Lo Ré, María Inés Vaccaro
XPO1 (exportin 1 (CRM1 homolog, yeast)) 226 Alessandra Ruggiero, Maria Giubettini, Patrizia Lavia
Leukaemia Section
t(11;18)(p15;q12) 231 Jean-Loup Huret
t(11;21)(q21;q22) 232 Jean-Loup Huret
t(8;17)(q24;q22) ???BCL3/MYC 234 Jean-Loup Huret
t(11;14)(q13;q32) in multiple myeloma Huret JL, Laï JL
Atlas Genet Cytogenet Oncol Haematol. 2012; 16(3)
Atlas of Genetics and Cytogenetics in Oncology and Haematology
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Deep Insight Section
Plasticity and Tumorigenicity 236 Elena Campos-Sanchez, Isidro Sanchez-Garcia, Cesar Cobaleda
Vacuolar H(+)-ATPase in Cancer Cells: Structure and Function 251 Xiaodong Lu, Wenxin Qin
Case Report Section
A case of Acute Lymphoblastic Leukemia with rare t(11;22)(q23;q13) 259 Jill D Kremer, Anwar N Mohamed
Insertion as an alternative mechanism of CBFB-MYH11 gene fusion in a new case of acute myeloid leukemia with an abnormal chromosome 16 262 Yaser Hussein, Vandana Kulkarni, Anwar N Mohamed
Editorial
Atlas Genet Cytogenet Oncol Haematol. 2012; 16(3) 185
Atlas of Genetics and Cytogenetics in Oncology and Haematology
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Why breast cancer and prostate cancer are so frequent? A new genetic mechanism, involving hormones and viruses Jean-Loup Huret
Atlas of Genetics and Cytogenetics in Oncology and Haematology Unit, University of Poitiers,
Department of Medical Information, CHU Poitiers Hospital, F-86021 Poitiers, France (JLH)
This work was presented at the 8th European Cytogenetics Conference, Porto, 2-5 July 2011
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2012 Atlas of Genetics and Cytogenetics in Oncology and Haematology
Abbreviated title: Hormones and viruses in breast and prostate cancers
Abstract Prostate and breast cancers, which are hormone-dependant cancers, are highly frequent (up to 1/3 of cancers in
male, 1/3 of cancers in female patients) and often multifocal. Multifocality, in particular, rings the bell of a
specific carcinogenetic agent (such as heritability is in retinoblastoma). Here we point a highly uneven
distribution of genetic events (translocation breakpoints) in prostate and breast cancers, which favours the
hypothesis of cooperation between viruses and hormone receptors to cut DNA at high rates, delete parts of it,
facilitating oncogene translocations and oncogenesis. If our hypothesis turns out to be right, vaccination against
breast cancer and prostate cancer might notably diminish the frequency of these cancers.
Looking at chromosomal rearrangements in
prostate adenocarcinoma, using the Atlas of
Genetics and Cytogenetics in Oncology and
Haematology (Huret et al., 2003), the Mitelman
Database (Mitelman et al., 2012), and Goldenpath
(Fujita et al., 2011)
(http://atlasgeneticsoncology.org/, http://cgap.nci.
nih.gov/Chromosomes/Mitelman, and
http://genome.ucsc.edu/ respectively), we noted
that, out of 42 relevant rearrangements available in
early 2011, 10 exhibited the two partner
breakpoints in the same chromosome band (e.g.
5q31 fused to 5q31). Given that 312 chromosome
bands are at risk of rearrangement, the probability
of the observed distribution is p=1.5 x 10-16
(binomial distribution). Such a non random close
proximity of the two partner breakpoints is even
more striking at the base level (e.g. 6 kb in the
5q31-5q31 rearrangement; see Table 1).
The situation is very similar with breast
adenocarcinoma: Of 39 rearrangements, 20 have
breakpoints in close proximity (Table 2). The
probability of such an event is p=6 x 10-39
. We
herein uncover a highly significant non random
distribution of breakpoints in breast and prostate
cancer DNA rearragements and microdeletions (by
comparison, only 1 of 10 rearrangements in lung
adenocarcinoma exhibit both breakpoints in the
same band (R3HDM2/NFE2 in the
del(12)(q13q13)). A bias of publications may exist,
but cannot account for such a highly unexpected
finding.
Why breast cancer and prostate cancer are so frequent? A new genetic mechanism, involving hormones and viruses
Huret JL
Atlas Genet Cytogenet Oncol Haematol. 2012; 16(3) 186
Table 1. Distance in base pairs in rearrangements with the two breakpoints on the same chromosomal
band in prostate adenocarcinoma
fusion gene rearrangement coordinates 1st gene coordinates 2nd gene distance
WDR55/DND1 t(5;5)(q31;q31) 140044384 140050382 6 kb
MBTPS2/YY2 t(X;X)(p22;p22) 21857656 21874603 17 kb
ZNF649/ZNF577 t(19;19)(q13;q13) 52392489 52374553 18 kb
C19ORF25/APC2 t(19;19)(p13;p13) 1473201 1450148 23 kb
SLC45A3/ELK4 t(1;1)(q32;q32) 205626981 205588398 39 kb
USP10/ZDHHC7 del(16)(q24q24) 84733555 85008067 275 kb
RERE/PIK3CD del(1)(p36p36) 8412466 9711790 1,3 Mb
HJURP/EIF4E2 t(2;2)(q37;q37) 234745487 233415357 1,3 Mb
TMPRSS2/ERG t(21;21)(q22;q22) 42836479 39751952 3 Mb
PIK3C2A/TEAD1 del(11)(p15p15) 17108126 12695969 4,4 Mb
Note. These fusion genes were first described in Tomlins et al., 2005; Maher et al., 2009a; et al., 2009b;
Rickman et al., 2009.
Table 2. Distance in base pairs in rearrangements with the two breakpoints on the same chromosomal
band in breast adenocarcinoma
fusion gene rearrangement coordinates 1st gene coordinates 2nd gene distance
EFTUD2/KIF18B del(17)(q21q21) 42927655 43003449 76 kb
PLXND1/TMCC1 del(3)(q22q22) 129274056 129366637 93 kb
PAPOLA/AK7 del(14)(q32q32) 96968720 96858448 110 kb
SEPT8/AFF4 del(5)(q31q31) 132086509 132211072 125 kb
SLC26A6/PRKAR2A del(3)(p21p21) 48663158 48788093 125 kb
AC141586/CCNF del(16)(p13p13) 2653351 2479395 174 kb
ERO1L/FERMT2 del(14)(q22q22) 53108607 53323990 215 kb
HN1/USH1G del(17)(q25q25) 73131344 72912176 219 kb
HMGXB3/PPARGC1B del(5)(q32q32) 149380169 149109864 270 kb
INTS4/GAB2 del(11)(q14q14) 77589768 77926343 337 kb
PLA2R1/RBMS1 del(2)(q24q24) 160798012 161128663 330 kb
RASA2/ACPL2 del(3)(q23q23) 141205926 140950682 255 kb
BC017255/TMEM49 t(17;17)(q22;q23) 57183959 57784863 600 kb
LDHC/SERGEF del(11)(p15p15) 18433853 17809599 624 kb
KCNQ5/RIMS1 del(6)(q13q13) 73331571 72596650 735 kb
MYO9B/FCHO1 del(19)(p13p13) 17186591 17858527 672 kb
STRADB/NOP58 del(2)(q33q33) 202316392 203130515 814 kb
SMYD3/ZNF695 del(1)(q44q44) 245912645 247148625 1,2 Mb
CYTH1/PRPSAP1 del(17)(q25q25) 76670131 74306868 2,4 Mb
RAF1/DAZL t(3;3)(p24;p25) 12625102 16628303 4 Mb
Note. These fusion genes were first described in Maher et al., 2009b; Stephens, P.J. et al., 2009.
Why breast cancer and prostate cancer are so frequent? A new genetic mechanism, involving hormones and viruses
Huret JL
Atlas Genet Cytogenet Oncol Haematol. 2012; 16(3) 187
Prostate and breast share two specificities: high
frequency of cancer, cancers that are frequently
multifocal. Prostate cancer represents up to 1/3 of
cancers in men, breast cancer 1/3 of cancers in
female patients in western countries. Prostate
cancer is a multicentric tumour in 75-80% of cases.
At autopsy, up to 30 to 70 % of men aged 70-80
years have cancerous foci in the prostate; after 80,
90% have hyperplasia, and more than 70% have a
neoplastic disease. Breast adenocarcinoma is a
multifocal tumour in at least 10-15% of cases.
Multifocality, in particular, rings the bell of a
specific "helper" carcinogenetic agent (such as
heritability in retinoblastoma).
Androgen and estrogen receptors are crucial for the
normal development as well as for cancer
progression of the target organs, respectively the
androgen receptor (AR) for the prostate and the
estrogen receptor (ER) for the breast. Hormone
receptors bind DNA at specific motifs called
hormone responsive elements: AR binds to a
specific TGT/AGGGA/T motif and ER binds to the
consensus core element AGGGTCA.
Some retroviruses, such as the mouse mammary
tumour virus (MMTV) and its human homolog
HMTV contain hormone responsive elements (Cato
et al., 1987; Pogo et al., 2010). A retrovirus
containing androgen response elements remains to
be found, since the candidate, XMRV, appears now
to be of experimental recombinant origin (Paprotka
et al., 2011).
Both androgen and estrogen receptors induce DNA
double strands breaks (DSBs) (Lin et al., 2009,
Williamson and Lees-Miller, 2011); such DSBs can
seed the formation of genomic/chromosome
rearrangements, and, at random, the possible
junction of oncogene loci normally separated (Lin
et al., 2009, Mani et al., 2009). It has been found
that androgen receptor signaling and topoisomerase
II mediate DSBs and TMPRSS2-ERG
rearrangements in prostate cancer (Haffner et al.,
2010). In case of a TMPRSS2-ERG rearrangement,
a deletion of 3 mb occurs (Table 1).
HMTV is found in 40% of breast cancers in
American women, in 60% of milk from patients
with a history of breast cancer and in 5% of milk
from normal subjects (cited in Pogo et al., 2010).
HMTV/MMTV sequences and enhanced Wnt-1
expression were found in breast ductal carcinoma
(Lawson et al., 2010). However, other viruses may
be implicated, and it must be kept in mind that
HBV, HPV, EBV, CMV have also been found to be
associated with breast cancer.
We Hypothesize that HMTV and other viruses can
integrate in the cell genome of breast or prostatic
cells as proviruses in multiple sites, at random.
Hormone receptors (ER or AR) would bind DNA at
hormone responsive elements sites, including those
added in numerous copies by the proviruses.
Hormone receptors would induce DNA breaks, as
usually, DNA deletions would occur in a certain
percentage of cases, facilitating oncogene
translocations. Not all breaks, not all fusion genes
are pathogenetically significant, but the cooperation
of viruses and hormone receptors (together with
other factors: genotoxic stress, inflammation...) to
cut and saw DNA would greatly enhance the risk
for an oncogenic event to occur.
There is no reason a priori for an organ to fall "too"
frequently into a cancerous process in the absence
of an additional carcinogenetic agent. In skin
cancer, ultraviolet radiation is the known major
helper, and lung cancer is a rare cancer without a
history of smoking. The "abnormally" high
frequency of prostate and breast cancers may well
be due to this association in crime of viruses and
hormone receptors.
If our hypothesis turns to be right, inhibitors for
androgens/estrogens receptors and vaccination
against breast cancer prostate cancer (as it is now
available for cervix cancer / papilloma virus) might
abrogate an important proportion of DSBs, and
notably diminish the frequency of these cancers
and/or facilitate their cure.
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Fujita PA, Rhead B, Zweig AS, Hinrichs AS, Karolchik D, Cline MS, Goldman M, Barber GP, Clawson H, Coelho A, Diekhans M, Dreszer TR, Giardine BM, Harte RA, Hillman-Jackson J, Hsu F, Kirkup V, Kuhn RM, Learned K, Li CH, Meyer LR, Pohl A, Raney BJ, Rosenbloom KR, Smith KE, Haussler D, Kent WJ. The UCSC Genome Browser database: update 2011. Nucleic Acids Res 2011; 39:D876-882
Haffner MC, Aryee MJ, Toubaji A, Esopi DM, Albadine R, Gurel B, Isaacs WB, Bova GS, Liu W, Xu J, Meeker AK, Netto G, De Marzo AM, Nelson WG, Yegnasubramanian S. Androgen-induced TOP2B-mediated double-strand breaks and prostate cancer gene rearrangements. Nat Genet 2010; 42:668-675.
Huret JL, Dessen P, Bernheim A. An Internet database on genetics in oncology. Oncogene 2003; 22:1907.
Lawson JS, Glenn WK, Salmons B, Ye Y, Heng B, Moody P, Johal H, Rawlinson WD, Delprado W, Lutze-Mann L, Whitaker NJ. Mouse mammary tumor virus-like sequences in human breast cancer. Cancer Res 2010; 70:3576-3585.
Lin C, Yang L, Tanasa B, Hutt K, Ju BG, Ohgi K, Zhang J, Rose DW, Fu XD, Glass CK, Rosenfeld MG. Nuclear receptor-induced chromosomal proximity and DNA breaks underlie specific translocations in cancer. Cell 2009; 139:1069-1083.
Maher CA, Kumar-Sinha C, Cao X, Kalyana-Sundaram S, Han B, Jing X, Sam L, Barrette T, Palanisamy N, Chinnaiyan AM. Transcriptome sequencing to detect gene fusions in cancer. Nature 2009a; 458:97-101.
Maher CA, Palanisamy N, Brenner JC, Cao X, Kalyana-Sundaram S, Luo S, Khrebtukova I, Barrette TR, Grasso C, Yu J, Lonigro RJ, Schroth G, Kumar-Sinha C, Chinnaiyan AM. Chimeric transcript discovery by paired-
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end transcriptome sequencing. Proc Natl Acad Sci USA 2009b; 106:12353-12358.
Mani RS, Tomlins SA, Callahan K, Ghosh A, Nyati MK, Varambally S, Palanisamy N, Chinnaiyan AM. Induced chromosomal proximity and gene fusions in prostate cancer. Science 2009; 326:1230-1232.
Mitelman F, Johansson B. and Mertens F. (Eds.). 2011. Mitelman Database of Chromosome Aberrations and Gene Fusions in Cancer.
Paprotka T, Delviks-Frankenberry KA, Cingöz O, Martinez A, Kung HJ, Tepper CG, Hu WS, Fivash MJ Jr, Coffin JM, Pathak VK. Recombinant Origin of the Retrovirus XMRV. Science 2011; 333:97-101.
Pogo BG, Holland JF, Levine PH. Human mammary tumor virus in inflammatory breast cancer. Cancer 2010; 116:2741-2744.
Rickman DS, Pflueger D, Moss B, VanDoren VE, Chen CX, de la Taille A, Kuefer R, Tewari AK, Setlur SR, Demichelis F, Rubin MA. SLC45A3-ELK4 is a novel and frequent erythroblast transformation-specific fusion transcript in prostate cancer. Cancer Res 2009; 69: 2734-2738.
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Greenman CD, Jia M, Latimer C, Teague JW, Lau KW, Burton J, Quail MA, Swerdlow H, Churcher C, Natrajan R, Sieuwerts AM, Martens JW, Silver DP, Langerød A, Russnes HE, Foekens JA, Reis-Filho JS, van 't Veer L, Richardson AL, Børresen-Dale AL, Campbell PJ, Futreal PA, Stratton MR. Complex landscapes of somatic rearrangement in human breast cancer genomes. Nature 2009; 462:1005-1010.
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This article should be referenced as such:
Huret JL. Why breast cancer and prostate cancer are so frequent? A new genetic mechanism, involving hormones and viruses. Atlas Genet Cytogenet Oncol Haematol. 2012; 16(3):185-188.
Gene Section Review
Atlas Genet Cytogenet Oncol Haematol. 2012; 16(3) 189
Atlas of Genetics and Cytogenetics in Oncology and Haematology
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CUX1 (cut-like homeobox 1) Benjamin Kühnemuth, Patrick Michl
Department of Gastroenterology and Endocrinology, University of Marburg, Marburg, Germany (BK,
PM)
Published in Atlas Database: October 2011
Online updated version : http://AtlasGeneticsOncology.org/Genes/CUX1ID403ch7q22.html Printable original version : http://documents.irevues.inist.fr/bitstream/DOI CUX1ID403ch7q22.txt This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2012 Atlas of Genetics and Cytogenetics in Oncology and Haematology
Identity Other names: CASP, CDP, CDP/Cut, CDP1,
COY1, CUTL1, CUX, Clox, Cux/CDP, FLJ31745,
GOLIM6, Nbla10317, p100, p110, p200, p75
HGNC (Hugo): CUX1
Location: 7q22.1
DNA/RNA
Description
The human CUX1 gene is located on chromosome
7q22 (Scherer et al., 1993). It comprises 33 exons
and spans 468 kb.
Five alternative splice variants have been identified.
Most of the splicing sites are located in the regions
downstream of exon 14 and 15 (Rong Zeng et al.,
2000). Two alternative sites for transcript
termination have been identified. Termination at
UGA in exon 24 leads to production of CUX1
mRNA comprising exon 1-24. Elongation up to
exon 33 results in alternative splicing and the
production of CASP mRNA comprising exon 1-15
and 25-33 (Lievens et al., 1997; Rong Zeng et al.,
2000).
The first transcriptional start site is located in exon
1 but transcription can be initiated at several sites in
a 200 bp region upstream of exon 1 (Rong Zeng et
al., 2000). Initiation within intron 20 leads to
production of an mRNA coding for the shortened
p75 isoform (Goulet et al., 2002).
Several putative translation initiation codons can be
found in exon 1 but ATG at position 550 has been
described as the predominant initiation site (Rong
Zeng et al., 2000).
Protein
Description
The human full length CUX1 protein (p200)
consists of 1505 amino acids and contains four
DNA binding domains: three CUT-repeats and one
CUT-homeodomain (Harada et al., 1994).
Several shortened CUX1 isoforms have been
described that are named according to their
molecular weight. CUX1 p75 is the product of a
shortened mRNA that is generated by the use of an
alternative transcription start site in exon 20 (Rong
Zeng et al., 2000; Goulet et al., 2002). CUX1 p150,
p110, p90 and p80 are generated by proteolytic
processing of the full length protein by a nuclear
isoform of Cathepsin L and other not yet identified
proteases such as caspases (Goulet et al., 2004;
Goulet et al., 2006; Maitra et al., 2006; Truscott et
al., 2007).
The presence of DNA binding domains in the
CUX1 isoforms determines their interaction with
DNA and their transcriptional activity. The full
length protein p200 shows unstable DNA binding,
carries the CCAAT-displacement activity and
functions predominantly as a transcriptional
repressor. In contrast, the p110, p90, p80 and p75
isoforms show stable DNA binding and function
both as transcriptional repressors or activators
(Truscott et al., 2004; Goulet et al., 2002; Goulet et
al., 2006; Moon et al., 2001). According to Maitra
et al., the p150 isoform is incapable of DNA
binding (Maitra et al., 2006).
Several posttranslational modifications are known
to modulate the DNA binding activities of the
CUX1 proteins.
CUX1 (cut-like homeobox 1) Kühnemuth B, Michl P
Atlas Genet Cytogenet Oncol Haematol. 2012; 16(3) 190
Cux1 isoforms. The p75 isoform is the product of a shortened mRNA that is generated by the use of an alternative
transcriptional start site. In contrast, the p150, p110, p90 and p80 isoforms are produced by proteolytic processing of the full length protein (p200). CR = cut repeat; HD = homeodomain.
Protein kinase C and Casein kinase II are able to
phosphorylate serine or threonine residues within
the cut repeats (Coqueret et al., 1998b; Li et al.,
2007). Protein kinase A and cyclin A/Cdk1
phosphorylate specific serine residues in a region
between the Cut repeat 3 and the homeodomain
(Michl et al., 2006; Santaguida et al., 2001). PCAF
acetyl-transferase is able to acetylate CUX1 on a
lysine residue in the homeodomain (Li et al., 2000).
Both, phosphorylation and acetylation have been
shown to inhibit CUX1 DNA binding (Sansregret et
al., 2010; Li et al., 2000). Consistent with this,
dephosphorylation by Cdc 25A phosphatase is able
to increase DNA binding of CUX1 (Coqueret et al,
1998a).
Expression
Early studies suggested that in mammalian cells,
CUX1 represses genes that are upregulated in
differentiated tissues. Furthermore, the expression
of CUX1 might be restricted to proliferating and
undifferentiated cells and is inversely related to the
degree of differentiation (vanden Heuvel et al.,
1996; Pattison et al., 1997; van Gurp et al., 1999).
More recently however, studies in mice revealed
that CUX1 is also expressed in terminally
differentiated cells of many tissues (Khanna-Gupta
et al., 2001; Ellis et al., 2001).
Increased CUX1 expression was found in various
tumour types including multiple myelomas, acute
lymphoblastic leukaemia, breast carcinoma and
pancreatic cancer (De Vos et al., 2002; Tsutsumi et
al., 2003; Michl et al., 2005; Ripka et al., 2007).
It has been shown that the cellular expression of
CUX1 mRNA and protein is elevated following
TGF-beta stimulation in many cell types including
fibroblasts, pancreatic cancer cells, breast cancer
cells and malignant plasma cells (Fragiadaki et al.,
2011; Michl et al., 2005; De Vos et al., 2002). This
regulation of CUX1 expression by TGF-beta is
probably mediated by p38MAPK and Smad4
signalling (Michl et al., 2005).
Localisation
Studies indicate that phosphorylated CUX1 is
preferentially localized in the cytoplasm whereas
dephosphorylation leads to translocation into the
nucleus (Sansregret et al., 2010).
Function
The vast majority of studies describes CUX1 as a
transcriptional repressor (Lievens et al., 1995; Ai et
al., 1999; Catt et al., 1999a; Catt et al., 1999b; Ueda
et al., 2007). The repressor activity can be mediated
by competition for DNA binding sites with
transcriptional activators (Kim et al., 1997; Stünkel
et al., 2000), by recruitment of histone deacetylases
(Li et al., 1999) or by recruitment of histone lysine
methyltransferases (Nishio and Walsh, 2004).
CUX1 may also negatively regulate gene
expression by binding to matrix attachment regions
and by modulating their association with the
nuclear scaffold (Banan et al., 1997; Stünkel et al.,
2000; Goebel et al., 2002; Kaul-Ghanekar et al.,
2004). In contrast, the mechanisms underlying its
effects on transcriptional activation are less well
understood.
CUX1 is involved in at least three cellular
processes important for cancer progression: cell
proliferation, cell motility/invasiveness and
apoptosis.
Proliferation Studies indicate that the pro-proliferative effects of
CUX1 are mainly mediated by the p110 isoform.
This isoform is produced by proteolytic cleavage of
the full length protein occuring during G1/S-
transition in the cell cycle (Goulet et al., 2004;
Moon et al., 2001). Cells stably transfected with
p110 CUX1 showed increased proliferation due to a
shortened G1-phase whereas embryonic fibroblasts
obtained from CUX1 knockout mice showed
elongated G1-phase and less proliferation compared
to cells isolated from wild-type mice (Sansregret et
al., 2006).
A genome-wide location array for p110 CUX1
binding sites in transformed and non-transformed
cell lines identified numerous CUX1 target genes
that are related to proliferation and cell cycle
progression (Harada et al., 2008). Most of these
genes are activated by p110 CUX1 including DNA
polymerase-alpha, cyclin A2 and cyclin E2. In
CUX1 (cut-like homeobox 1) Kühnemuth B, Michl P
Atlas Genet Cytogenet Oncol Haematol. 2012; 16(3) 191
contrast, other genes are repressed such as the
CDK-inhibitor p21 (Truscott et al., 2003; Nishio
and Walsh, 2004; Harada et al., 2008).
Cell motility First evidence that CUX1 plays a role in cell
motility originates from knockdown studies in
fibroblasts and a panel of human cancer cell lines
that revealed that depletion of CUX1 leads to
decreased cell migration and invasion (Michl et al.,
2005). In agreement with this, cells stably
expressing p110 and p75 CUX1 show increased
cell migration and invasion (Kedinger et al., 2009;
Cadieux et al., 2009). Additionally, tail vein
injection of cells stably expressing shRNA against
CUX1 resulted in reduced formation of lung
metastases, whereas injection of cells stably
overexpressing CUX1 led to increased lung
metastases (Michl et al., 2005; Cadieux et al.,
2009).
The molecular basis for these effects on cell
motility was in part elucidated in a genome-wide
location analysis in several cell lines (Kedinger et
al., 2009). In this study, CUX1 was found to inhibit
the expression of genes that repress cell migration
(e.g. E-cadherin, occludin) and to turn on the
expression of genes that promote cell migration
(e.g. FAK, N-cadherin, vimentin) (Kedinger et al.,
2009). The regulation of these genes seems to be
mediated both directly by binding of CUX1 to the
gene promoters but also indirectly by modulation of
transcription factors and signaling proteins involved
in EMT (e.g. SNAI1, SNAI2, Src, Wnt5a)
(Kedinger et al., 2009; Aleksic et al., 2007; Ripka
et al., 2007). Additionally, several of the CUX1
target genes are known GTPases important for
actin-cytoskeleton polymerization (Kedinger et al.,
2009).
Apoptosis Studies in pancreatic cancer cell lines showed that
depletion of CUX1 by siRNA increases TNFalpha-
and TRAIL-induced apoptosis whereas
overexpression of CUX1 rescues from apoptosis.
Additionally, treatment of xenograft tumours with
siRNA for CUX1 lead to retarded tumour growth
and increased apoptosis. These effects are at least in
part explained by a positive regulation of the
antiapoptotic protein BCL2 by CUX1 (Ripka et al.,
2010a). Subsequently, the glutamate receptor
GRIA3 was identified as another downstream target
of CUX1 able to mediate its antiapoptotic effects
(Ripka et al., 2010b).
Homology
Cut homeodomain proteins are highly conserved in
evolution of metazoans. Homologues of the
Drosophila melanogaster Cut protein have been
described at least in human, dog and mouse
(Neufeld et al., 1992; Andres et al., 1992; Valarché
et al., 1993). In humans, a homologue gene, called
CUX2, was described (Jacobsen et al., 2001).
Mutations
Note
A missense mutation affecting the homeodomain
has been described in one patient suffering from
acute myeloid leukaemia, the significance of which
remains to be elucidated (Thoennissen et al., 2011).
Implicated in
Pancreatic cancer
Note
In pancreatic cancer CUX1 expression is elevated
compared to normal pancreas tissue (Ripka et al.,
2010a). Furthermore, an increased expression in
high-grade tumours compared to low grade tumours
was described (Michl et al., 2005).
The expression of CUX1 is accompanied by the
overexpression of its downstream targets WNT5a
and GRIA3 that, at least in part, mediate the
proinvasive and proproliferative effects of CUX1
(Ripka et al., 2006; Ripka et al., 2010b).
Antiapoptotic effects of CUX1 in pancreatic cancer,
that have been shown in in vitro studies and in
xenograft models, are associated with a positive
regulation of BCL2 and downregulation of tumour
necrosis factor alpha and are, at least in part,
mediated by the glutamate receptor GRIA3 (Ripka
et al., 2010a; Ripka et al., 2010b).
Breast cancer
Note
In mammary carcinoma the CUX1 expression is
increased in high-grade tumours compared to low
grade tumours and a reverse correlation between
CUX1 mRNA levels and the relapse free- and
overall-survival was shown (Michl et al., 2005).
Furthermore, is has been shown that the expression
levels of the intron 20-initiated mRNA, that leads to
the synthesis of the p75 CUX1 isoform, is
specifically expressed in breast cancer and
positively correlated with a diffuse infiltrative
growth pattern (Goulet et al., 2002). Transgenic
mice expressing p75 and p110 CUX1 under the
control of the mouse mammary tumour virus-long
terminal repeat developed breast cancer after a long
latency period. This tumour development was
accompanied by an increased activity of WNT-β-
catenin signalling (Cadieux et al., 2009).
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This article should be referenced as such:
Kühnemuth B, Michl P. CUX1 (cut-like homeobox 1). Atlas Genet Cytogenet Oncol Haematol. 2012; 16(3):189-193.
Gene Section Review
Atlas Genet Cytogenet Oncol Haematol. 2012; 16(3) 194
Atlas of Genetics and Cytogenetics in Oncology and Haematology
OPEN ACCESS JOURNAL AT INIST-CNRS
DNAJA3 (DnaJ (Hsp40) homolog, subfamily A, member 3) June L Traicoff, Stephen M Hewitt, Joon-Yong Chung
Center for Peer Review and Science Management, SRA International, Inc Maryland, USA (JLT),
Applied Molecular Pathology Laboratory & Tissue Array Research Program, Laboratory of
Pathology, Center for Cancer Research, National Cancer Institute, National Institutes of Health,
Bethesda, MD, USA (SMH), Applied Molecular Pathology Laboratory, Laboratory of Pathology,
Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD,
USA (JYC)
Published in Atlas Database: October 2011
Online updated version : http://AtlasGeneticsOncology.org/Genes/DNAJA3ID40342ch16p13.html Printable original version : http://documents.irevues.inist.fr/bitstream/DOI DNAJA3ID40342ch16p13.txt This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2012 Atlas of Genetics and Cytogenetics in Oncology and Haematology
Identity
Other names: FLJ45758, TID1, hTid-1
HGNC (Hugo): DNAJA3
Location: 16p13.3
Local order: According to NCBI Map Viewer,
genes flanking DNAJA3 are COR07-PAM16,
NMRAL1, and HMOX2.
Note
DNAJA3 was first identified by its ability to form
complexes with the human papillomavirus E7
oncoprotein (Schilling et al., 1998) in a yeast-two
hybrid screen. Sequence analysis revealed that
DNAJA3 was the human homolog of the
Drosophila tumor suppressor protein Tid56.
Furthermore, DNAJA3 contained a J-domain which
is characteristic of the family of DnaJ proteins
which interact with and stimulate the ATPase
activity of heat shock cognate 70 (hsc70) family
members (Schilling et al., 1998).
DNA/RNA
Note
DNAJA3 belongs to the evolutionarily conserved
DNAJ/HSP40 family of proteins. There are 41
known DnaJ/Hsp40 proteins in the human genome
(Qiu et al., 2006).
According to NCBI Gene, the DNAJA3 gene is
conserved in human chimpanzee, cow, mouse, rat,
chicken, zebrafish, fruit fly, mosquito, C. elegans,
S. pombe, S. cerevisiae, K. lactis, E. gossypii, M.
grisea, N. crassa, and rice.
Description
The DNAJA3 gene is located on chromosome
16p13.3 between markers D16S521 and D16S418.
This chromosomal region carries several loci
implicated in human proliferation disorders,
including the tuberous sclerosis 2 gene (TSC2),
polycystic kidney disease 1 gene (PKD1), and the
CREB binding protein (CBP) locus (Yin and
Rozakis-Adcock, 2001).
Chromosome 16 - NC_000016.9. Modified from NCBI Map Viewer.
DNAJA3 (DnaJ (Hsp40) homolog, subfamily A, member 3) Traicoff JL, et al.
Atlas Genet Cytogenet Oncol Haematol. 2012; 16(3) 195
DNAJA3 is approximately 34 kb and is composed
of 12 exons separated by 11 introns. Exon sizes
vary from 64 to 232 nucleotides, with the exception
of exon 12 corresponding to the 3' untranslated
region of DNAJA3, which extends over 1.1 kb.
Intron sizes vary from 618 to 8291 nucleotides (Yin
and Rozakis-Adcock, 2001).
Sequence encoding the DNAJ domain is present in
exons 2, 3 and 4, sequence encoding the Cys-rich
domain is found in exons 5 an 6, and the COOH-
terminal region is found in exons 7 through 11 (Yin
and Rozakis-Adcock, 2001).
Transcription
Promoter elements. DNAJA3 contains a putative
transcriptional start site 21 nucleotides upstream of
the initiating methionine. The presumptive
promoter is characterized by the lack of TATA and
CAAT motifs, and a high G+C content. The 5'
flanking region contains several consensus binding
sites for transcription factors that regulate gene
expression during tissue and organ development,
such as myeloid zinc finger (MZF1), Ikaros 2 and
homeodomain proteins, as well as factors
implicated in cell growth and survival responses,
including AP-1, PEA3, E2F and NF-kB.
Splice variants. Alternative splicing of a single
heteronuclear RNA (hnRNA) species generates the
three DNAJA3 isoforms. The long form DNAJA3L
(hTID1L) fully incorporates all exons. The
intermediate form DNAJA3I (hTID1I) is generated
by splicing of exon 10 to exon 12. This results in
the loss of the 34 C-terminal-most amino acids as
well as the stop codon; these are replaced with six
amino acids KRSTGN from exon 12. The short
form DNAJA3S (hTID1S) results from an in-frame
deletion of 50 amino acids that correspond
precisely to exon 5 (Yin and Rozakis-Adcock,
2001).
RNA expression. DNAJA3 mRNA was detected in
50 different human fetal and adult tissues. However
the relative abundance correlated with metabolic
activity of the tissues, with the highest levels
observed in liver and skeletal muscle (Kurzik-
Dumke and Czaja, 2007).
Human tissues and cell lines showed differential
expression of the three DNAJA3 splice variant
mRNAs. Fetal brain tissue predominantly expressed
DNAJA3I, while breast tissues and T-cells
predominantly expressed DNAJA3L. Cell lines
derived from prostate epithelia, skin and lung
fibroblasts, normal astrocytes, and an osteosarcoma
predominantly expressed DNAJA3I with low levels
of DNAJA3L also present. DNAJA3S transcript
was undetectable in all samples (Yin and Rozakis-
Adcock, 2001).
DNAJA3 transcripts showed differential expression
during development. Expression of DNAJA3
transcripts in mouse neonatal cardiomyocytes
increased as development of the heart proceeded
and reached a maximal level at 4 weeks of age,
when cardiac myocytes have matured (Hayashi et
al., 2006). DNAJA3 expression also increased in
pathological cardiac hypertrophic states (Hayashi et
al., 2006).
Pseudogene
Paralogs. According to GeneCards, DNAJC16 is a
paralog for DNAJA3. DNAJC16 is located on
chromosome 1p36.1.
Protein
Note
The DNAJA3 gene encodes three cytosolic (Tid50,
Tid48, Tid46) proteins and three mitochondrial
(Tid43, Tid40, Tid38) proteins. Proteins encoded
by the longer splice variant DNAJA3L have often
been designated in the literature as Tid1L. Proteins
encoded by the shorter splice variant DNAJA3S
have often been named Tid1S. In this review,
Tid1L will be designated DNAJA3L, and Tid1S
will be designated DNAJA3S. Specific isoforms
will be designated by size, e.g., Tid 50 will be
designated as DNAJA3 (50 kD).
Description
DNAJA3 protein is present in two isoforms,
corresponding to splice variants encoding them.
The longer DNAJA3L isoform is a 480 amino acid
protein with a predicted size of 52 kD. The shorter
DNAJA3S isoform is a 453 amino acid protein with
a predicted size of 49 kD (Lu et al., 2006; UniProt).
Expression
DNAJA3 protein has been detected in human
breast, colon, ovarian, lung, and head and neck
squamous cell carcinoma (HNSCC) tissues
(Traicoff et al., 2007; Kurzik-Dumke et al., 2008;
Chen et al., 2009).
Localisation
DNAJA3 localizes to human mitochondrial
nucleoids, which are large protein complexes bound
to mitochondrial DNA. Unlike other DnaJs,
DNAJA3L and DNAJA3S form heterocomplexes;
both unassembled and complexed DNAJA3 are
observed in human cells. DNAJA3L showed a
longer residency time in the cytosol prior to
mitochondrial import as compared with DNAJA3S;
DNAJA3L was also significantly more stable in the
cytosol than DNAJA3S, which is rapidly degraded
(Lu et al., 2006).
Function
I. Binding partners Human DNAJA3 protein has been shown to
interact with diverse partners, including viral
proteins, heat shock proteins, and key regulators of
cell signaling and growth.
Viral proteins Hepatitis B virus core protein: DNAJA3
associated with the hepatitis B virus core protein,
DNAJA3 (DnaJ (Hsp40) homolog, subfamily A, member 3) Traicoff JL, et al.
Atlas Genet Cytogenet Oncol Haematol. 2012; 16(3) 196
specifically with the carboxyl-terminal region
(amino acids 94-185). The N-terminal end of
DNAJA3 (amino acids 1-447) was required for this
interaction. Furthermore, the DNAJA3S precursor
co-sedimented with viral capsid-like particles
composed of the full-length core protein (Sohn et
al., 2006). Interaction between DNAJA3 and the
HBV core protein was confirmed in co-
immunoprecipitation experiments using transfected
hepatoma cells (Sohn et al., 2006).
Epstein-Barr virus-encoded BARF1 protein: DNAJA3 (amino acids 149-320) associated with
the Epstein-Barr virus-encoded BARF1 protein
(amino acids 21-221). Interaction between
DNAJA3 and BARF1 was confirmed in co-
immunoprecipitation experiments using transfected
HeLa cells (Wang et al., 2006).
Herpes simplex virus type 1 UL9 protein: DNAJA3 associated with the herpes simplex virus
type 1 (HSV-1) UL9 protein. UL9 protein is an
origin-binding protein. Interaction between
DNAJA3 and UL9 was confirmed by in vitro co-
immunoprecipitation (Eom and Lehman, 2002).
Human T cell leukemia virus type 1 (HTLV-1)
Tax protein: DNAJA3 associated with HTLV-1
Tax. The interaction occurred through a central
cysteine-rich zinc finger-like region of DNAJA3
(amino acids 236 to 300). Interaction between
DNAJA3 and Tax was confirmed by co-
immunoprecipitation experiments using transfected
human embryonic kidney cells (HEK) (Cheng et
al., 2001). Furthermore, the DNAJA3 and Tax
interaction occurred through a complex comprised
of DNAJA3, Tax, and heat shock protein 70
(Hsp70), in which the cysteine-rich region of
DNAJA3 interacted with Tax, while the J domain
of DNAJA3 interacted with Hsp70 (Cheng et al.,
2001).
Human papilloma virus-16 (HPV-16) E7
oncoprotein: DNAJA3 was initially characterized
through its interaction with the HPV-16 E7
oncoprotein. DNAJA3 amino acids 1 to 235 and
297 to 342 independently interacted with HPV-16
E7. Interaction between DNAJA3 and HPV-16 E7
was confirmed by in vitro binding assays and co-
immunoprecipitation experiments using transfected
human osteosarcoma (U2OS) cells (Schilling et al.,
1998).
Heat shock proteins Hsp70 and Hsc70: endogenous DNAJA3
(specifically the cytosolic form)
immunoprecipitated with the heat shock proteins
Hsp70 and Hsc70 in normal colon epithelium and
colon cancer cell lines (Kurzik-Dumke and Czaja,
2007). Endogenous DNAJA3 also interacted with
Hsp70/Hsc70 in HEp2 cells, and this interaction
was reduced in cells treated with interferon-gamma
(Sarkar et al., 2001). The J domain of DNAJA3 was
shown to be required for interaction with Hsp70 in
HEK cells (Cheng et al., 2001).
Proteins encoded by the long and short splice forms
of DNAJA3, DNAJA3L and DNAJA3S,
respectively, showed differential interactions with
heat shock proteins. Unassembled DNAJA3L (the
long splice variant) was shown to interact with
Hsc70 specifically in the cytosol (Lu et al., 2006).
The unique carboxyl terminus of DNAJA3L was
required for this interaction (Lu et al., 2006). Both
DNAJA3S and DNAJA3L could interact with
Hsp70 (Kim et al., 2004). Endogenous DNAJA3L
and DNAJA3S coimmunoprecipitated with
mitochondrial Hsp70, but not Hsc70, in U2OS
osteosarcoma cells (Syken et al., 1999).
Tumor suppressor proteins Adenomatous polyposis coli (APC): endogenous
cytosolic DNAJA3 proteins interacted with APC in
normal colon epithelium and colorectal cancer cell
lines (HT-29, Caco-2, and HRT-18). The N-
terminal Armadillo domain of APC was sufficient
for binding to DNAJA3. The DNAJA3 and APC
interaction comprised part of a larger multi-
component complex that also contained Hsp70,
Hsc70, Actin, Dvl, and Axin. This complex
functions independently of the known roles of APC
in beta-catenin degradation and proliferation
mediated by Wg/Wnt signaling (Kurzik-Dumke and
Czaja, 2007).
Endogenous DNAJA3 proteins were shown to
interact with the caspase-cleaved N-terminus of
APC in HCT116 cells (Qian et al., 2010). The
caspase-cleaved APC protein has an important
physiological role in mediating apoptosis (Qian et
al., 2010).
Patched: endogenous human Patched interacted
with the cytosolic forms of the DNAJA3 proteins in
human colon epithelium and colon tumor cells
(Kurzik-Dumke and Czaja, 2007). The tumor-
associated polymorphism in Patched (Ptch FVB
allele) was associated with poorer binding to
DNAJA3 (Wakabayashi et al., 2007).
INT6: endogenous human DNAJA3 interacted with
INT6 (the p48 subunit of the eIF3 translation
initiation factor) in log phase, but not confluent,
Jurkat T-cells (Traicoff et al., 2007).
Von Hippel-Lindau protein (VHL): endogenous
pVHL co-immunoprecipitated with DNAJA3L
protein in HEK293 cells (Bae et al., 2005).
p53: DNAJA3 directly interacts with p53 through
the DNAJA3 DNAJ domain. Either the N- or C-
terminal domains of p53 was sufficient for the
interaction (Trinh et al., 2010).
Receptors
Interferon-gamma receptor (IFN-gammaR)
subunit IFN-gammaR2: DNAJA3 interacted with
IFN-gamma R2 in transfected COS cells.
Furthermore, DNAJA3 bound more efficiently to a
IFN-gammaR2 chimera with an active kinase
domain than to a similar construct with an inactive
kinase domain (Sarkar et al., 2001).
DNAJA3 (DnaJ (Hsp40) homolog, subfamily A, member 3) Traicoff JL, et al.
Atlas Genet Cytogenet Oncol Haematol. 2012; 16(3) 197
ErbB-2 (HER2/neu): endogenous ErbB-2 and
DNAJA3 co-immunoprecipitated in SK-BR-3
breast cancer cells (Kim et al., 2004). The
cytoplasmic domains of ErbB-2 and DNAJA3 were
sufficient for this interaction (Kim et al., 2004).
ErbB-2 co-immunoprecipiated with DNAJA3 and
the carboxyl terminus of heat shock cognate 70
interacting protein (CHIP). This complex was
demonstrated in tissue extracts from breast tumor
specimens as well as in transfected cell lines (Jan et
al., 2011).
Trk receptor tyrosine kinases: the carboxyl-
terminal end of DNAJA3 (residues 224-429) bound
to Trk at its activation loop in a phosphotyrosine-
dependent manner (Liu et al., 2005).
Muscle-specific kinase (MuSK) component of
the agrin receptor: DNAJA3S, but not DNAJA3L,
associated with the cytoplasmic portion of MuSK in
mouse skeletal muscle cells (Linnoila et al., 2008).
Signaling proteins NF-kappaB: DNAJA3 strongly associated with the
cytoplasmic protein complex of NF-kappaB-
IkappaB through direct interaction with
IkappaBalpha/IkappaBbeta and the IKKalpha/beta
subunits of the IkappaB kinase complex. The
endogenous interaction was observed in Jurkat,
SAOS-2, and HEK293 cells (Cheng et al., 2005).
JAK/STAT: Jak2 interacted with DNAJA3S as
well as DNAJA3L as shown by
immunoprecipitation from transfected COS-1 cells
expressing these proteins. Endogenous DNAJA3
and Jak2 were shown to interact in HEp2 cells
(Sarkar et al., 2001).
The carboxyl terminus of endogenous DNAJA3L,
but not DNAJA3S, co-immunoprecipitated with
STAT1 and with STAT3 in U2OS cells (Lu et al.,
2006). DNAJA3L remained associated with
activated phosphorylated STAT1 upon treatment
with interferon-gamma (Lu et al., 2006).
The DNAJ domain of DNAJA3 interacted with the
transactivation domain of Stat5b in hematopoietic
cell lines (Dhennin-Duthille et al., 2011).
p120 GTPase-activating protein (GAP): both the
cytoplasmic precursor and mitochondrial mature
forms of murine DNAJA3 associated with GAP in
vivo in rodent cells. GAP selectively bound to the
unphosphorylated form of murine DNAJA3
(Trentin et al., 2001).
DNA replication proteins
DNA polymerase gamma (Polga) alpha subunit: endogenous DNAJA3 interacted with the alpha
subunit of Polga in HEK293 cells. Polga is the only
mitochondrial DNA polymerase responsible for all
mitochondrial DNA synthetic reactions (Hayashi et
al., 2006).
II. Signaling pathways and cellular effects DNAJA3 modulates diverse signaling pathways
and cellular effects that are vital for cell growth and
differentiation.
Neural pathways Neuromuscular synaptogenesis: DNAJA3 is an
essential component of the agrin signaling pathway
that is crucial for synaptic development.
Motoneuron-derived agrin clusters nicotinic
acetylcholine receptors (AChRs) in mammalian
cells. DNAJA3 binds to the cytoplasmic domain of
muscle-specific kinase (MuSK), a component of the
agrin receptor and colocalizes with AchRs at
developing, adult, and denvervated motor
endplates. DNAJA3 transduces signals from MuSK
activation to AchR clustering, culmintating in
cross-linking to the subsynaptic cytoskeleton, as
demonstrated by knockdown and overexpression
experiments.
Knockdown of DNAJA3 in skeletal muscle fibers
resulted in dispersed synaptic AchR clusters and
impaired neuromuscular transmission. Knockdown
of DNAJA3 in myotubes resulted in inhibition of
AchR clustering, inhibition of agrin-induced
activation of the Rac and Rho small GTPases and
tyrosine phosphorylation of AchR, and decreased
Dok-7-induced clustering of AChRs. In contrast,
overexpression of the N-terminal half of DNAJA3
induced agrin-and MuSK-independent
phosphorylation and clustering of AChRs (Linnoila
et al., 2008; Song and Balice-Gordon, 2008).
Neurite outgrowth: DNAJA3 regulated nerve
growth factor (NGF)-induced neurite outgrowth in
PC12-derived nnr5 cells. DNAJA3 bound to Trk at
the activation loop and DNAJA3 was tyrosine
phosphorylated by Trk in yeast cells, transfected
cells, and in neurotophin-stimulated primary rat
hippocampal neurons. Overexpression of DNAJA3
led to NGF-induced neurite outgrowth in TrkA-
expressing nnr5 cells. In contrast, knockdown of
DNAJA3 resulted in reduced NGF-induced neurite
growth in nnr5-TrkA cells (Liu et al., 2005).
Viral pathways Hepatitis B virus replication: expression of
DNAJA3 suppressed replication of HBV in human
hepatoma cells, while knockdown of DNAJA3 led
to increased HBV replication. The mechanism for
inhibited replication was through accelerated
degradation and destabilization of the viral core and
HBx proteins (Sohn et al., 2006).
Herpes simplex virus type 1 replication: the
HSV-1 UL9 protein is an origin-binding protein
that is essential for viral DNA replication. DNAJA3
modulates DNA replication by enhancing the
binding of UL9 protein to an HSV-1 origin and
facilitating formation of the multimer from the
dimeric UL9 protein, perhaps through a chaperone
function. However, DNAJA3 had no effect on the
DNA-dependent ATPase or helicase activities
associated with the UL9 protein (Eom and Lehman,
2002).
Epstein-Barr virus secretion: the EBV BARF1
gene encodes a secretory protein with transforming
and mitogenic activities. Coexpression experiments
DNAJA3 (DnaJ (Hsp40) homolog, subfamily A, member 3) Traicoff JL, et al.
Atlas Genet Cytogenet Oncol Haematol. 2012; 16(3) 198
with BARF1 and DNAJA3 showed that DNAJA3
could promote secretion of BARF1, perhaps
through chaperone functions (Wang et al., 2006).
Motility and metastasis DNAJA3 was shown to negatively regulate the
motility and metastasis of breast cancer cells
through attenuation of nuclear factor kappaB
activity on the promoter of the IL8 gene (Kim et al.,
2005). Reductions of DNAJA3 levels in MDA-
MB231 breast cancer cells increased their migration
as a result of increased interleukin-8 (IL-8)
secretion without affecting survival or growth rate.
Furthermore, DNAJA3 was shown to negatively
modulate de novo synthesis of IL-8 through
regulating NFkappaB activity. Additionally,
DNAJA3 knockdown enhanced the metastasis of
breast cancer cells in animals (Kim et al., 2005).
Other studies also indicate a potential role for
DNAJA3 in inhibiting transformation and
metastasis. Stable DNAJA3 knockdown cells
exhibited an enhanced ability for anchorage-
independent growth, as measured by an increase in
soft-agar colony formation (Edwards and Münger,
2004). In contrast, ectopic expression of DNAJA3
in HNSCC cells was shown to significantly inhibit
cell proliferation, migration, invasion, anchorage-
independent growth, and xenotransplantation
tumorigenicity (Chen et al., 2009). Expression of
DNAJA3 inhibited the transformation phenotype of
two human lung adenocarcinoma cell lines (Cheng
et al., 2001).
Apoptosis DNAJA3 encodes two mitochondrial matrix
localized splice variants: DNAJA3 (43 kD) and
DNAJA3 (40 kD). DNAJA3 (43 kD) and DNAJA3
(40 kD) do not themselves induce apoptosis;
instead they have opposing effects on apoptosis
induced by exogenous stimuli.
Expression of DNAJA3 (43 kD) increases apoptosis
induced by both the DNA-damaging agent
mitomycin c and tumor necrosis factor-alpha. This
activity is J domain-dependent, since a J domain
mutant of DNAJA3 (43 kD) suppressed apoptosis.
Conversely, expression of DNAJA3 (40 kD)
suppressed apoptosis, while expression of a J
domain mutant of DNAJA3 (40 kD) increased
apoptosis (Syken et al., 1999).
Cells lacking expression of DNAJA3 proteins were
protected from cell death in response to multiple
stimuli, including cisplatin, tumor necrosis factor
alpha/cycloheximide and mitomycin C (Edwards
and Münger, 2004).
DNAJA3 regulates activation-induced cell death
(AICD) in the Th2 subset of helper T cells. AICD is
an apoptotic process induced by stimulation
through the T-cell receptor and Th2 cells are
significantly less prone to AICD than Th1 cells are.
The antiapoptotic variant, Tid-1S was shown to be
selectively induced in murine Th2 cells following
activation. Expression of a dominant-negative
mutant of hTid-1S in a Th2 cell line strikingly
enhanced activation of caspase 3 in response to
CD3 stimulation, and caused the cells to become
sensitive to AICD. Therefore, the accumulation of
Tid-1S in Th2 cells following activation may
contribute to the induction of apoptosis resistance
during the activation of Th2 cells (Syken et al.,
2003).
DNAJA3 mediates apoptosis through the
nuclear factor kappaB (NF-kappaB) pathway. DNAJA3 repressed the activity of NF-kappaB
through physical and functional interactions with
the IKK complex and IkappaB. Overexpression of
DNAJA3 led to inhibition of cell proliferation and
induction of apoptosis of human osteosarcoma cells
and human melanoma cells regardless of the p53
expression status. In contrast, cells transduced with
a DNAJA3 mutant that has an N-terminal J domain
deletion and that lost suppressive activity on IKK,
continued to proliferate (Cheng et al., 2005).
DNAJA3 mediates apoptosis through the Bcl-2
pathway. DNAJA3 induced apoptosis in SF767
glioma cells that contained a tumor-associated
mutation at the DNAJA3 locus. Apoptosis resulted
from caspase activation and cytochrome c release
from mitochondria. However, Bcl-XL protected
cells from hTid-1S-induced cell death and
cytochrome c release. However, hTid1S caused S
and G2/M arrest in cells with wild type Tid1.
Interestingly, hTid1L had no effect on growth of
glioma cells (Trentin et al., 2004).
Immature dnaja3(-/-) DN4 thymocytes exhibited
significantly reduced expression of the
antiapoptotic bcl-2 gene (Lo et al., 2005).
Expression of constitutively active AKT (pAKT)
counteracted and inhibited DNAJA3-induced
apoptosis in HNSCC cells (Chen et al., 2009).
DNAJA3 mediates apoptosis through APC. DNAJA3 (40 kD) isoform inhibited apoptosis
through antagonizing the apoptotic function of the
N-terminal region of the APC protein (Qian et al.,
2010).
DNAJA3 mediates apoptosis through p53. Overexpression of DNAJA3 enhanced p53-
dependent apoptosis, and restored pro-apoptotic
activity of mutant p53 in colon, breast, and glioma
cell lines (Ahn et al., 2010). The mechanism is
through direct interaction of the DNAJ domain of
DNAJA3 and p53 (Trinh et al., 2010). In contrast,
depletion of DNAJA3 resulted in the inhibition of
hypoxia or genotoxic stress-induced p53
mitochondrial localization and apoptosis (Trinh et
al., 2010).
Mitochondrial functions Although DNAJA3 has many cellular functions,
DNAJA3 often localizes to the mitochondria and
also has important functions in the mitochondria.
Epidermal growth factor (EGF) response: GAP
and DNAJA3 were shown to colocalize at
DNAJA3 (DnaJ (Hsp40) homolog, subfamily A, member 3) Traicoff JL, et al.
Atlas Genet Cytogenet Oncol Haematol. 2012; 16(3) 199
perinuclear mitochondrial membranes in response
to EGF stimulation (Trentin et al., 2001).
p53 localization and apoptotic function: depletion of DNAJA3 prevented p53 accumulation
at the mitochondria and resulted in resistance to
apoptosis under hypoxic or genotoxic stresses
(Trinh et al., 2010). DNAJA3 formed a complex
with p53 under hypoxic conditions that directed
p53 translocation to the mitochondria and the
subsequent initiation of apoptosis (Ahn et al.,
2010). Loss of DNAJA3 expression abrogated p53
translocation to the mitochondria and inhibited
apoptosis (Ahn et al., 2010). Conversely,
overexpression of DNAJA3 promoted p53
mitochondrial localization and apoptosis (Ahn et
al., 2010).
Viral protein localization: in the absence of Tax,
expression of the DNAJA3/Hsp70 molecular
complex was targeted to perinuclear mitochondrial
clusters. In the presence of Tax, DNAJA3 and its
associated Hsp70 are sequestered within a
cytoplasmic "hot spot" structure, a subcellular
distribution that is characteristic of Tax in HEK
cells (Cheng et al., 2001).
APC interaction: the amino terminus of APC
interacted with DNAJA3 at the mitochondria in
vivo in colorectal cancer cell lines (Qian et al.,
2010).
Chaperone function: DNAJA3 isoforms were also
shown to exhibit a conserved mitochondrial DnaJ-
like function substituting for the yeast
mitochondrial DnaJ-like protein Mdj1p (Lu et al.,
2006).
Mitochondrial biogenesis: DNAJA3 was shown to
be crucial for mitochondrial biogenesis partly
through chaperone activity on DNA polymerase
gamma (Hayashi et al., 2006). Mice deficient in
Dnaja3 developed dilated cardiomyopathy (DCM)
and died before 10 weeks of age (Hayashi et al.,
2006). Progressive respiratory chain deficiency and
decreased copy number of mitochondrial DNA
were observed in cardiomyocytes lacking Dnaja3
(Hayashi et al., 2006).
Tumor suppressor pathways APC: DNAJA3 directly bound to the APC tumor
suppressor protein and promoted a physiological
function for APC that was independent of APC's
involvement in beta-catenin degradation or
regulation of the actin cytoskeleton (Kurzik-Dumke
and Czaja, 2007).
pVHL: TID1L directly interacted with von Hippel-
Lindau protein and enhanced the interaction
between HIF-1 alpha and pVHL. This resulted in
destabilization of HIF-1 alpha protein, decreased
vascular endothelial growth factor expression, and
inhibition of angiogenesis (Bae et al., 2005).
Interferon-gamma: DNAJA3L and DNAJA3S
interacted with the interferon-gamma receptor chain
IFN-gammaR2 and modulated IFN-gamma-
mediated transcriptional activity. Furthermore, IFN-
gamma treatment reduced the interaction between
Hsp70/Hsc70 and DNAJA3 (Sarkar et al., 2001).
Oncogenic pathways Erb-B2/HER2: DNAJA3 physically interacted
with the signaling domain of ErbB-2 and ErbB-2
were shown to colocalize in mammary carcinoma
cells (SK-BR-3). Overexpression of DNAJA3
induced growth arrest and apoptosis in ErbB-2-
overexpressing breast cancer cells; the DNAJ and
C-terminal domains of DNAJA3 were critical for
mediating apoptosis. Downregulation of
ERK1/ERK2 and BMK1 MAPK pathways also
contributed to apoptosis. DNAJA3S negatively
regulated ErbB-2 signaling pathways by enhancing
the degradation of ErbB-2. Finally, increased
cellular DNAJA3 inhibited the growth of ErbB-2-
dependent tumors in mice (Kim et al., 2004).
Mammary tumor tissue from breast cancer patients
and transgenic mice carrying the rat HER-2/neu
oncogene suggest that DNAJA3 suppresses ErbB-2
in breast cancers (Kurzik-Dumke et al., 2010).
NF-kappaB: expression of DNAJA3 was
upregulated upon cellular senescence in rat and
mouse embryo fibroblasts, as well as in premature
senescence of REF52 cells triggered by activated
ras. Conversely, spontaneous immortalization of rat
embryo fibroblasts was suppressed upon ectopic
expression of DNAJA3. Suppression of endogenous
DNAJA3 activity alleviated the suppression of
tumor necrosis factor alpha-induced NF-kappaB
activity by DNAJA3. These results suggest that
DNAJA3 contributes to senescence by repressing
NF-kappa B signaling (Tarunina et al., 2004).
DNAJA3 repressed NF-kappaB activity induced by
Tax, tumor necrosis factor alpha (TNFalpha), and
Bcl10. DNAJA3 specifically suppressed serine
phosphorylation of IkappaBalpha by activated
IkappaB kinase beta (IKKbeta).
The suppressive activity of DNAJA3 on IKKbeta
required a functional J domain that mediates
association with heat shock proteins and resulted in
prolonging the half-life of the NF-kappaB inhibitors
IkappaBalpha and IkappaBbeta (Cheng et al.,
2002).
AKT: overexpression of DNAJA3 in HNSCC cells
inhibited cell proliferation, migration, invasion,
anchorage-independent growth, and
xenotransplantation tumorigenicity. Overexpression
of DNAJA3 attenuated EGFR activity and blocked
the activation of AKT in HNSCC cells, which are
known to be involved in the regulation of survival
in HNSCC cells. Conversely, ectopic expression of
constitutively active AKT greatly reduced apoptosis
induced by DNAJA3 overexpression (Chen et al.,
2009).
JAK2: DNAJA3L and DNAJA3S interacted with
Jak2 in vivo in COS-1 cells. Interaction was
primarily in the cytoplasm and predominantly with
the active kinase domain of Jak2 (Sarkar et al.,
2001).
DNAJA3 (DnaJ (Hsp40) homolog, subfamily A, member 3) Traicoff JL, et al.
Atlas Genet Cytogenet Oncol Haematol. 2012; 16(3) 200
c-MET receptor tyrosine kinase (MetR): MetR
interacted with DNAJA3L and DNAJA3S, but
showed preferential binding to DNAJA3S.
Interaction occurred through the J domain. In RCC
cells, overexpression of DNAJA3S enhanced HGF-
mediated MetR autophosphorylation, while
DNAJA3L showed modest inhibition of MetR
activity. Modulation of MetR phosphorylation
levels was independent of pVHL. DNAJA3S
enhanced HGF-mediated cell migration and
modulated HGF-mediated MAPK phosphorylation.
DNAJA3 knockdown inhibited MetR activation
and migration in response to HGF (Copeland et al.,
2011).
Signal transducers and activators of
transcription (STAT) 5b: DNAJA3 specifically
interacted with STAT5b but not STAT5a in
hematopoietic cell lines. Interaction involved the
DNAJ domain. DNAJA3 negatively regulated the
expression and transcriptional activity of STAT5b
and suppressed the growth of hematopoietic cells
transformed by an oncogenic form of STAT5b
(Dhennin-Duthille et al., 2011).
Cell Fate DNAJA3 was shown to be required for the T-cell
transition from double-negative 3 to double-
positive stages. Mice with dnaja3 specifically
deleted in T cells developed thymic atrophy, with
dramatic reduction of double-positive and single-
positive thymocytes in the dnaja3(-/-) thymus.
DNAJA3 deficiency inhibited cell proliferation and
enhanced cell death of DN4 cells. The expression
profile of genes involved in cytokine receptor
signaling was altered in DN4 T-cells. Expression of
human bcl-2 transgene restored T lymphocyte
proliferation and differentiation in the dnaja3
knockout mice. These results suggest that dnaja3 is
critical in early thymocyte development, especially
during transition from the DN3 to double-positive
stages, possibly through its regulation of bcl-2
expression, which provides survival signals.
Homology
Mouse (laboratory): Dnaja3
Rat: Dnaja3
Cattle: DNAJA3
Chimpanzee: DNAJA3
Dog (domestic): DNAJA3
Mutations
Note
The SF767 glioma cell line exhibits an aberrant 52
kD molecular weight protein. Sequence analysis of
cDNA generated from this line showed two
mutations: an additional thymine at nucleotide
position 1438 and an additional cytosine at
nucleotide position 1449. These mutations alter the
reading frame of the DNAJA3 sequence,
introducing an additional 71 amino acids following
the penultimate threonine residue at position 479.
The mutations appear to increase the steady-state
abundance of the mutant protein, resulting in
aberrantly high levels of the DNAJA3 mutant
variant (Trentin et al., 2004).
Implicated in
Colon cancer
Disease
DNAJA3 and INT6 protein levels, as well as
DNAJA3 and Patched protein levels, were
positively correlated in human colon tumor tissues
(Traicoff et al., 2007). However, there were no
correlations between DNAJA3 and p53, c-Jun, or
phospho-c-Jun protein levels (Traicoff et al., 2007).
These results were demonstrated by multiplex
tissue immunoblotting of tissue microarrays
(Traicoff et al., 2007).
Progression of colorectal cancers correlated with
overexpression and loss of polarization of
expression of DNAJA3. These changes were
associated with upregulation of Hsp70 and loss of
compartmentalization of APC (Kurzik-Dumke et
al., 2008).
Breast cancer
Disease
DNAJA3 protein expression showed a strong
correlation with negative or weakly positive
expression of ErbB2 in human breast cancer tissue
samples. High DNAJA3 levels were strongly
correlated with high levels of CHIP (carboxyl
terminus of heat shock cognate 70 interacting
protein). Lower expression of DNAJA3 had a
higher risk of unfavorable tumor grade, later
pathological stage, larger tumor size, and
microscopic features of a more malignant histology
(Jan et al., 2011). Higher expression of DNAJA3
correlated with increased 10-year overall and
disease-free survival rate (Jan et al., 2011).
The expression of the three DNAJA3 isoform
transcripts was examined in human breast cancer
carcinomas by RT-PCR. Aberrant expression of all
three forms correlated with malignant
transformation. Furthermore, elevated DNAJA3L
expression was associated with less aggressive
tumors (Kurzik-Dumke et al., 2010).
Immunohistochemical analysis demonstrated high
levels of DNAJA3 protein in tumors of the luminal
A subtype, but significantly lower levels of
DNAJA3 protein in the luminal B subtype, triple
negative tumors, and the HER-2 subtype which
overexpresses HER-2 (Kurzik-Dumke et al., 2010).
Multiplex tissue immunoblotting of human breast
tumor tissue microarrays was used to test
correlations between DNAJA3 protein levels and a
set of tumor suppressor proteins. DNAJA3 protein
levels showed strongly positive correlations with
p53, Patched, and INT6 proteins (Traicoff et al.,
2007). Additionally, DNAJA3 protein levels
DNAJA3 (DnaJ (Hsp40) homolog, subfamily A, member 3) Traicoff JL, et al.
Atlas Genet Cytogenet Oncol Haematol. 2012; 16(3) 201
showed moderate positive correlations with c-Jun
and phospho-c-Jun proteins (Traicoff et al., 2007).
Head and neck squamous cell carcinoma (HNSCC)
Disease
The clinical association between DNAJA3
expression and progression of HNSCC was
explored using immunohistochemical analysis of
primary HNSCC patient tumor tissue. DNAJA3
expression was negatively associated with tumor T
stage, overall stage, survival, and recurrence.
Patients with higher expression of DNAJA3 were
predicted to have better overall survival than those
with low or undetectable expression of DNAJA3
protein (Chen et al., 2009). Highly malignant
HNSCC cell lines also demonstrated low or
undetectable levels of DNAJA3, in contrast to less
aggressive lines where DNAJA3 protein was easily
detected (Chen et al., 2009).
Ovarian cancer
Disease
Multiplex tissue immunoblotting of ovarian tumor
tissues demonstrated that DNAJA3 protein levels
showed moderate positive correlations with INT6,
c-Jun, phospho-c-Jun, and p53. No correlations
were observed between DNAJA3 and Patched
(Traicoff et al., 2007).
Lung cancer
Disease
Multiplex tissue immunoblotting of lung tumor
tissues demonstrated that DNAJA3 protein levels
were strongly correlated with INT6. DNAJA3
protein levels were moderately correlated with
Patched, c-Jun, and p53. However, DNAJA3
proteins showed negative correlation with phospho-
c-Jun in these samples (Traicoff et al., 2007).
Cardiomyopathy
Note
Mice deficient in Dnaja3 developed dilated
cardiomyopathy (DCM) and died before 10 weeks
of age (Hayashi et al., 2006). Progressive
respiratory chain deficiency and decreased copy
number of mitochondrial DNA were observed in
cardiomyocytes lacking Dnaja3 (Hayashi et al.,
2006).
References Schilling B, De-Medina T, Syken J, Vidal M, Münger K. A novel human DnaJ protein, hTid-1, a homolog of the Drosophila tumor suppressor protein Tid56, can interact with the human papillomavirus type 16 E7 oncoprotein. Virology. 1998 Jul 20;247(1):74-85
Syken J, De-Medina T, Münger K. TID1, a human homolog of the Drosophila tumor suppressor l(2)tid, encodes two mitochondrial modulators of apoptosis with opposing functions. Proc Natl Acad Sci U S A. 1999 Jul 20;96(15):8499-504
Cheng H, Cenciarelli C, Shao Z, Vidal M, Parks WP, Pagano M, Cheng-Mayer C. Human T cell leukemia virus type 1 Tax associates with a molecular chaperone complex containing hTid-1 and Hsp70. Curr Biol. 2001 Nov 13;11(22):1771-5
Sarkar S, Pollack BP, Lin KT, Kotenko SV, Cook JR, Lewis A, Pestka S. hTid-1, a human DnaJ protein, modulates the interferon signaling pathway. J Biol Chem. 2001 Dec 28;276(52):49034-42
Trentin GA, Yin X, Tahir S, Lhotak S, Farhang-Fallah J, Li Y, Rozakis-Adcock M. A mouse homologue of the Drosophila tumor suppressor l(2)tid gene defines a novel Ras GTPase-activating protein (RasGAP)-binding protein. J Biol Chem. 2001 Apr 20;276(16):13087-95
Yin X, Rozakis-Adcock M. Genomic organization and expression of the human tumorous imaginal disc (TID1) gene. Gene. 2001 Oct 31;278(1-2):201-10
Cheng H, Cenciarelli C, Tao M, Parks WP, Cheng-Mayer C. HTLV-1 Tax-associated hTid-1, a human DnaJ protein, is a repressor of Ikappa B kinase beta subunit. J Biol Chem. 2002 Jun 7;277(23):20605-10
Eom CY, Lehman IR. The human DnaJ protein, hTid-1, enhances binding of a multimer of the herpes simplex virus type 1 UL9 protein to oris, an origin of viral DNA replication. Proc Natl Acad Sci U S A. 2002 Feb 19;99(4):1894-8
Sehgal PB. Plasma membrane rafts and chaperones in cytokine/STAT signaling. Acta Biochim Pol. 2003;50(3):583-94
Syken J, Macian F, Agarwal S, Rao A, Münger K. TID1, a mammalian homologue of the drosophila tumor suppressor lethal(2) tumorous imaginal discs, regulates activation-induced cell death in Th2 cells. Oncogene. 2003 Jul 24;22(30):4636-41
Edwards KM, Münger K. Depletion of physiological levels of the human TID1 protein renders cancer cell lines resistant to apoptosis mediated by multiple exogenous stimuli. Oncogene. 2004 Nov 4;23(52):8419-31
Kim SW, Chao TH, Xiang R, Lo JF, Campbell MJ, Fearns C, Lee JD. Tid1, the human homologue of a Drosophila tumor suppressor, reduces the malignant activity of ErbB-2 in carcinoma cells. Cancer Res. 2004 Nov 1;64(21):7732-9
Tarunina M, Alger L, Chu G, Munger K, Gudkov A, Jat PS. Functional genetic screen for genes involved in senescence: role of Tid1, a homologue of the Drosophila tumor suppressor l(2)tid, in senescence and cell survival. Mol Cell Biol. 2004 Dec;24(24):10792-801
Trentin GA, He Y, Wu DC, Tang D, Rozakis-Adcock M. Identification of a hTid-1 mutation which sensitizes gliomas to apoptosis. FEBS Lett. 2004 Dec 17;578(3):323-30
Bae MK, Jeong JW, Kim SH, Kim SY, Kang HJ, Kim DM, Bae SK, Yun I, Trentin GA, Rozakis-Adcock M, Kim KW. Tid-1 interacts with the von Hippel-Lindau protein and modulates angiogenesis by destabilization of HIF-1alpha. Cancer Res. 2005 Apr 1;65(7):2520-5
Cheng H, Cenciarelli C, Nelkin G, Tsan R, Fan D, Cheng-Mayer C, Fidler IJ. Molecular mechanism of hTid-1, the human homolog of Drosophila tumor suppressor l(2)Tid, in the regulation of NF-kappaB activity and suppression of tumor growth. Mol Cell Biol. 2005 Jan;25(1):44-59
Kim SW, Hayashi M, Lo JF, Fearns C, Xiang R, Lazennec G, Yang Y, Lee JD. Tid1 negatively regulates the migratory potential of cancer cells by inhibiting the production of interleukin-8. Cancer Res. 2005 Oct 1;65(19):8784-91
Kittler R, Pelletier L, Ma C, Poser I, Fischer S, Hyman AA, Buchholz F. RNA interference rescue by bacterial artificial
DNAJA3 (DnaJ (Hsp40) homolog, subfamily A, member 3) Traicoff JL, et al.
Atlas Genet Cytogenet Oncol Haematol. 2012; 16(3) 202
chromosome transgenesis in mammalian tissue culture cells. Proc Natl Acad Sci U S A. 2005 Feb 15;102(7):2396-401
Liu HY, MacDonald JI, Hryciw T, Li C, Meakin SO. Human tumorous imaginal disc 1 (TID1) associates with Trk receptor tyrosine kinases and regulates neurite outgrowth in nnr5-TrkA cells. J Biol Chem. 2005 May 20;280(20):19461-71
Lo JF, Zhou H, Fearns C, Reisfeld RA, Yang Y, Lee JD. Tid1 is required for T cell transition from double-negative 3 to double-positive stages. J Immunol. 2005 May 15;174(10):6105-12
Hayashi M, Imanaka-Yoshida K, Yoshida T, Wood M, Fearns C, Tatake RJ, Lee JD. A crucial role of mitochondrial Hsp40 in preventing dilated cardiomyopathy. Nat Med. 2006 Jan;12(1):128-32
Lu B, Garrido N, Spelbrink JN, Suzuki CK. Tid1 isoforms are mitochondrial DnaJ-like chaperones with unique carboxyl termini that determine cytosolic fate. J Biol Chem. 2006 May 12;281(19):13150-8
Qiu XB, Shao YM, Miao S, Wang L. The diversity of the DnaJ/Hsp40 family, the crucial partners for Hsp70 chaperones. Cell Mol Life Sci. 2006 Nov;63(22):2560-70
Sohn SY, Kim SB, Kim J, Ahn BY. Negative regulation of hepatitis B virus replication by cellular Hsp40/DnaJ proteins through destabilization of viral core and X proteins. J Gen Virol. 2006 Jul;87(Pt 7):1883-91
Wang L, Tam JP, Liu DX. Biochemical and functional characterization of Epstein-Barr virus-encoded BARF1 protein: interaction with human hTid1 protein facilitates its maturation and secretion. Oncogene. 2006 Jul 20;25(31):4320-31
Kurzik-Dumke U, Czaja J. Htid-1, the human homolog of the Drosophila melanogaster l(2)tid tumor suppressor, defines a novel physiological role of APC. Cell Signal. 2007 Sep;19(9):1973-85
Traicoff JL, Chung JY, Braunschweig T, Mazo I, Shu Y, Ramesh A, D'Amico MW, Galperin MM, Knezevic V, Hewitt SM. Expression of EIF3-p48/INT6, TID1 and Patched in cancer, a profiling of multiple tumor types and correlation of expression. J Biomed Sci. 2007 May;14(3):395-405
Wakabayashi Y, Mao JH, Brown K, Girardi M, Balmain A. Promotion of Hras-induced squamous carcinomas by a polymorphic variant of the Patched gene in FVB mice. Nature. 2007 Feb 15;445(7129):761-5
Kurzik-Dumke U, Hörner M, Czaja J, Nicotra MR, Simiantonaki N, Koslowski M, Natali PG. Progression of colorectal cancers correlates with overexpression and loss of polarization of expression of the htid-1 tumor suppressor. Int J Mol Med. 2008 Jan;21(1):19-31
Linnoila J, Wang Y, Yao Y, Wang ZZ. A mammalian homolog of Drosophila tumorous imaginal discs, Tid1, mediates agrin signaling at the neuromuscular junction. Neuron. 2008 Nov 26;60(4):625-41
Song Y, Balice-Gordon R. New dogs in the dogma: Lrp4 and Tid1 in neuromuscular synapse formation. Neuron. 2008 Nov 26;60(4):526-8
Chen CY, Chiou SH, Huang CY, Jan CI, Lin SC, Hu WY, Chou SH, Liu CJ, Lo JF. Tid1 functions as a tumour suppressor in head and neck squamous cell carcinoma. J Pathol. 2009 Nov;219(3):347-55
Ahn BY, Trinh DL, Zajchowski LD, Lee B, Elwi AN, Kim SW. Tid1 is a new regulator of p53 mitochondrial translocation and apoptosis in cancer. Oncogene. 2010 Feb 25;29(8):1155-66
Kurzik-Dumke U, Hörner M, Nicotra MR, Koslowski M, Natali PG. In vivo evidence of htid suppressive activity on ErbB-2 in breast cancers over expressing the receptor. J Transl Med. 2010 Jun 17;8:58
Maselli RA, Arredondo J, Cagney O, Ng JJ, Anderson JA, Williams C, Gerke BJ, Soliven B, Wollmann RL. Mutations in MUSK causing congenital myasthenic syndrome impair MuSK-Dok-7 interaction. Hum Mol Genet. 2010 Jun 15;19(12):2370-9
Qian J, Perchiniak EM, Sun K, Groden J. The mitochondrial protein hTID-1 partners with the caspase-cleaved adenomatous polyposis cell tumor suppressor to facilitate apoptosis. Gastroenterology. 2010 Apr;138(4):1418-28
Trinh DL, Elwi AN, Kim SW. Direct interaction between p53 and Tid1 proteins affects p53 mitochondrial localization and apoptosis. Oncotarget. 2010 Oct;1(6):396-404
Copeland E, Balgobin S, Lee CM, Rozakis-Adcock M. hTID-1 defines a novel regulator of c-Met Receptor signaling in renal cell carcinomas. Oncogene. 2011 May 12;30(19):2252-63
Dhennin-Duthille I, Nyga R, Yahiaoui S, Gouilleux-Gruart V, Régnier A, Lassoued K, Gouilleux F. The tumor suppressor hTid1 inhibits STAT5b activity via functional interaction. J Biol Chem. 2011 Feb 18;286(7):5034-42
Jan CI, Yu CC, Hung MC, Harn HJ, Nieh S, Lee HS, Lou MA, Wu YC, Chen CY, Huang CY, Chen FN, Lo JF. Tid1, CHIP and ErbB2 interactions and their prognostic implications for breast cancer patients. J Pathol. 2011 Nov;225(3):424-37
This article should be referenced as such:
Traicoff JL, Hewitt SM, Chung JY. DNAJA3 (DnaJ (Hsp40) homolog, subfamily A, member 3). Atlas Genet Cytogenet Oncol Haematol. 2012; 16(3):194-202.
Gene Section Short Communication
Atlas Genet Cytogenet Oncol Haematol. 2012; 16(3) 203
Atlas of Genetics and Cytogenetics in Oncology and Haematology
OPEN ACCESS JOURNAL AT INIST-CNRS
MYEOV (myeloma overexpressed (in a subset of t(11;14) positive multiple myelomas)) Jérôme Moreaux
INSERM U1040, institut de recherche en biotherapie, CHRU Saint Eloi, 80 Av Augustain Fliche,
34295 Montpellier CEDEX 5, France (JM)
Published in Atlas Database: October 2011
Online updated version : http://AtlasGeneticsOncology.org/Genes/MYEOVID395.html Printable original version : http://documents.irevues.inist.fr/bitstream/DOI MYEOVID395.txt This article is an update of : Janssen JWG. MYEOV myeloma overexpressed (in a subset of t(11;14) positive multiple myelomas). Atlas Genet Cytogenet Oncol Haematol 2003;7(1) This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2012 Atlas of Genetics and Cytogenetics in Oncology and Haematology
Identity
Other names: OCIM
HGNC (Hugo): MYEOV
Location: 11q13.3
Local order: 350 kb centromeric of cyclin D1.
Note
Detected by application of the NIH/3T3
tumorigenicity assay. However MYEOV cDNA
was not positive in NIH/3T3 assay.
DNA/RNA
Note
The MYEOV gene was originally isolated by the
application of the NIH/3T3 tumorigenicity assay
with DNA from a gastric carcinoma. The
chromosomal region 11q13 is frequently associated
with genetic rearrangements in a large number of
human malignancies, including B-cell malignancies
and overexpression of MYEOV is frequently
observed in breast tumors and oral, esophageal
squamous cell carcinomas and multiple myeloma.
The presence of functional domains such as RNP-1
(motif typical of RNA binding protein) and the
studies of the short hydrophobic regions and of the
C-terminal leucine/isoleucine tail showed that
MYEOV might be directed to the membrane.
MYEOV small interfering RNA (siRNA) decreased
proliferation of gastric cancer cells, colon cancer
cell lines and multiple myeloma cells in vitro.
Description
2 exons; 3,5 kb transcript represents unspliced
mRNA.
Transcription
Main transcript 2,8 kb (broad band because of
alternative splice products); minor transcript 3,5 kb;
coding sequence 313 or 255 amino acids. In normal
tissues hardly any expression detectable. High
expression in a subset of multiple myeloma cell
lines with a t(11;14)(q13;q32) and in breast tumors
and esophageal squamous cell carcinomas with or
without 11q13 amplification.
Pseudogene
No pseudogenes have been reported for MYEOV.
MYEOV (myeloma overexpressed (in a subset of t(11;14) positive multiple myelomas))
Moreaux J
Atlas Genet Cytogenet Oncol Haematol. 2012; 16(3) 204
Protein
Description
313 or 255 amino acids; contains one RNP-1 motif
and 6 regions that might function as a
transmembrane domain. Leucine-rich stretch at C-
terminal.
Expression
5' UTR inhibits efficient translation of the protein.
Localisation
In endoplasmic reticulum and mitochondria.
Homology
No known homology.
Implicated in
t(11;14)(q13;q32)
Disease
Subset of multiple myeloma cell lines with
t(11;14)(q13;q32).
Cytogenetics
MYEOV overexpression due to juxtaposition to the
5' enhancer or the most telomeric 3' enhancer of the
immunoglobulin heavy chain (IgH).
11q13 amplification and/or overexpression
Disease
Breast cancer; esophageal squamous cell
carcinomas.
Prognosis
MYEOV DNA amplification correlated with
estrogen and progesterone receptor-positive cancer,
invasive lobular carcinoma type and axillary nodal
involvement. In contrast to Cyclin D1
amplification, no association with disease outcome
could be found.
Multiple myeloma
Prognosis
In a cohort of 171 myeloma patients, patients with
MYEOVabsent
MMC have an increased event-free
survival compared to patients with MYEOVpresent
MMC, after high-dose therapy and stem cell
transplantation and a trend for increased overall
survival. In a Cox proportional hazard model,
MYEOV expression in MMC is predictive for
event-free survival for patients independently of
International Staging System stage, t(4;14)
translocation, albumin, or B2M serum levels. In a
second independent cohort of 208 patients (LR-
TT3, from the University of Arkansas for Medical
Sciences (Little Rock, AR, USA)), MYEOV had a
"present" call in MMCs of 73% of patients. Patients
with MYEOVabsent
MMCs had a significant better
overall survival in the LR-TT3 cohort.
Oncogenesis
In a cohort of 171 patients, MMC of 79% of the
patients with newly diagnosed MM express
MYEOV gene. A treatment with 5-aza-2'-
deoxycytidine of 2 MYEOVabsent
myeloma cell lines
induced MYEOV expression without affecting that
in the MYEOVpresent
myeloma cells. MYEOV
siRNA did not significantly induce apoptosis in
myeloma cell lines, but it blocked the cell cycle
entry into the S-phase.
Colon cancer
Oncogenesis
Knockout of MYEOV RNA (siRNA) has been
shown to decrease proliferation of colon cancer cell
lines in vitro. Furthermore, in colon cancer,
MYEOV stimulates colorectal cancer cell migration
in vitro. MYEOV expression is enhanced by PGE2
treatment in colorectal cancer cells.
Gastric cancer
Oncogenesis
Knockout of MYEOV RNA (siRNA) has been
shown to decrease proliferation and invasion of
gastric cancer cells in vitro.
Neuroblastoma
Oncogenesis
MYEOV is a candidate gene target in
neuroblastoma that was identified by chromosomal
gain 11q13 through SNP analysis. MYEOV
expression was analyzed in 55 neuroblastoma
samples including 25 cell lines. MYEOV was
shown to be upregulated in 11 out of 25
neuroblastoma cell lines and 7 out of 20 fresh
tumors. Knockout of MYEOV RNA (siRNA) has
been shown to decrease proliferation of
neuroblastoma cell line in vitro.
Oral squamous cell carcinoma
Oncogenesis
Gain of 11q13 was significantly associated with
cervical lymph node metastasis in oral squamous
cell carcinoma (54 patients included in the study).
Copy number amplification of MYEOV is
associated with cervical lymph node metastasis in
oral squamous cell carcinoma. Lymph node
metastasis is associated with a significant decrease
of 5-years survival in oral squamous cell
carcinoma.
References Janssen JW, Vaandrager JW, Heuser T, Jauch A, Kluin PM, Geelen E, Bergsagel PL, Kuehl WM, Drexler HG, Otsuki T, Bartram CR, Schuuring E. Concurrent activation of a novel putative transforming gene, myeov, and cyclin D1 in a subset of multiple myeloma cell lines with t(11;14)(q13;q32). Blood. 2000 Apr 15;95(8):2691-8
Janssen JW, Cuny M, Orsetti B, Rodriguez C, Vallés H, Bartram CR, Schuuring E, Theillet C. MYEOV: a candidate gene for DNA amplification events occurring centromeric to
MYEOV (myeloma overexpressed (in a subset of t(11;14) positive multiple myelomas))
Moreaux J
Atlas Genet Cytogenet Oncol Haematol. 2012; 16(3) 205
CCND1 in breast cancer. Int J Cancer. 2002 Dec 20;102(6):608-14
Janssen JW, Imoto I, Inoue J, Shimada Y, Ueda M, Imamura M, Bartram CR, Inazawa J. MYEOV, a gene at 11q13, is coamplified with CCND1, but epigenetically inactivated in a subset of esophageal squamous cell carcinomas. J Hum Genet. 2002;47(9):460-4
Leyden J, Murray D, Moss A, Arumuguma M, Doyle E, McEntee G, O'Keane C, Doran P, MacMathuna P. Net1 and Myeov: computationally identified mediators of gastric cancer. Br J Cancer. 2006 Apr 24;94(8):1204-12
Moss AC, Lawlor G, Murray D, Tighe D, Madden SF, Mulligan AM, Keane CO, Brady HR, Doran PP, MacMathuna P. ETV4 and Myeov knockdown impairs colon cancer cell line proliferation and invasion. Biochem Biophys Res Commun. 2006 Jun 23;345(1):216-21
Lawlor G, Doran PP, MacMathuna P, Murray DW. MYEOV (myeloma overexpressed gene) drives colon cancer cell migration and is regulated by PGE2. J Exp Clin Cancer Res. 2010 Jun 22;29:81
Moreaux J, Hose D, Bonnefond A, Reme T, Robert N, Goldschmidt H, Klein B. MYEOV is a prognostic factor in multiple myeloma. Exp Hematol. 2010 Dec;38(12):1189-1198.e3
Sugahara K, Michikawa Y, Ishikawa K, Shoji Y, Iwakawa M, Shibahara T, Imai T. Combination effects of distinct cores in 11q13 amplification region on cervical lymph node metastasis of oral squamous cell carcinoma. Int J Oncol. 2011 Oct;39(4):761-9
Takita J, Chen Y, Okubo J, Sanada M, Adachi M, Ohki K, Nishimura R, Hanada R, Igarashi T, Hayashi Y, Ogawa S. Aberrations of NEGR1 on 1p31 and MYEOV on 11q13 in neuroblastoma. Cancer Sci. 2011 Sep;102(9):1645-50
This article should be referenced as such:
Moreaux J. MYEOV (myeloma overexpressed (in a subset of t(11;14) positive multiple myelomas)). Atlas Genet Cytogenet Oncol Haematol. 2012; 16(3):203-205.
Gene Section Review
Atlas Genet Cytogenet Oncol Haematol. 2012; 16(3) 206
Atlas of Genetics and Cytogenetics in Oncology and Haematology
OPEN ACCESS JOURNAL AT INIST-CNRS
PCNA (proliferating cell nuclear antigen) Ivaylo Stoimenov, Thomas Helleday
Department of Genetics Microbiology and Toxicology, Stockholm University, S-106 91 Stockholm,
Sweden (IS), Department of Genetics Microbiology and Toxicology, Stockholm University, S-106 91
Stockholm, Sweden; Gray Institute for Radiation Oncology & Biology, University of Oxford, Oxford,
OX3 7DQ, UK (TH)
Published in Atlas Database: October 2011
Online updated version : http://AtlasGeneticsOncology.org/Genes/PCNAID41670ch20p12.html Printable original version : http://documents.irevues.inist.fr/bitstream/DOI PCNAID41670ch20p12.txt This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2012 Atlas of Genetics and Cytogenetics in Oncology and Haematology
Identity
Other names: MGC8367
HGNC (Hugo): PCNA
Location: 20p12.3
DNA/RNA
Description
The PCNA gene is situated on human chromosome
20 and it spans about 12 kb. It is a single-copy
gene, however, several pseudogenes have been
noted. The precise localization of the PCNA gene is
at the border of two histological G-bands (p12.3
and p13) (Webb et al., 1990), thus it is reported in
both locations depending on the probe used. The
human PCNA gene was first cloned and
characterized in 1989 by Travali and co-workers
(Travali et al., 1989).
Transcription
There are two reported gene transcripts, which
encode the same protein.
PCNA transcript variant 1 is 1355 bp long after the
completion of mRNA splicing. It has NCBI
Reference Sequence code NM_002592.2 (NCBI).
The PCNA transcript variant 1 has seven exons, six
of which are contributing to the protein sequence.
The first intron is relatively large in comparison
with the other PCNA transcript variant. Following
the splicing the length of the transcript is shortened
to about 12% of that of the initial transcript. The
translation starts from the middle of the 2nd
exon
and ends in the beginning of 7th
exon. The product
is a full length protein, designated as NP_002583.1
(NCBI), with 261 amino acids.
PCNA transcript variant 2 is 1319 bp long after the
completion of mRNA splicing.
The localisation of the PCNA gene (in red) at the interface between 20p12.3 and 20p13 histological bands on chromosome 20.
NCBI Reference
Sequence
Length
(unspliced)
Length
(spliced) Exons Protein AA
PCNA transcript variant 1 NM_002592.2 11670 bp 1355 bp 7 NP_002583.1 261
PCNA transcript variant 2 NM_182649.1 5049 bp 1319 bp 6 NP_872590.1 261
PCNA (proliferating cell nuclear antigen) Stoimenov I, Helleday T
Atlas Genet Cytogenet Oncol Haematol. 2012; 16(3) 207
It has NCBI Reference Sequence code
NM_182649.1 (NCBI). The PCNA transcript
variant 2 has six exons, which are contributing to
the protein sequence. After the splicing the length
of the transcript is shortened to about 26% of that of
the initial transcript. Translation starts from the end
of the 1st exon and ends in the beginning of 7
th
exon. The product is a full length protein,
designated as NP_872590.1 (NCBI), with 261
amino acids.
Pseudogene
PCNAP - one pseudogene on human chromosome
X - p11 (Ku et al., 1989; Webb et al., 1990).
PCNAP1 and PCNAP2 - two pseudogenes in
tandem on human chromosome 4 - q24 (Taniguchi
et al., 1996).
There are several other possible pseudogenes:
LOC390102 on chromosome 11 - p15.1 (Webb et
al., 1990), LOC392454 on chromosome X - p11.3
(Ku et al., 1989; Webb et al., 1990).
Protein
Description
The human PCNA protein is a polypeptide of 261
amino acids and theoretical molecular weight of
about 29 kDa. The functional protein is a
homotrimer, build from three identical units
interacting head-to-tail and forming a doughnut
shaped molecule. There is an evidence for the
existence of a double homotrimer in vivo
(Naryzhny et al., 2005).
Expression
Expressed in nearly all proliferating tissues with
high levels detected in thymus, bone marrow, foetal
liver and certain cells of the small intestine and
colon.
Localisation
PCNA is exclusively localized in the nucleus. It can
be detected by immunofluorescence in all
proliferating nuclei as discrete nuclear foci,
representing sites of ongoing DNA replication
and/or DNA repair.
Function
PCNA was originally discovered as an antigen,
reacting with antibodies derived from sera of
patients with systemic lupus erythematosus
(Miyachi et al., 1978). The first assigned function
of the PCNA protein is as an auxiliary factor of
polymerase delta (Tan et al., 1986; Prelich et al.,
1987). Later it was suggested that PCNA functions
as a cofactor to many other eukaryotic polymerases
such as polymerase epsilon, polymerase beta and
several specialised polymerases known as
translesion synthesis polymerases (eta, kappa,
lambda, theta, etc.), with which PCNA is known to
interact (Naryzhny, 2008). The role of PCNA in
DNA replication is thoroughly investigated and
PCNA is proposed to serve as a switch between the
priming polymerase alpha and replicative
polymerases (delta and epsilon) and functioning as
a cofator of the latter polymerases. Complementary
to enhancing the processivity of DNA replication,
PCNA is known to coordinate the maturation of
Okazaki fragments through interaction with FEN1
and stimulation of the flap endonuclease activity.
PCNA interacts with large number of proteins,
suggesting many functions in vivo (Naryzhny,
2008; Stoimenov and Helleday, 2009). There is
evidence, derived from experiments in yeast, that
PCNA may be involved in the establishment of
sister chromatid cohesion in S phase of the cell
cycle (Moldovan et al., 2006). PCNA is an
indispensable factor for different DNA repair
pathways including mismatch repair, nucleotide
excision repair and sub-pathways of base excision
repair. There is a growing body of evidence for the
function of PCNA in the chromatin remodelling
and organisation. The interaction of PCNA and
CAF1 is in the heart of the nucleosome assembly,
while the chromatin modification is also known to
be regulated by PCNA through the known
interaction with DNMT1 and HDAC1.
PCNA and mapped interactions with several proteins (D-type of cyclins, CDKN1A, FEN1, RFC complex, polymerase epsilon and polymerase delta). Two residues are highlighted, lysine at position 164 (site of ubiquitylation) and tyrosine at position 211 (site of
phosphorylation).
PCNA (proliferating cell nuclear antigen) Stoimenov I, Helleday T
Atlas Genet Cytogenet Oncol Haematol. 2012; 16(3) 208
One of the most stable interactions of PCNA is that
with the cyclin-kinase inhibitor CDKN1A, which
suggests a role of PCNA in the cell cycle
progression. Another evidence for the involvement
of PCNA in the cell cylcle control is the interaction
with cyclin-D. Several amino-acid residues are
post-translationally modified, suggesting even more
complex functions (Stoimenov and Helleday,
2009). PCNA could be subjected to post-
translational phosphorylation, acetylation,
methylation, ubiquitylation and SUMOylation.
Implicated in
Note
The absence of the proliferating nuclear cell antigen
(PCNA) protein is embryonic lethal in mice (Roa et
al., 2008; Peled et al., 2008). The embryonic
lethality in mice also suggests a critical importance
of the PCNA protein for humans at least in
proliferating tissues (Moldovan et al., 2007). The
knockout mice for PCNA (Pcna-/-
) are dying in
embryonic state, consistent with the role of PCNA
in orchestrating DNA replication (Moldovan et al.,
2007). In addition to this fact, there are no known
mutations of the PCNA protein in humans, which
therefore leads to a speculation that PCNA is so
vital that any alternation of its sequence would have
deleterious consequences. One suggestion for such
essential function is the fact that both sequences of
the PCNA protein and of the respective gene are
highly conserved during evolution (Stoimenov and
Helleday, 2009). Indeed, a human population study
of PCNA polymorphisms shows only 7 intronic
single nucleotide polymorphisms (SNP) and 2
synonymous exonic SNPs (Ma et al., 2000).
According to OMIM and Human Locus Specific
Mutation Databases there is no known disease,
which is caused by mutation or loss of function of
the PCNA protein.
The only implication of PCNA in human disease is
as a prognostic or diagnostic marker, sometimes
used together with other markers. The utilisation of
PCNA as a marker is very much restricted to an
illustration of proliferation potential and therefore
cannot be specific for any disease. However, PCNA
is indeed used as a prognostic and diagnostic
marker in several human diseases in clinical
practice, as shown below. The list is far from
complete since any human disease associated with
proliferation could utilise PCNA as a marker.
Primary breast cancer
Note
A group of patients with high PCNA labeling index
was associated with poor overall survival compared
with the low PCNA labeling index group in several
immunohistochemical studies (Horiguchi et al.,
1998; Chu et al., 1998). PCNA labeling index is
stated to be an independent predictor in primary
breast cancer patients (Horiguchi et al., 1998) with
a prognostic value (Chu et al., 1998).
Chronic lymphoid leukemia (CLL)
Note
There are attempts to correlate the levels of the
PCNA protein in cells derived from patients with
chronic lymphoid leukemia and the prognosis of
survival (del Giglio et al., 1992; Faderl et al., 2002).
The high level of PCNA in the cells of CLL
patients suggests a higher proliferative activity and
potentially shorter survival (del Giglio et al., 1992).
Intracellular levels of PCNA protein can be used as
marker to predict clinical behaviour and overall
survival in patients with CLL (Faderl et al., 2002).
Non-Hodgkin's lymphoma
Note
In studies conducting immunohistochemical
staining of materials from patients with non-
Hodgkin's lymphoma, PCNA labeling index
together with AgNOR score can be used to predict
overall survival (Korkolopoulou et al., 1998).
PCNA is the only independent predictor of the post-
relapse survival and the histologic grade, which is
the most important indicator of disease-free
survival (Korkolopoulou et al., 1998).
Malignant and nonmalignant skin diseases
Note
In one study of comparison between malignant skin
diseases (squamous cell carcinoma, adult T
lymphotrophic leukemia, mycosis fungoides,
malignant melanoma and malignant lymphoma)
and nonmalignant skin diseases (resistant atopic
dermatitis, psoriasis vulgaris, verruca vulgaris) the
anti-PCNA staining was used as a prognostic
marker (Kawahira, 1999). The percentage of
PCNA-positive cells reported in the study was
higher for malignant skin diseases in comparison
with the non-malignant skin deseases (Kawahira,
1999). The localization of PCNA-positive cells was
found to be in the dermis and the basal layer in case
of the malignant skin diseases, whereas in the
nonmalignant skin diseases PCNA-positive cells
were detected only in the basal layer (Kawahira,
1999). The PCNA labeling index and the
distribution of PCNA-positive cells in the skin were
suggested to be helpful in the early diagnosis of
skin malignancies.
Systemic lupus erythematosus (SLE)
Note
The anti-PCNA antibodies were originally found in
patients with systemic lupus erythematosus
(Miyachi et al., 1978), most of whom had diffuse
proliferative glomerulonephritis in a small clinical
study (Fritzler et al., 1983).
PCNA (proliferating cell nuclear antigen) Stoimenov I, Helleday T
Atlas Genet Cytogenet Oncol Haematol. 2012; 16(3) 209
References Miyachi K, Fritzler MJ, Tan EM. Autoantibody to a nuclear antigen in proliferating cells. J Immunol. 1978 Dec;121(6):2228-34
Fritzler MJ, McCarty GA, Ryan JP, Kinsella TD. Clinical features of patients with antibodies directed against proliferating cell nuclear antigen. Arthritis Rheum. 1983 Feb;26(2):140-5
Tan CK, Castillo C, So AG, Downey KM. An auxiliary protein for DNA polymerase-delta from fetal calf thymus. J Biol Chem. 1986 Sep 15;261(26):12310-6
Prelich G, Tan CK, Kostura M, Mathews MB, So AG, Downey KM, Stillman B. Functional identity of proliferating cell nuclear antigen and a DNA polymerase-delta auxiliary protein. Nature. 1987 Apr 2-8;326(6112):517-20
Ku DH, Travali S, Calabretta B, Huebner K, Baserga R. Human gene for proliferating cell nuclear antigen has pseudogenes and localizes to chromosome 20. Somat Cell Mol Genet. 1989 Jul;15(4):297-307
Travali S, Ku DH, Rizzo MG, Ottavio L, Baserga R, Calabretta B. Structure of the human gene for the proliferating cell nuclear antigen. J Biol Chem. 1989 May 5;264(13):7466-72
Webb G, Parsons P, Chenevix-Trench G. Localization of the gene for human proliferating nuclear antigen/cyclin by in situ hybridization. Hum Genet. 1990 Nov;86(1):84-6
del Giglio A, O'Brien S, Ford R, Saya H, Manning J, Keating M, Johnston D, Khetan R, el-Naggar A, Deisseroth A. Prognostic value of proliferating cell nuclear antigen expression in chronic lymphoid leukemia. Blood. 1992 May 15;79(10):2717-20
Taniguchi Y, Katsumata Y, Koido S, Suemizu H, Yoshimura S, Moriuchi T, Okumura K, Kagotani K, Taguchi H, Imanishi T, Gojobori T, Inoko H. Cloning, sequencing, and chromosomal localization of two tandemly arranged human pseudogenes for the proliferating cell nuclear antigen (PCNA). Mamm Genome. 1996 Dec;7(12):906-8
Chu JS, Huang CS, Chang KJ. Proliferating cell nuclear antigen (PCNA) immunolabeling as a prognostic factor in invasive ductal carcinoma of the breast in Taiwan. Cancer Lett. 1998 Sep 25;131(2):145-52
Horiguchi J, Iino Y, Takei H, Maemura M, Takeyoshi I, Yokoe T, Ohwada S, Oyama T, Nakajima T, Morishita Y. Long-term prognostic value of PCNA labeling index in primary operable breast cancer. Oncol Rep. 1998 May-Jun;5(3):641-4
Korkolopoulou P, Angelopoulou MK, Kontopidou F, Tsengas A, Patsouris E, Kittas C, Pangalis GA. Prognostic implications of proliferating cell nuclear antigen (PCNA), AgNORs and P53 in non-Hodgkin's lymphomas. Leuk Lymphoma. 1998 Aug;30(5-6):625-36
Kawahira K. Immunohistochemical staining of proliferating cell nuclear antigen (PCNA) in malignant and nonmalignant skin diseases. Arch Dermatol Res. 1999 Jul-Aug;291(7-8):413-8
Ma X, Jin Q, Försti A, Hemminki K, Kumar R. Single nucleotide polymorphism analyses of the human proliferating cell nuclear antigen (pCNA) and flap endonuclease (FEN1) genes. Int J Cancer. 2000 Dec 15;88(6):938-42
Faderl S, Keating MJ, Do KA, Liang SY, Kantarjian HM, O'Brien S, Garcia-Manero G, Manshouri T, Albitar M. Expression profile of 11 proteins and their prognostic significance in patients with chronic lymphocytic leukemia (CLL). Leukemia. 2002 Jun;16(6):1045-52
Naryzhny SN, Zhao H, Lee H. Proliferating cell nuclear antigen (PCNA) may function as a double homotrimer complex in the mammalian cell. J Biol Chem. 2005 Apr 8;280(14):13888-94
Moldovan GL, Pfander B, Jentsch S. PCNA controls establishment of sister chromatid cohesion during S phase. Mol Cell. 2006 Sep 1;23(5):723-32
Moldovan GL, Pfander B, Jentsch S. PCNA, the maestro of the replication fork. Cell. 2007 May 18;129(4):665-79
Naryzhny SN. Proliferating cell nuclear antigen: a proteomics view. Cell Mol Life Sci. 2008 Nov;65(23):3789-808
Peled JU, Kuang FL, Iglesias-Ussel MD, Roa S, Kalis SL, Goodman MF, Scharff MD. The biochemistry of somatic hypermutation. Annu Rev Immunol. 2008;26:481-511
Roa S, Avdievich E, Peled JU, Maccarthy T, Werling U, Kuang FL, Kan R, Zhao C, Bergman A, Cohen PE, Edelmann W, Scharff MD. Ubiquitylated PCNA plays a role in somatic hypermutation and class-switch recombination and is required for meiotic progression. Proc Natl Acad Sci U S A. 2008 Oct 21;105(42):16248-53
Stoimenov I, Helleday T. PCNA on the crossroad of cancer. Biochem Soc Trans. 2009 Jun;37(Pt 3):605-13
This article should be referenced as such:
Stoimenov I, Helleday T. PCNA (proliferating cell nuclear antigen). Atlas Genet Cytogenet Oncol Haematol. 2012; 16(3):206-209.
Gene Section Short Communication
Atlas Genet Cytogenet Oncol Haematol. 2012; 16(3) 210
Atlas of Genetics and Cytogenetics in Oncology and Haematology
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RASSF5 (Ras association (RalGDS/AF-6) domain family member 5) Lee Schmidt, Geoffrey J Clark
University of Louisville, Room 119C, Baxter II Research Building, 580 S Preston Street, Louisville,
KY 40202, USA (LS, GJC)
Published in Atlas Database: October 2011
Online updated version : http://AtlasGeneticsOncology.org/Genes/RASSF5ID42059ch1q32.html Printable original version : http://documents.irevues.inist.fr/bitstream/DOI RASSF5ID42059ch1q32.txt This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2012 Atlas of Genetics and Cytogenetics in Oncology and Haematology
Identity Other names: MGC10823, MGC17344, Maxp1,
NORE1, NORE1A, NORE1B, RAPL, RASSF3
HGNC (Hugo): RASSF5
Location: 1q32.1
Note
Murine RASSF5 originally named Nore1a. Nore1B
independently identified and designated RAPL. Rat
RASSF5 also cloned independently and designated
Maxp1.
DNA/RNA
Description
The human gene for RASSF5 is 81 kb in length and
is located on chromosome 1(q32.1). The gene can
produce 4 protein isoforms, two via differential
exon usage, a third via differential promoter usage
and the genesis of the 4th
(which can be found as an
EST clone) is not yet clear. The largest isoform, A,
is 418 amino acids long and has a molecular weight
of about 47 kD. The protein structure of RASSF5A
contains a proline-rich region at the N-terminus
which contains potential SH3 binding sites and a
nuclear localization signal. This is followed by a
cystein rich domain, sometimes referred to as a zinc
finger. Next is the Ras association domain and this
is followed by sequence containing the SARAH
motif required for binding to the pro-apoptotic
kinases MST1 and MST2. A second nuclear
localization sequence has been reported between
amino acids 200-260 and a nuclear export sequence
between amino acids 260-300.
Figure 1. Isoform A is shown as the longest isoform with 6 exons. Isoform B, without an alternate exon, shows that the frameshift gives a shortened and unique C-terminus. Isoform C is shown with a special 5' UTR and lacks an in-frame coding region leading
to a unique N-terminus. The total coding sequence for Isoform A is about 1260 bases with the other isoforms being smaller.
RASSF5 (Ras association (RalGDS/AF-6) domain family member 5)
Schmidt L, Clark GJ
Atlas Genet Cytogenet Oncol Haematol. 2012; 16(3) 211
Figure 2. A figure showing the processed mRNA as well as the amino acid sequence for isoforms A-D followed by motif
explanation of isoform A (Nore1a).
RASSF5 (Ras association (RalGDS/AF-6) domain family member 5)
Schmidt L, Clark GJ
Atlas Genet Cytogenet Oncol Haematol. 2012; 16(3) 212
Protein
Description
The full length cDNA (for isoform A) encodes for a
47-kDa protein which contains a proline-rich region
at the N-terminus followed by a putative
diacylglycerol/phorbol ester binding domain. This
is followed by the Ras association (RA) domain and
then the domain containing a SARAH motif. This
later is responsible for binding to the pro-apoptotic
kinases MST1 and MST2.
Expression
Nore1a mRNA is expressed in the lung, kidney,
liver, brain, spleen, thymus and heart.
Localisation
It can be detected on microtubules, in the
centrosome, but appears most obvious in the
nucleus.
Function
RASSF5A is a pro-apoptotic Ras effector that can
bind and relocalize the pro-apoptotic MST kinases
in the presence of activated Ras. It can also promote
cell cycle arrest and modulate the activity of p53 by
regulating its' nuclear localization. Knockdown of
RASSF5A promotes cellular proliferation and soft
agar growth. Thus, RASSF5A appears to function
as a Ras regulated tumor suppressor. Analysis of
human tumors has found little evidence of somatic
mutation but the gene is frequently inactivated by
promoter methylation in a broad range of human
tumors. RASSF5C (also known as Nore1b or
RAPL) has been reported to modulate cellular
adhesion and to be regulated by the Ras related
protein Rap1a. RASSF5C has also been implicated
as serving as an adaptor protein to facilitate the
interaction of Ras and CARMA1.
Mutations
Note
No tumor mutations yet reported.
Implicated in
Clear cell renal carcinoma
Note
RASSF5 is frequently down-regulated by promoter
methylation in a variety of tumors including clear
cell renal carcinomas. Moreover, a rare hereditary
form of kidney cancer has been reported that maps
with a translocation inactivating the RASSF5 gene.
Various cancers
Note
Nore1a is frequently inactivated by promoter
methylation in renal carcinoma, breast cancer, lung
cancer, liver cancer and neurological tumors.
References Vavvas D, Li X, Avruch J, Zhang XF. Identification of Nore1 as a potential Ras effector. J Biol Chem. 1998 Mar 6;273(10):5439-42
Khokhlatchev A, Rabizadeh S, Xavier R, Nedwidek M, Chen T, Zhang XF, Seed B, Avruch J. Identification of a novel Ras-regulated proapoptotic pathway. Curr Biol. 2002 Feb 19;12(4):253-65
Chen J, Lui WO, Vos MD, Clark GJ, Takahashi M, Schoumans J, Khoo SK, Petillo D, Lavery T, Sugimura J, Astuti D, Zhang C, Kagawa S, Maher ER, Larsson C, Alberts AS, Kanayama HO, Teh BT. The t(1;3) breakpoint-spanning genes LSAMP and NORE1 are involved in clear cell renal cell carcinomas. Cancer Cell. 2003 Nov;4(5):405-13
Hesson L, Dallol A, Minna JD, Maher ER, Latif F. NORE1A, a homologue of RASSF1A tumour suppressor gene is inactivated in human cancers. Oncogene. 2003 Feb 13;22(6):947-54
Vos MD, Martinez A, Ellis CA, Vallecorsa T, Clark GJ. The pro-apoptotic Ras effector Nore1 may serve as a Ras-regulated tumor suppressor in the lung. J Biol Chem. 2003 Jun 13;278(24):21938-43
Aoyama Y, Avruch J, Zhang XF. Nore1 inhibits tumor cell growth independent of Ras or the MST1/2 kinases. Oncogene. 2004 Apr 22;23(19):3426-33
Praskova M, Khoklatchev A, Ortiz-Vega S, Avruch J. Regulation of the MST1 kinase by autophosphorylation, by the growth inhibitory proteins, RASSF1 and NORE1, and by Ras. Biochem J. 2004 Jul 15;381(Pt 2):453-62
Avruch J, Praskova M, Ortiz-Vega S, Liu M, Zhang XF. Nore1 and RASSF1 regulation of cell proliferation and of the MST1/2 kinases. Methods Enzymol. 2006;407:290-310
Calvisi DF, Ladu S, Gorden A, Farina M, Conner EA, Lee JS, Factor VM, Thorgeirsson SS. Ubiquitous activation of Ras and Jak/Stat pathways in human HCC. Gastroenterology. 2006 Apr;130(4):1117-28
Donninger H, Vos MD, Clark GJ. The RASSF1A tumor suppressor. J Cell Sci. 2007 Sep 15;120(Pt 18):3163-72
Kumari G, Singhal PK, Rao MR, Mahalingam S. Nuclear transport of Ras-associated tumor suppressor proteins: different transport receptor binding specificities for arginine-rich nuclear targeting signals. J Mol Biol. 2007 Apr 13;367(5):1294-311
Calvisi DF, Donninger H, Vos MD, Birrer MJ, Gordon L, Leaner V, Clark GJ. NORE1A tumor suppressor candidate modulates p21CIP1 via p53. Cancer Res. 2009 Jun 1;69(11):4629-37
Richter AM, Pfeifer GP, Dammann RH. The RASSF proteins in cancer; from epigenetic silencing to functional characterization. Biochim Biophys Acta. 2009 Dec;1796(2):114-28
Bee C, Moshnikova A, Mellor CD, Molloy JE, Koryakina Y, Stieglitz B, Khokhlatchev A, Herrmann C. Growth and tumor suppressor NORE1A is a regulatory node between Ras signaling and microtubule nucleation. J Biol Chem. 2010 May 21;285(21):16258-66
Kumari G, Singhal PK, Suryaraja R, Mahalingam S. Functional interaction of the Ras effector RASSF5 with the tyrosine kinase Lck: critical role in nucleocytoplasmic transport and cell cycle regulation. J Mol Biol. 2010 Mar 19;397(1):89-109
Park J, Kang SI, Lee SY, Zhang XF, Kim MS, Beers LF, Lim DS, Avruch J, Kim HS, Lee SB. Tumor suppressor ras
RASSF5 (Ras association (RalGDS/AF-6) domain family member 5)
Schmidt L, Clark GJ
Atlas Genet Cytogenet Oncol Haematol. 2012; 16(3) 213
association domain family 5 (RASSF5/NORE1) mediates death receptor ligand-induced apoptosis. J Biol Chem. 2010 Nov 5;285(45):35029-38
Overmeyer JH, Maltese WA. Death pathways triggered by activated Ras in cancer cells. Front Biosci. 2011 Jan 1;16:1693-713
This article should be referenced as such:
Schmidt L, Clark GJ. RASSF5 (Ras association (RalGDS/AF-6) domain family member 5). Atlas Genet Cytogenet Oncol Haematol. 2012; 16(3):210-213.
Gene Section Short Communication
Atlas Genet Cytogenet Oncol Haematol. 2012; 16(3) 214
Atlas of Genetics and Cytogenetics in Oncology and Haematology
OPEN ACCESS JOURNAL AT INIST-CNRS
RGS17 (regulator of G-protein signaling 17) Chenguang Li, Lei Wang, Yihua Sun, Haiquan Chen
Department of Thoracic Oncology, Fudan University Shanghai Cancer Center and Department of
Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, China (CL, LW, YS, HC)
Published in Atlas Database: October 2011
Online updated version : http://AtlasGeneticsOncology.org/Genes/RGS17ID47522ch6q25.html Printable original version : http://documents.irevues.inist.fr/bitstream/DOI RGS17ID47522ch6q25.txt This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2012 Atlas of Genetics and Cytogenetics in Oncology and Haematology
Identity
Other names: RGS-17, RGSZ2, hRGS17
HGNC (Hugo): RGS17
Location: 6q25.2
DNA/RNA
Description
The RGS17 gene spans over a region of 120 kbp
DNA including 4 coding exons and 1 non-coding
exon (exon 1).
Transcription
The RGS17 gene mRNA consists of about 1472
nucleotides with an open reading frame (ORF) of
633 bases.
Pseudogene
RGS17P1 regulator of G-protein signaling 17
pseudogene 1.
Protein
Note
210 amino acids; 24 kDa.
Description
The RGS17 protein consists of 210 amino acid
residues. This gene encodes a member of the
regulator of G-protein signaling family. This
protein contains a conserved, 120 amino acid motif
called the RGS domain and a cysteine-rich region.
Expression
Widely expressed in human organs.
Localisation
Its cellular localization has not been formally
monitored to date.
Function
The protein attenuates the signaling activity of G-
proteins by binding to activated, GTP-bound G
alpha subunits and acting as a GTPase activating
protein (GAP), increasing the rate of conversion of
the GTP to GDP. RGS proteins are GTPase-
activating proteins for Gi and Gq class G-alpha
proteins. They accelerate transit through the cycle
of GTP binding and hydrolysis and thereby
accelerate signaling kinetics and termination. This
hydrolysis allows the G alpha subunits to bind G
beta/gamma subunit heterodimers, forming inactive
G-protein heterotrimers, thereby terminating the
signal.
Diagram of the RGS17 protein in scale. The numbers represent specific residues. The regions are RGS_RZ-like (Regulator of G
protein signaling (RGS) domain found in the RZ protein), putative G-alpha interaction site. C: Carboxyl-terminal; N: Amino-terminal.
RGS17 (regulator of G-protein signaling 17) Li C, et al.
Atlas Genet Cytogenet Oncol Haematol. 2012; 16(3) 215
Homology
The RGS17 gene is conserved in chimpanzee, dog,
cow, mouse, rat, chicken, and zebrafish.
Mutations
Germinal
No germline mutations in this gene have been
reported.
Somatic
A synonymous-coding somatic mutations of this
gene is reported in pancreas cancer at codon 166,
P166P (COSMIC).
Implicated in
Various cancer
Note
Lung cancer, prostate cancer.
Disease
RSG17 is overexpressed in lung and prostate cancer
(James et al., 2009). Expression of RGS17 is up-
regulated in 80% of lung tumors, and also up-
regulated in prostate tumors. Overexpression of
RGS17 induce and maintain cell proliferation.
Lung cancer
Disease
hsa-mir-182 is involved in the down regulation of
RGS17 expression through two conserved sites
located in its 3' UTR region (Sun et al., 2010).
Two SNPs in the first intron of RGS17 (rs4083914
and rs9479510) were found associated with familial
lung cancer susceptibility (You et al., 2009).
Ovarian cancer
Disease
RGS2, RGS5, RGS10 and RGS17 transcripts are
expressed at significantly lower levels in cells
resistant to chemotherapy compared with parental,
chemo-sensitive cells in ovarian cancer cells
(Hooks et al., 2010).
Prognosis
RGS17 loss of expression contributes to the
development of chemoresistance in ovarian cancer
cells.
References James MA, Lu Y, Liu Y, Vikis HG, You M. RGS17, an overexpressed gene in human lung and prostate cancer, induces tumor cell proliferation through the cyclic AMP-PKA-CREB pathway. Cancer Res. 2009 Mar 1;69(5):2108-16
You M, Wang D, Liu P, Vikis H, James M, Lu Y, Wang Y, Wang M, Chen Q, Jia D, Liu Y, Wen W, Yang P, et al. Fine mapping of chromosome 6q23-25 region in familial lung cancer families reveals RGS17 as a likely candidate gene. Clin Cancer Res. 2009 Apr 15;15(8):2666-74
Hooks SB, Callihan P, Altman MK, Hurst JH, Ali MW, Murph MM. Regulators of G-Protein signaling RGS10 and RGS17 regulate chemoresistance in ovarian cancer cells. Mol Cancer. 2010 Nov 2;9:289
Sun Y, Fang R, Li C, Li L, Li F, Ye X, Chen H. Hsa-mir-182 suppresses lung tumorigenesis through down regulation of RGS17 expression in vitro. Biochem Biophys Res Commun. 2010 May 28;396(2):501-7
This article should be referenced as such:
Li C, Wang L, Sun Y, Chen H. RGS17 (regulator of G-protein signaling 17). Atlas Genet Cytogenet Oncol Haematol. 2012; 16(3):214-215.
Gene Section Short Communication
Atlas Genet Cytogenet Oncol Haematol. 2012; 16(3) 216
Atlas of Genetics and Cytogenetics in Oncology and Haematology
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SLC39A1 (solute carrier family 39 (zinc transporter), member 1) Renty B Franklin, Leslie C Costello
Department of Oncology and Diagnostic Sciences, Dental School and The Greenebaum Cancer
Center, University of Maryland, Baltimore, MD, 21201, USA (RBF, LCC)
Published in Atlas Database: October 2011
Online updated version : http://AtlasGeneticsOncology.org/Genes/SLC39A1ID46571ch1q21.html Printable original version : http://documents.irevues.inist.fr/bitstream/DOI SLC39A1ID46571ch1q21.txt This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2012 Atlas of Genetics and Cytogenetics in Oncology and Haematology
Identity
Other names: ZIP1, ZIRTL
HGNC (Hugo): SLC39A1
Location: 1q21.3
DNA/RNA
Description
The SLC39A1 gene contains 5 exons, three of
which are coding. The length of the gene is 8600
base pairs according to the Entrez Gene database.
Several transcripts have been reported containing
either 3, 4, or 5 exons. However, the coding
sequence for SLC39A1 is the same for all reported
transcripts.
Transcription
Only a single isoform has been reported; mRNA
2445 bases in length; coding region of 975 bases.
Pseudogene
None reported.
Protein
Description
SLC39A1 encodes Zrt/Irt-like protein family
member 1 (ZIP1).
ZIP1 is a 35 kDa molecular weight protein
consisting of 324 amino acids. The protein contains
8 transmembrane spanning domains and shows the
characteristics of a zinc transporter (Gaither and
Eide, 2001).
Expression
ZIP1 is ubiquitously expressed in mammalian cells
(Gaither and Eide, 2001). Expression is down
regulated in prostate malignancy (Franklin et al.,
2005). Its constitutive expression is reported to be
regulated by SP and CREB1 (Makhov et al., 2009).
Down regulation of expression in prostate
malignancy is reported due to transcription
repression by ras response element binding protein-
1 (RREB-1) (Milon et al., 2010).
Localisation
ZIP1 is located at the cell membrane.
Function
ZIP1 is a facilitated zinc uptake transporter
(Franklin et al., 2003). Activity of the transporter
results in the intracellular accumulation of zinc.
ZIP1 is involved in apoptosis induction in prostate
cancer cells.
Homology
Mus musculus Slc39a1; Rattus norvegicus Slc39a1;
Bos taurus Slc39a1; Danio rerio slc39a1.
Mutations
Note
No diseases related to mutation are reported.
Implicated in
Prostate cancer
Note
SLC39A1 is down regulated in prostate cancer
(Franklin et al., 2005). Knockdown of the
SLC39A1 (solute carrier family 39 (zinc transporter), member 1)
Franklin RB, Costello LC
Atlas Genet Cytogenet Oncol Haematol. 2012; 16(3) 217
SLC39A1 expression decreases cellular zinc and
increases growth of PC-3 cells (Franklin et al.,
2003). Over expression of SLC39A1 inhibits
prostate tumor growth in a xenograft model
(Golovine et al., 2008).
References Gaither LA, Eide DJ. The human ZIP1 transporter mediates zinc uptake in human K562 erythroleukemia cells. J Biol Chem. 2001 Jun 22;276(25):22258-64
Franklin RB, Ma J, Zou J, Guan Z, Kukoyi BI, Feng P, Costello LC. Human ZIP1 is a major zinc uptake transporter for the accumulation of zinc in prostate cells. J Inorg Biochem. 2003 Aug 1;96(2-3):435-42
Franklin RB, Feng P, Milon B, Desouki MM, Singh KK, Kajdacsy-Balla A, Bagasra O, Costello LC. hZIP1 zinc uptake transporter down regulation and zinc depletion in prostate cancer. Mol Cancer. 2005 Sep 9;4:32
Golovine K, Makhov P, Uzzo RG, Shaw T, Kunkle D, Kolenko VM. Overexpression of the zinc uptake transporter hZIP1 inhibits nuclear factor-kappaB and reduces the malignant potential of prostate cancer cells in vitro and in vivo. Clin Cancer Res. 2008 Sep 1;14(17):5376-84
Makhov P, Golovine K, Uzzo RG, Wuestefeld T, Scoll BJ, Kolenko VM. Transcriptional regulation of the major zinc uptake protein hZip1 in prostate cancer cells. Gene. 2009 Feb 15;431(1-2):39-46
Milon BC, Agyapong A, Bautista R, Costello LC, Franklin RB. Ras responsive element binding protein-1 (RREB-1) down-regulates hZIP1 expression in prostate cancer cells. Prostate. 2010 Feb 15;70(3):288-96
This article should be referenced as such:
Franklin RB, Costello LC. SLC39A1 (solute carrier family 39 (zinc transporter), member 1). Atlas Genet Cytogenet Oncol Haematol. 2012; 16(3):216-217.
Gene Section Mini Review
Atlas Genet Cytogenet Oncol Haematol. 2012; 16(3) 218
Atlas of Genetics and Cytogenetics in Oncology and Haematology
OPEN ACCESS JOURNAL AT INIST-CNRS
CBX7 (chromobox homolog 7) Ana O'Loghlen, Jesus Gil
Cell Proliferation Group, MRC Clinical Sciences Centre, Imperial College London, Hammersmith
Campus, London W12 0NN, UK (AO, JG)
Published in Atlas Database: November 2011
Online updated version : http://AtlasGeneticsOncology.org/Genes/CBX7ID43845ch22q13.html Printable original version : http://documents.irevues.inist.fr/bitstream/DOI CBX7ID43845ch22q13.txt This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2012 Atlas of Genetics and Cytogenetics in Oncology and Haematology
Identity
HGNC (Hugo): CBX7
Location: 22q13.1
Note
Orientation: minus strand. Size: 32508 bases.
DNA/RNA
Description
DNA size is 4081 bp with 6 exons. CBX7 is a
highly conserved gene in chimpanzee, dog, cow, rat
and mouse.
Transcription
mRNA size: 3964 bp.
Protein
Note
251 amino acids. Isoelectric point: 10,0228.
Molecular weight of the protein: 28209 Da.
Description
CBX7 has a chromodomain region which is
commonly found in proteins associated with the
remodelling and manipulation of chromatin. In
mammals, chromodomain-containing proteins are
responsible for aspects of gene regulation related to
chromatin remodelling and formation of
heterochromatin regions. Chromodomain-
containing proteins also bind methylated histones
and appear in the RNA-induced transcriptional
silencing complex. Specifically, CBX7 is involved
in maintaining the transcriptionally repressive state
of its target genes. The better characterized target of
CBX7 is the INK4a/ARF locus, which is repressed
by CBX7 in order to overcome the senescent
phenotype in several mouse and human cell lines.
Repression of other targets like E-cadherin has been
also suggested.
Figure 1. Location of Cbx7 within Chromosome 22.
Figure 2. Diagram of Cbx7 transcript. Cbx7 has 6 exons. The black boxes indicate the consensus coding sequences (CCDS).
CBX7 (chromobox homolog 7) O'Loghlen A, Gil J
Atlas Genet Cytogenet Oncol Haematol. 2012; 16(3) 219
Figure 3. Structure of Cbx7 protein. Cbx7 has a chromodomain motif and a Polycomb (Pc) box which are indicated in grey.
Expression
CBX7 is expressed ubiquitously, but at higher
levels in the nervous system, thyroid gland,
prostate, fallopian tubes and bladder in normal
tissue. CBX7 expression is also high in ES cells.
Localisation
In the nucleus.
Function
CBX7 is a member of the Polycomb group (PcG)
genes, which are transcriptional repressors that play
an essential role in development, cancer progression
and stem cell maintenance. Mainly two different
PcG complexes have been described: Polycomb
Repressive Complex 1 (PRC1) and PRC2. PRC2 is
the complex implicated in initiating the silencing of
its target genes by methylating histone H3 on
lysines 9 and 27. PRC1 is implicated in stabilizing
this repressive state by recognizing the methylation
marks through the Polycomb proteins and by
ubiquitinating the histone H2A on Lys119. CBX7
belongs to the PRC1 complex and has been
described to be a regulator of cellular lifespan by
repressing the INK4a/ARF locus in several mouse
and human cell lines. On the other hand, depletion
of CBX7 from the cell induces a senescent
phenotype by increasing the expression of the cell
cycle regulators p16/ARF.
X chromosome inactivation CBX7 has high affinity for binding H3K9me3 and
H3K27me3. It associates with heterochromatin,
binds RNA and it's enriched in the X chromosome,
giving CBX7 a role in maintaining the repression of
genes in the X chromosome.
Epigenetic regulation CBX7, as part of the PRC1 complex, has a role in
maintaining the repressive state of its target genes.
CBX7 binds to the long non-coding RNA ANRIL
in order to represses the INK4a/ARF locus and this
interaction is essential for CBX7's function. Both
CBX7 and ANRIL have been found to have high
levels in prostate cancer tissues.
Stem cells self-renewal CBX7 has been recently implicated to be essential
for maintaining the pluripotency state of stem cells
(ES cells). Overexpression of CBX7 in ESC
impairs cell differentation. On the other hand,
depletion of CBX7 from ESC induces spontaneous
differentiation. Two different miR families (miR-
125 and miR-181) were identified in a screening for
CBX7 regulators and have been described to have a
role in ESC differentiation by targeting the 3'UTR
of CBX7.
Figure 4. 4a: Summary of Cbx7's mechanism in
embryonic stem cells (ESC). Cbx7 is essential for ESC self-renewal. Loss of Cbx7, either by differentiating ESC or by an exogenous/endogenous induction of the microRNA
(miR) families miR-125 and miR-181, induces ESC differentiation. This is accompanied by an increase in other
Cbxs as they are targets of Cbx7. On the other hand, overexpression of Cbx7 in ESC reinforces pluripotency and
keeps the cells in an ESC-like state when forced to differentiate. 4b and 4c: Summary of Cbx7's mechanism
in human primary fibroblasts (IMR-90). Ectopic expression of the miR families miR-125 and miR-181
induces a degradation of Cbx7 mRNA in IMR-90. Depletion of Cbx7 induces the cells to senesce. Thus, overexpression
of miR-125 and miR-181 induces senescence through downregulation of Cbx7.
Mutations
Note
Expression of CBX7 without the Pc box or with
point mutations in the chromodomain region
(F11A, K31A, W32A, W35A) does not extend the
life span of human or mouse cells. The mutant
R17Q, which affects the binding of CBX7 to RNA,
CBX7 (chromobox homolog 7) O'Loghlen A, Gil J
Atlas Genet Cytogenet Oncol Haematol. 2012; 16(3) 220
extended the lifespan of cells, but to a lesser extent
than CBX7 wt. Point mutations in the Pc box as
F234D or F244D result in loss or reduced
interaction of CBX7 with RNF2.
Implicated in
Various cancers
Disease
CBX7 has been implicated in several tumors such
as gastric cancer, follicular lymphoma, breast
cancer, colon carcinoma, pancreatic cancer, tyroid
cancer, glioma.
Prognosis
There is a controversy in the role of CBX7 in
cancer, as some papers associate CBX7
overexpression with poor prognosis and advanced
estate of the tumor and aggressiveness, while others
state that depletion of CBX7 from certain cancers
indicates the state of malignancy of the tumor. The
ability of CBX7 to regulate multiple targets and the
relevance of those targets in different tumor types
and stages probably explain those paradoxical
findings.
References Gil J, Bernard D, Martínez D, Beach D. Polycomb CBX7 has a unifying role in cellular lifespan. Nat Cell Biol. 2004 Jan;6(1):67-72
Bernard D, Martinez-Leal JF, Rizzo S, Martinez D, Hudson D, Visakorpi T, Peters G, Carnero A, Beach D, Gil J. CBX7 controls the growth of normal and tumor-derived prostate cells by repressing the Ink4a/Arf locus. Oncogene. 2005 Aug 25;24(36):5543-51
Gil J, Bernard D, Peters G. Role of polycomb group proteins in stem cell self-renewal and cancer. DNA Cell Biol. 2005 Feb;24(2):117-25
Bernstein E, Duncan EM, Masui O, Gil J, Heard E, Allis CD. Mouse polycomb proteins bind differentially to methylated histone H3 and RNA and are enriched in facultative heterochromatin. Mol Cell Biol. 2006 Apr;26(7):2560-9
Scott CL, Gil J, Hernando E, Teruya-Feldstein J, Narita M, Martínez D, Visakorpi T, Mu D, Cordon-Cardo C, Peters G, Beach D, Lowe SW. Role of the chromobox protein CBX7 in lymphomagenesis. Proc Natl Acad Sci U S A. 2007 Mar 27;104(13):5389-94
Pallante P, Federico A, Berlingieri MT, Bianco M, Ferraro A, Forzati F, Iaccarino A, Russo M, Pierantoni GM, Leone V, Sacchetti S, Troncone G, Santoro M, Fusco A. Loss of the CBX7 gene expression correlates with a highly malignant phenotype in thyroid cancer. Cancer Res. 2008 Aug 15;68(16):6770-8
Yap KL, Li S, Muñoz-Cabello AM, Raguz S, Zeng L, Mujtaba S, Gil J, Walsh MJ, Zhou MM. Molecular interplay of the noncoding RNA ANRIL and methylated histone H3 lysine 27 by polycomb CBX7 in transcriptional silencing of INK4a. Mol Cell. 2010 Jun 11;38(5):662-74
Morey L, Pascual G, Cozzuto L, Roma G, Wutz A, Benitah SA, Di Croce L. Nonoverlapping functions of the polycomb group cbx family of proteins in embryonic stem cells. Cell Stem Cell. 2012 Jan 6;10(1):47-62
O'Loghlen A, Muñoz-Cabello AM, Gaspar-Maia A, Wu HA, Banito A, Kunowska N, Racek T, Pemberton HN, Beolchi P, Lavial F, Masui O, Vermeulen M, Carroll T, Graumann J, Heard E, Dillon N, Azuara V, Snijders AP, Peters G, Bernstein E, Gil J. MicroRNA Regulation of Cbx7 Mediates a Switch of Polycomb Orthologs during ESC Differentiation. Cell Stem Cell. 2012 Jan 6;10(1):33-46
This article should be referenced as such:
O'Loghlen A, Gil J. CBX7 (chromobox homolog 7). Atlas Genet Cytogenet Oncol Haematol. 2012; 16(3):218-220.
Gene Section Short Communication
Atlas Genet Cytogenet Oncol Haematol. 2012; 16(3) 221
Atlas of Genetics and Cytogenetics in Oncology and Haematology
OPEN ACCESS JOURNAL AT INIST-CNRS
RPRM (reprimo, TP53 dependent G2 arrest mediator candidate) Alejandro H Corvalan, Veronica A Torres
Laboratory of Molecular Pathology and Epidemiology, Department of Hemathology - Oncology,
School of Medicine - P Universidad Catolica de Chile, 391 Marcoleta St - Santiago 8330074 Chile
(AHC, TorresVAT)
Published in Atlas Database: November 2011
Online updated version : http://AtlasGeneticsOncology.org/Genes/RPRMID42082ch2q23.html Printable original version : http://documents.irevues.inist.fr/bitstream/DOI RPRMID42082ch2q23.txt This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2012 Atlas of Genetics and Cytogenetics in Oncology and Haematology
Identity
Other names: FLJ90327, REPRIMO
HGNC (Hugo): RPRM
Location: 2q23.3
DNA/RNA
Description
Reprimo gene consists of 1 exon. The gene spans
1,47 kb of genomic DNA on the chromosome 2 in
the minus strand.
Transcription
The mRNA is 1496 bp in length.
Protein
Description
The open reading frame encodes a 109 amino acid
protein with an estimated molecular weight of
11774 Da. Reprimo is a highly glycosylated protein
which has two sites in amino acids 7 and 18. The
protein has a potential transmembrane site covering
amino acids 56 to 76.
Expression
The expression of Reprimo is induced by tumor
protein p53 following X-ray irradiation.
Localisation
When Reprimo is ectopically expressed, it is
localized in the cytoplasm.
Function
Reprimo is a candidate tumor suppresor gene
involved in the G2/M phase cell cycle arrest
mediated by tumor protein p53. Reprimo induces
cell cycle arrest by inhibiting the nuclear
translocation of the Cdc2-Cyclin B1 complex.
Implicated in
Various cancers
Note
The aberrant methylation of the promoter region of
Reprimo is a common event that may contribute to
the pathogenesis of some types of human cancer.
Promoter methylation of Reprimo was found in
pancreatic cancer (91%), gastric cancer (90%),
gallbladder cancer (62%), lymphomas (57%),
colorectal cancer (56%) and esophageal
adenocarcinomas (40%). In breast cancer,
leukemias and lung cancer, promoter methylation of
Reprimo was found in less than 40% of tested
cases.
Gastric cancer
Disease
Aberrant hypermethylation of Reprimo is
frequently found in primary gastric cancer as well
as in pair plasma samples. In plasma from
asymptomatic controls, Reprimo is infrequently
methylated. Therefore, plasmatic detection of
Reprimo is a putative biomarker for early detection
of gastric cancer.
RPRM (reprimo, TP53 dependent G2 arrest mediator candidate)
Corvalan AH, TorresVA
Atlas Genet Cytogenet Oncol Haematol. 2012; 16(3) 222
The above histogram represents the percentage of positive cases for Reprimo and other genes (APC, SHP1, CDH-1, ER, SEMA3B and 3OST2) in 43 prospectively collected gastric cancer cases and 31 asymptomatic age- and gender-matched
controls. Only Reprimo shows a significant difference in plasma between gastric cancer and asymptomatic controls (Bernal et al., Clin Cancer Res. 2008;14:6264-9).
Pancreatic cancer
Disease
Aberrant hypermethylation of Reprimo is also
common in pancreatic cell lines (91%) and in
pancreatic adenocarcinomas (66%). Reprimo
methylation is correlated with poor prognosis in a
large series of resected pancreatic cancers. This fact
raises the possibility that aberrant methylation of
Reprimo is an epigenetic event that may have a
mechanistic role in pancreatic cancer.
References Ohki R, Nemoto J, Murasawa H, Oda E, Inazawa J, Tanaka N, Taniguchi T. Reprimo, a new candidate mediator of the p53-mediated cell cycle arrest at the G2 phase. J Biol Chem. 2000 Jul 28;275(30):22627-30
Sato N, Fukushima N, Maitra A, Matsubayashi H, Yeo CJ, Cameron JL, Hruban RH, Goggins M. Discovery of novel targets for aberrant methylation in pancreatic carcinoma using high-throughput microarrays. Cancer Res. 2003 Jul 1;63(13):3735-42
Suzuki M, Shigematsu H, Takahashi T, Shivapurkar N, Sathyanarayana UG, Iizasa T, Fujisawa T, Gazdar AF. Aberrant methylation of Reprimo in lung cancer. Lung Cancer. 2005 Mar;47(3):309-14
Takahashi T, Suzuki M, Shigematsu H, Shivapurkar N, Echebiri C, Nomura M, Stastny V, Augustus M, Wu CW, Wistuba II, Meltzer SJ, Gazdar AF. Aberrant methylation of Reprimo in human malignancies. Int J Cancer. 2005 Jul 1;115(4):503-10
Hamilton JP, Sato F, Jin Z, Greenwald BD, Ito T, Mori Y, Paun BC, Kan T, Cheng Y, Wang S, Yang J, Abraham JM, Meltzer SJ. Reprimo methylation is a potential biomarker of Barrett's-Associated esophageal neoplastic progression. Clin Cancer Res. 2006 Nov 15;12(22):6637-42
Sato N, Fukushima N, Matsubayashi H, Iacobuzio-Donahue CA, Yeo CJ, Goggins M. Aberrant methylation of Reprimo correlates with genetic instability and predicts poor prognosis in pancreatic ductal adenocarcinoma. Cancer. 2006 Jul 15;107(2):251-7
Bernal C, Aguayo F, Villarroel C, Vargas M, Díaz I, Ossandon FJ, Santibáñez E, Palma M, Aravena E, Barrientos C, Corvalan AH. Reprimo as a potential biomarker for early detection in gastric cancer. Clin Cancer Res. 2008 Oct 1;14(19):6264-9
This article should be referenced as such:
Corvalan AH, TorresVA. RPRM (reprimo, TP53 dependent G2 arrest mediator candidate). Atlas Genet Cytogenet Oncol Haematol. 2012; 16(3):221-222.
Gene Section Mini Review
Atlas Genet Cytogenet Oncol Haematol. 2012; 16(3) 223
Atlas of Genetics and Cytogenetics in Oncology and Haematology
OPEN ACCESS JOURNAL AT INIST-CNRS
VMP1 (vacuole membrane protein 1) Alejandro Ropolo, Andrea Lo Ré, María Inés Vaccaro
Molecular Pathophysiology Lab, School of Pharmacie and Biochemistry, University of Buenos Aires,
Argentina (AR, AL, MIV)
Published in Atlas Database: November 2011
Online updated version : http://AtlasGeneticsOncology.org/Genes/VMP1ID50079ch17q23.html Printable original version : http://documents.irevues.inist.fr/bitstream/DOI VMP1ID50079ch17q23.txt This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2012 Atlas of Genetics and Cytogenetics in Oncology and Haematology
Identity
Other names: DKFZp566I133, EPG3, TMEM49
HGNC (Hugo): VMP1
Location: 17q23.1
DNA/RNA
Description
12 exons, spans approximately 133 kb of genomic
DNA in the centromere-to-telomere orientation.
The translation initiation codon is located to exon 2,
and the stop codon to exon 12.
Transcription
mRNA of 2,17 kb.
Protein
Description
The pancreatitis-associated protein vacuole
membrane protein 1 (VMP1) is a transmembrane
protein of 406 amino-acid length containing 6
putative transmembrane domains and with no
known homologues in yeast.
Expression
VMP1 was characterized because is not
constitutively expressed in pancreatic acinar cells
and it is highly activated early during experimental
acute pancreatitis in acinar cells.
Localisation
Autophagosomal membrane.
Function
VMP1 is an autophagy-related membrane protein.
VMP1 expression triggers autophagy, even under
nutrient-replete conditions. VMP1 is required for
autophagosome development through interaction
with Beclin1. Recently, it has been demonstrated
that participate in a novel selective form of
autophagy, called zymophagy, mediated by VMP1-
USP9x-p62 pathway during acute pancreatitis.
Genomic organization of the VMP1/TMEM49 gene.
VMP1 (vacuole membrane protein 1) Ropolo A, et al.
Atlas Genet Cytogenet Oncol Haematol. 2012; 16(3) 224
Schematic representation of VMP1 protein and localization of transmembrane domains.
Implicated in
Pancreatic cancer
Disease
Pancreatic ductal adenocarcinoma is one of the
most aggressive human malignancies with a 2-3%
5-year survival rate. This is due to both the
aggressive nature of the disease and the lack of
specific symptoms and early-detection tools. It is
relatively refractory to traditional cytotoxic agents
and radiotherapy. Gemcitabine, the standard
chemotherapy agent for the treatment of pancreatic
cancer, induces autophagy of cancer cells and that
this process mediates the cell death-promoting
activity of this compound. Early induction of
autophagy by gemcitabine leads to cancer cell death
and this cellular process is mediated by the
activation of VMP1 expression. In PANC-1 and
MIAPaCa-2 cells the inhibition of autophagy
significantly reduced the percentage of dead cells in
response to gemcitabine. In addition, gemcitabine
promoted early VMP1 expression, and
downregulation of VMP1 expression significantly
reduced cell death.
Acute pancreatitis
Disease
VMP1 was characterized because is not
constitutively expressed in pancreatic acinar cells
and it is highly activated early during experimental
acute pancreatitis in acinar cells. VMP1 is an
autophagy-related membrane protein involved in
the initial steps of the mammalian cell autophagic
process. VMP1 is a transmembrane protein that co-
localizes with LC3, a marker of the
autophagosomes, in pancreas tissue undergoing
pancreatitis-induced autophagy. VMP1 interacts
with with Beclin1, a mammalian autophagy
initiator, to start autophagosome formation. We
developed the ElaI-VMP1 mouse in which acinar
cell-specific constitutive expression of a VMP1-
EGFP chimera induces the formation of
autophagosomes. Upon CCK-R hyperstimulation,
wild type mice developed acute pancreatitis with
high amylase and lipase serum levels.
On the contrary, enzymatic levels in cerulein-
treated ElaI-VMP1 mice were significantly lower
compared to wild type mice. Consistently, ElaI-
VMP1 mouse pancreata showed remarkably less
macroscopic evidence of acute pancreatitis
compared to wild type animals, which showed
marked edema and hemorrhage. Histological
analyses displayed a high degree of necrosis as well
as infiltration in wild type pancreata with acute
pancreatitis. In contrast, neither necrosis nor
significant inflammation was seen in cerulein-
treated ElaI-VMP1 mice. ElaIVMP1 mice showed
secretory granules with normal ultrastructural
characteristics CCK-R hyperstimulation in wild
type animals induced a markedly altered
distribution pattern of the secretory granules.
Acinar cells lose their polarity, which results in the
relocation of zymogen granules to the basolateral
membrane. These alterations in vesicular traffic are
known to occur in acinar cells during acute
pancreatitis and upon hyperstimulation of their
CCK-R with cerulein. ElaI-VMP1 mice subjected
to CCK-R hyperstimulation revealed that acinar
cells preserve their structure and polarity with
negligible or no alteration in vesicular transport.
Surprisingly, in pancreata from cerulein-treated
ElaI-VMP1 mice, we observed autophagosomes
containing zymogen granules displaying a distinct
localization to the apical area of the acinar cell.
VMP1, the ubiquitin-protease USP9x, and the
ubiquitin-binding protein p62 mediate this process.
Moreover, VMP1 interacts with USP9x, indicating
that there is a close cooperation between the
autophagy pathway and the ubiquitin recognition
machinery required for selective autophagosome
formation. We have coined the term "zymophagy"
to refer to this process. Zymophagy is activated by
experimental pancreatitis and by acute pancreatitis
in humans. Furthermore, zymophagy has
pathophysiological relevance by controlling
pancreatitis-induced intracellular zymogen
activation and helping to prevent cell death. This
new selective autophagy is activated in pancreatic
acinar cells during pancreatitis-induced vesicular
transport alteration to sequester and degrade
potentially deleterious activated zymogen granules.
VMP1 (vacuole membrane protein 1) Ropolo A, et al.
Atlas Genet Cytogenet Oncol Haematol. 2012; 16(3) 225
Confocal microscopy of AR42J cell transfected with
pEGFP-VMP1.
Diabetes
Disease
Experimental diabetes activates VMP1 expression
and autophagy in pancreas beta cells as a direct
response to streptozotocin (STZ). VMP1 mRNA
expression is activated after STZ treatment by islet
beta cells. Electron microscopy shows chromatin
aggregation and autophagy morphology that was
confirmed by LC3 expression and LC3-VMP1 co-
localization. Apoptotic cell death and the reduction
of beta cell pool are evident after 24h treatment,
while VMP1 is still expressed in the remaining
cells. VMP1-Beclin1 colocalization in pancreas
tissue from STZ-treated rats suggests that VMP1-
Beclin1 interaction is involved in the autophagic
process activation during experimental diabetes.
Pancreas beta cells trigger VMP1 expression and
autophagy during the early cellular events in
response to experimental diabetes.
References Dusetti NJ, Jiang Y, Vaccaro MI, Tomasini R, Azizi Samir A, Calvo EL, Ropolo A, Fiedler F, Mallo GV, Dagorn JC, Iovanna JL. Cloning and expression of the rat vacuole membrane protein 1 (VMP1), a new gene activated in pancreas with acute pancreatitis, which promotes vacuole formation. Biochem Biophys Res Commun. 2002 Jan 18;290(2):641-9
Vaccaro MI, Grasso D, Ropolo A, Iovanna JL, Cerquetti MC. VMP1 expression correlates with acinar cell cytoplasmic vacuolization in arginine-induced acute pancreatitis. Pancreatology. 2003;3(1):69-74
Jiang PH, Motoo Y, Vaccaro MI, Iovanna JL, Okada G, Sawabu N. Expression of vacuole membrane protein 1 (VMP1) in spontaneous chronic pancreatitis in the WBN/Kob rat. Pancreas. 2004 Oct;29(3):225-30
Ropolo A, Grasso D, Pardo R, Sacchetti ML, Archange C, Lo Re A, Seux M, Nowak J, Gonzalez CD, Iovanna JL, Vaccaro MI. The pancreatitis-induced vacuole membrane protein 1 triggers autophagy in mammalian cells. J Biol Chem. 2007 Dec 21;282(51):37124-33
Vaccaro MI. Autophagy and pancreas disease. Pancreatology. 2008;8(4-5):425-9
Vaccaro MI, Ropolo A, Grasso D, Iovanna JL. A novel mammalian trans-membrane protein reveals an alternative initiation pathway for autophagy. Autophagy. 2008 Apr;4(3):388-90
Grasso D, Sacchetti ML, Bruno L, Lo Ré A, Iovanna JL, Gonzalez CD, Vaccaro MI. Autophagy and VMP1 expression are early cellular events in experimental diabetes. Pancreatology. 2009;9(1-2):81-8
Pardo R, Lo Ré A, Archange C, Ropolo A, Papademetrio DL, Gonzalez CD, Alvarez EM, Iovanna JL, Vaccaro MI. Gemcitabine induces the VMP1-mediated autophagy pathway to promote apoptotic death in human pancreatic cancer cells. Pancreatology. 2010;10(1):19-26
Grasso D, Ropolo A, Lo Ré A, Boggio V, Molejón MI, Iovanna JL, Gonzalez CD, Urrutia R, Vaccaro MI. Zymophagy, a novel selective autophagy pathway mediated by VMP1-USP9x-p62, prevents pancreatic cell death. J Biol Chem. 2011 Mar 11;286(10):8308-24
This article should be referenced as such:
Ropolo A, Lo Ré A, Vaccaro MI. VMP1 (vacuole membrane protein 1). Atlas Genet Cytogenet Oncol Haematol. 2012; 16(3):223-225.
Gene Section Review
Atlas Genet Cytogenet Oncol Haematol. 2012; 16(3) 226
Atlas of Genetics and Cytogenetics in Oncology and Haematology
OPEN ACCESS JOURNAL AT INIST-CNRS
XPO1 (exportin 1 (CRM1 homolog, yeast)) Alessandra Ruggiero, Maria Giubettini, Patrizia Lavia
CNR (National Research Council), Institute of Molecular Biology and Pathology, c/o Sapienza
University of Rome, via degli Apuli 4, 00185 Rome, Italy (AR, MG, PL)
Published in Atlas Database: November 2011
Online updated version : http://AtlasGeneticsOncology.org/Genes/XPO1ID44168ch2p15.html Printable original version : http://documents.irevues.inist.fr/bitstream/DOI XPO1ID44168ch2p15.txt This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2012 Atlas of Genetics and Cytogenetics in Oncology and Haematology
Identity
Other names: CRM1, DKFZp686B1823, emb
HGNC (Hugo): XPO1
Location: 2p15
Note
The human XPO1/hCRM1 gene is localized on the
2p16 region (Fornerod et al., 1997a).
DNA/RNA
Transcription
The human XPO1/hCRM1 gene is transcribed in a
cell cycle-dependent manner, with the onset of
mRNA transcription taking place in late G1 phase
and peaking in the G2/M phases of the cell cycle
(Kudo et al., 1997). NFY/CBP, Sp1 and p53
transcription factors are reported to interact with the
XPO1/hCRM1 gene promoter and play an
important role in XPO1/hCRM1 promoter activity
in transformed and cancer cells (van der Watt and
Leaner, 2011).
Protein
Note
A human protein, originally named CC112 based
on its apparent molecular weight, was identified in
a search for interacting partners of CAN/NUP214, a
nucleoporin regarded as a proto-oncogenic factor.
CAN was implicated in acute myeloid leukemia
and in myelodysplastic syndrome (von Lindern et
al., 1992) as part of the DEK-CAN fusion gene
generated in the translocation t(6;9)(p23;q34).
Another potentially oncogenic fusion protein
involving CAN was identified in a patient with
acute undifferentiated leukemia, in which case the
t(6;9) yielded a SET-CAN fusion. Wild-type CAN
is identical to the nucleoporin NUP214. CC112 was
capable of interacting with both wild-type
CAN/NUP214 and with both its fusion proteins,
DEK-CAN and SET-CAN, suggesting potential
roles in proliferation of cancer cells (Fornerod et
al., 1996).
Description
The human XPO1/CRM1 protein is composed of
1071 aminoacidic residues with a molecular weight
of 112 kDa (Fornerod et al., 1997b). It is a modular
protein composed of several fuctional domains:
- The N-terminal region shares sequence similarity
with importin β in a region called the CRIME
domain (acronym for CRM1, importin beta etc.).
This domain interacts with the GTPase RAN. In the
GTP-bound form, RAN stabilizes export complex
formed by CRM1 and NES-containing proteins.
- Most of the XPO1/CRM1 protein is composed of
19 HEAT repeat motifs. HEAT repeat 8 contains an
acidic loop which cooperates with the CRIME
domain in RANGTP binding.
- The central region of XPO1/CRM1 is involved in
NES binding. Cys528, lying in this region, is
specifically blocked by the inhibitor leptomycin B
(LMB), which therefore blocks the export activity
of XPO1/CRM1 (Wolff et al., 1997).
- The C-terminal region is thought to modulate the
affinity of XPO1/CRM1 for its cargoes.
Structures The structure of the region corresponding to
residues 707-1034 (C-terminal region) was
elucidated by X-ray crystallography (Petosa et al.,
2004).
The structure of XPO1/CRM1 complexed to
various NESs and to RANGTP has been solved
(Güttler et al., 2010).
XPO1 (exportin 1 (CRM1 homolog, yeast)) Ruggiero A, et al.
Atlas Genet Cytogenet Oncol Haematol. 2012; 16(3) 227
The plates show the subcellular localisation of CRM1 (detected by indirect immunofluorescence) in interphase and mitotic human
HeLa cells. Upper row: an interphase cell showing CRM1 (in red in the left panel) within the nucleus and especially around the nuclear envelope, where it concentrates with a regular, punctuated pattern typical of the association with nuclear pore
complexes. The nuclear shape is depicted in the upper right panel by staining the DNA with the fluorochrome 4',6-diamidino-2-phenylindole (DAPI, in blue). Lower row: a metaphase cell showing CRM1 (in red in the left panel) concentrating at the
kinetochores (compare with the middle panel, where kinetochore proteins are stained using CREST antiserum and a blue-emitting secondary antibody). A CRM1 fraction is also visible at spindle poles (compare with the staining of the mitotic spindle
microtubules using an antibody against alpha-tubulin, in green). The merged picture shows a 3.5x magnification of the overlay of all three images: CRM1 (red) lies at the interface between the kinetochores (blue) and the microtubules (green) projecting from
opposite spindle poles.
Expression
XPO1/CRM1 protein levels remain constant
throughout the cell cycle (Kudo et al., 1997).
Localisation
Due to its function as a shuttling nuclear transport
receptor between the nucleus and cytoplasm, the
human XPO1/CRM1 protein is preferentially
localized at the nuclear envelope in interphase cells
(Kudo et al., 1997; Fornerod et al., 1997b). In the
nucleus it can be detected in specific bodies called
CRM1 nucleolar bodies (CNoBs). CNoBs depend
on RNA polymerase I activity, suggesting a role in
ribosome biogenesis (Ernoult-Lange et al., 2009).
In mitotic cells, a fraction of XPO1 is found at
centrosomes (Forgues et al., 2003; Wang et al.,
2005) and a substantial fraction localizes to the
kinetochores (Arnaoutov et al., 2005).
Function
hCRM1 was found to interact stably in complexes
containing not only NUP214/CAN (or its
derivatives), but also another component of nuclear
pores, the nucleoporin NUP88 (Fornerod et al.,
1997b). These interactions hinted at a possible role
of hCRM1 in nucleocytoplasmic transport. Further
studies indeed demonstrated that hCRM1 acts as a
nuclear export factor (reviewed by Fried and Kutaj,
2003; Hutten and Kehlenbach, 2007): it interacts
with various classes of RNAs and with proteins
carrying nuclear export signals (NES) (Fornerod et
al., 1997c; Fukuda et al., 1997; Ossareh-Nazari et
al., 1997), short aminoacidic stretches harbouring
hydrophobic residues (general consensus LX(2-
3)ΦX(2-3)LXΦ, where can be L, I, M or F), present
in many shuttling proteins of cellular or viral origin,
and transports these molecules out of the nucleus
through nuclear pore complexes in a manner
dependent on the GTPase RAN. The protein is
therefore alternatively called either exportin-1 or
XPO1, based on its function, or hCRM1, based on
evolutionary conservation.
Regulated export of some shuttling proteins (e.g.,
p53, p27, STAT, NF-kB and many viral proteins)
out of the nucleus is essential for regulated cell
cycle and cell proliferation (reviewed by Fabbro
and Henderson, 2003; Rensen et al., 2008). This has
lead some authors to view nuclear export as a
promising target process in cancer therapy
(reviewed by Yashiroda and Yoshida, 2003; Turner
and Sullivan, 2008).
Recent findings have revealed additional roles of
XPO1/CRM1 in mitosis: first, an XPO1/CRM1
XPO1 (exportin 1 (CRM1 homolog, yeast)) Ruggiero A, et al.
Atlas Genet Cytogenet Oncol Haematol. 2012; 16(3) 228
fraction regulates the localisation of nucleophosmin
(NPM/B23), a regulator of centrosome duplication.
XPO1/CRM1 is required to prevent centrosome
overduplication and the formation of multipolar
spindles (reviewed by Budhu and Wang, 2005;
Ciciarello and Lavia, 2005). Second, a kinetochore-
associated fraction of XPO1/CRM1 regulates the
assembly of the so-called k-fibers, bundles of
microtubules that stably connect the spindle poles
to the kinetochores of mitotic chromosomes to
ensure proper chromosome segregation (reviewed
by Arnaoutov and Dasso, 2005; Ciciarello and
Lavia, 2005; Dasso, 2006). Third, XPO1/CRM1
regulates survivin, a member of the chromosomal
passenger complex with roles in chromosome
segregation and apoptosis (reviewed by Knauer et
al., 2007).
In synthesis, XPO1/CRM1 acts in control of cell
proliferation, and affects loss of proliferation
control in cancer cells, through several pathways: 1.
as a nuclear export factor, it directly regulates the
subcellular localisation, and hence the activity, of
oncogenes and tumour suppressor proteins that
contain nuclear export sequences; 2. it acts in
control of the mitotic apparatus and chromosome
segregation; 3. it influences the maintenance of
nuclear and chromosome structure.
Homology
The human protein originally named CC112
showed homology to the Schizosaccharomyces
pombe CRM1 protein, first identified for being
implicated in the control of higher order
chromosome structure: mutation of the coding gene
was associated with the appearance of "deformed
nuclear chromosome domains" in fission yeast
conditional mutant strains. The gene product was
therefore named CRM1 (chromosome region
maintenance 1; Adachi and Yanagida, 1989). Based
on this homology, the human protein name of
CC112 was abandoned and the name hCRM1 was
used.
Implicated in
Ovarian cancer (Noske et al., 2008)
Prognosis
Increased nuclear (52.7%) and cytoplasmic (56.8%)
expression of CRM1 were reported observed in
carcinomas compared with borderline tumors and
benign lesions. Cytoplasmic CRM1 expression
significantly correlated with advanced tumor stage
(P= 0.043), poorly differentiated carcinomas (P=
0.011) and high mitotic rate (P= 0.008). Nuclear
CRM1 was significantly associated with high
cyclooxygenase-2 (COX-2) expression (P= 0.002)
and poor overall survival (P= 0.01). CRM1 was
previously directly implicated in nuclear export of
COX-2 (Jang et al., 2003). The study by Noske et
al. (2008) suggests that elevated expression of
CRM1 may be causal to COX-2 up-regulation, with
direct clinical relevance.
Oncogenesis
CRM1 is highly expressed in ovarian carcinomas
tissues and regulates export of COX-2.
Osteosarcoma (Yao et al., 2009)
Prognosis
The CRM1 protein is reported to be expressed with
increased abundance in osteosarcoma compared to
non-tumour tissues (P= 0.037, 57 patients). High
levels of CRM1 were significantly associated with
increased serum levels of alkaline phosphatase
(ALP, P= 0.001). In univariate analysis, a
significant association between CRM1 expression
and tumor size (P= 0.014), as well as histological
grade (P= 0.003) was observed. In Kaplan-Meier
survival analysis, high CRM1 expression was a
significant prognostic indicator for poor
progression-free survival (P= 0.016) as well as
overall survival (P= 0.008). Multivariate analysis
demonstrated that high expression of CRM1 was
significantly related to shorter survival (95% CI,
1.27-5.39).
Oncogenesis
CRM1 is significantly increased in osteosarcoma
compared with normal tissue.
Cervical cancer (van der Watt et al., 2009)
Oncogenesis
CRM1 protein abundance is significantly increased
in cervical cancer cells compared with normal
tissue (P< 0.05). Inhibition of CRM1 by RNA
interference resulted in increased cell death,
associated with nuclear retention of p53, likely
protecting p53 from degradation as the latter
predominantly occurs in the cytoplasm.
Pancreas cancer (Huang et al., 2009)
Prognosis
Increased expression abundance of CRM1 protein
was detected in pancreatic cancer tissues (P=
0.0013, 69 patients at stages I and II). CRM1
expression correlates with increased levels of serum
CEA (P= 0.002) and CA19.9 (P= 0.005), tumour
size (P= 0.011), lymphadenopathy (P= 0.004) and
metastasis (P= 0.0041). High CRM1 expression
was a prognostic indicator for progression-free
survival (PFS) (P= 0.0011) as well as overall
survival (OS) (P= 0.004). The authors proposed that
CRM1 be used as a prognostic parameter for poor
PFS and OS (95% CI, 1.27-5.39).
Glioma (Shen et al., 2009)
Prognosis
CRM1 overexpression is significantly associated
with the pathological state (P= 0.001, 56 patients),
with glioma tumour grade, with high expression of
phospho-ser10p27 and with reduced overall
abundance of p27.
XPO1 (exportin 1 (CRM1 homolog, yeast)) Ruggiero A, et al.
Atlas Genet Cytogenet Oncol Haematol. 2012; 16(3) 229
Oncogenesis
Given the direct implication of CRM1 in nuclear
export of p27, the data in this study suggest that
increased CRM1 abundance yields increased
cytoplasmic localisation of p27, which is probably
targeted to degradation, leading to uncontrolled
tumour growth. Phospho-ser10p27 may be resistant
to CRM1-mediated nuclear export. High CRM1
and low p27 expression are associated with high
grade glioma and high CRM1 protein expression is
proposed as a prognostic factor of overall survival
and poor outcome.
To be noted
Note
CRM1 protein levels are abnormally high in several
cancers, with high levels of CRM1 being associated
with poor patient survival (van der Watt and
Leaner, 2011).
References Adachi Y, Yanagida M. Higher order chromosome structure is affected by cold-sensitive mutations in a Schizosaccharomyces pombe gene crm1+ which encodes a 115-kD protein preferentially localized in the nucleus and its periphery. J Cell Biol. 1989 Apr;108(4):1195-207
von Lindern M, Fornerod M, van Baal S, Jaegle M, de Wit T, Buijs A, Grosveld G. The translocation (6;9), associated with a specific subtype of acute myeloid leukemia, results in the fusion of two genes, dek and can, and the expression of a chimeric, leukemia-specific dek-can mRNA. Mol Cell Biol. 1992 Apr;12(4):1687-97
Fornerod M, Boer J, van Baal S, Morreau H, Grosveld G. Interaction of cellular proteins with the leukemia specific fusion proteins DEK-CAN and SET-CAN and their normal counterpart, the nucleoporin CAN. Oncogene. 1996 Oct 17;13(8):1801-8
Fornerod M, van Baal S, Valentine V, Shapiro DN, Grosveld G. Chromosomal localization of genes encoding CAN/Nup214-interacting proteins--human CRM1 localizes to 2p16, whereas Nup88 localizes to 17p13 and is physically linked to SF2p32. Genomics. 1997a Jun 15;42(3):538-40
Fornerod M, van Deursen J, van Baal S, Reynolds A, Davis D, Murti KG, Fransen J, Grosveld G. The human homologue of yeast CRM1 is in a dynamic subcomplex with CAN/Nup214 and a novel nuclear pore component Nup88. EMBO J. 1997b Feb 17;16(4):807-16
Fornerod M, Ohno M, Yoshida M, Mattaj IW. CRM1 is an export receptor for leucine-rich nuclear export signals. Cell. 1997c Sep 19;90(6):1051-60
Fukuda M, Asano S, Nakamura T, Adachi M, Yoshida M, Yanagida M, Nishida E. CRM1 is responsible for intracellular transport mediated by the nuclear export signal. Nature. 1997 Nov 20;390(6657):308-11
Kudo N, Khochbin S, Nishi K, Kitano K, Yanagida M, Yoshida M, Horinouchi S. Molecular cloning and cell cycle-dependent expression of mammalian CRM1, a protein involved in nuclear export of proteins. J Biol Chem. 1997 Nov 21;272(47):29742-51
Ossareh-Nazari B, Bachelerie F, Dargemont C. Evidence for a role of CRM1 in signal-mediated nuclear protein export. Science. 1997 Oct 3;278(5335):141-4
Wolff B, Sanglier JJ, Wang Y. Leptomycin B is an inhibitor of nuclear export: inhibition of nucleo-cytoplasmic translocation of the human immunodeficiency virus type 1 (HIV-1) Rev protein and Rev-dependent mRNA. Chem Biol. 1997 Feb;4(2):139-47
Fabbro M, Henderson BR. Regulation of tumor suppressors by nuclear-cytoplasmic shuttling. Exp Cell Res. 2003 Jan 15;282(2):59-69
Forgues M, Difilippantonio MJ, Linke SP, Ried T, Nagashima K, Feden J, Valerie K, Fukasawa K, Wang XW. Involvement of Crm1 in hepatitis B virus X protein-induced aberrant centriole replication and abnormal mitotic spindles. Mol Cell Biol. 2003 Aug;23(15):5282-92
Fried H, Kutay U. Nucleocytoplasmic transport: taking an inventory. Cell Mol Life Sci. 2003 Aug;60(8):1659-88
Jang BC, Muñoz-Najar U, Paik JH, Claffey K, Yoshida M, Hla T. Leptomycin B, an inhibitor of the nuclear export receptor CRM1, inhibits COX-2 expression. J Biol Chem. 2003 Jan 31;278(5):2773-6
Yashiroda Y, Yoshida M. Nucleo-cytoplasmic transport of proteins as a target for therapeutic drugs. Curr Med Chem. 2003 May;10(9):741-8
Petosa C, Schoehn G, Askjaer P, Bauer U, Moulin M, Steuerwald U, Soler-López M, Baudin F, Mattaj IW, Müller CW. Architecture of CRM1/Exportin1 suggests how cooperativity is achieved during formation of a nuclear export complex. Mol Cell. 2004 Dec 3;16(5):761-75
Arnaoutov A, Azuma Y, Ribbeck K, Joseph J, Boyarchuk Y, Karpova T, McNally J, Dasso M. Crm1 is a mitotic effector of Ran-GTP in somatic cells. Nat Cell Biol. 2005 Jun;7(6):626-32
Arnaoutov A, Dasso M. Ran-GTP regulates kinetochore attachment in somatic cells. Cell Cycle. 2005 Sep;4(9):1161-5
Budhu AS, Wang XW. Loading and unloading: orchestrating centrosome duplication and spindle assembly by Ran/Crm1. Cell Cycle. 2005 Nov;4(11):1510-4
Ciciarello M, Lavia P. New CRIME plots. Ran and transport factors regulate mitosis. EMBO Rep. 2005 Aug;6(8):714-6
Wang W, Budhu A, Forgues M, Wang XW. Temporal and spatial control of nucleophosmin by the Ran-Crm1 complex in centrosome duplication. Nat Cell Biol. 2005 Aug;7(8):823-30
Dasso M. Ran at kinetochores. Biochem Soc Trans. 2006 Nov;34(Pt 5):711-5
Hutten S, Kehlenbach RH. CRM1-mediated nuclear export: to the pore and beyond. Trends Cell Biol. 2007 Apr;17(4):193-201
Knauer SK, Mann W, Stauber RH. Survivin's dual role: an export's view. Cell Cycle. 2007 Mar 1;6(5):518-21
Noske A, Weichert W, Niesporek S, Röske A, Buckendahl AC, Koch I, Sehouli J, Dietel M, Denkert C. Expression of the nuclear export protein chromosomal region maintenance/exportin 1/Xpo1 is a prognostic factor in human ovarian cancer. Cancer. 2008 Apr 15;112(8):1733-43
Rensen WM, Mangiacasale R, Ciciarello M, Lavia P. The GTPase Ran: regulation of cell life and potential roles in cell transformation. Front Biosci. 2008 May 1;13:4097-121
Turner JG, Sullivan DM. CRM1-mediated nuclear export of proteins and drug resistance in cancer. Curr Med Chem. 2008;15(26):2648-55
XPO1 (exportin 1 (CRM1 homolog, yeast)) Ruggiero A, et al.
Atlas Genet Cytogenet Oncol Haematol. 2012; 16(3) 230
Ernoult-Lange M, Wilczynska A, Harper M, Aigueperse C, Dautry F, Kress M, Weil D. Nucleocytoplasmic traffic of CPEB1 and accumulation in Crm1 nucleolar bodies. Mol Biol Cell. 2009 Jan;20(1):176-87
Huang WY, Yue L, Qiu WS, Wang LW, Zhou XH, Sun YJ. Prognostic value of CRM1 in pancreas cancer. Clin Invest Med. 2009 Dec 1;32(6):E315
Shen A, Wang Y, Zhao Y, Zou L, Sun L, Cheng C. Expression of CRM1 in human gliomas and its significance in p27 expression and clinical prognosis. Neurosurgery. 2009 Jul;65(1):153-9; discussion 159-60
van der Watt PJ, Maske CP, Hendricks DT, Parker MI, Denny L, Govender D, Birrer MJ, Leaner VD. The Karyopherin proteins, Crm1 and Karyopherin beta1, are overexpressed in cervical cancer and are critical for cancer cell survival and proliferation. Int J Cancer. 2009 Apr 15;124(8):1829-40
Yao Y, Dong Y, Lin F, Zhao H, Shen Z, Chen P, Sun YJ, Tang LN, Zheng SE. The expression of CRM1 is associated with prognosis in human osteosarcoma. Oncol Rep. 2009 Jan;21(1):229-35
Güttler T, Madl T, Neumann P, Deichsel D, Corsini L, Monecke T, Ficner R, Sattler M, Görlich D. NES consensus redefined by structures of PKI-type and Rev-type nuclear export signals bound to CRM1. Nat Struct Mol Biol. 2010 Nov;17(11):1367-76
van der Watt PJ, Leaner VD. The nuclear exporter, Crm1, is regulated by NFY and Sp1 in cancer cells and repressed by p53 in response to DNA damage. Biochim Biophys Acta. 2011 Jul;1809(7):316-26
This article should be referenced as such:
Ruggiero A, Giubettini M, Lavia P. XPO1 (exportin 1 (CRM1 homolog, yeast)). Atlas Genet Cytogenet Oncol Haematol. 2012; 16(3):226-230.
Leukaemia Section Short Communication
Atlas Genet Cytogenet Oncol Haematol. 2012; 16(3) 231
Atlas of Genetics and Cytogenetics in Oncology and Haematology
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t(11;18)(p15;q12) Jean-Loup Huret
Genetics, Dept Medical Information, University of Poitiers, CHU Poitiers Hospital, F-86021 Poitiers,
France (JLH)
Published in Atlas Database: October 2011
Online updated version : http://AtlasGeneticsOncology.org/Anomalies/t1118p15q12ID1466.html Printable original version : http://documents.irevues.inist.fr/bitstream/DOI t1118p15q12ID1466.txt This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2012 Atlas of Genetics and Cytogenetics in Oncology and Haematology
Clinics and pathology
Disease
T-cell acute lymphoid leukemia (T-ALL)
Epidemiology
One case to date, a 9-year-old boy.
Evolution
Remission was obtained and the patient remains in
complete remission 28 months after diagnosis.
Cytogenetics
Cytogenetics morphological
The translocation was accompanied with a del(12p).
Genes involved and proteins
NUP98
Location
11p15.4
Protein
Nucleoporin: associated with the nuclear pore
complex. Role in nucleocytoplasmic transport
processes.
SETBP1
Location
18q12.3
Protein
Contains 3 DNA binding domains (A.T hooks).
SETBP1 protects SET from protease cleavage.
SETBP1 forms a complex with SET and PP2A
(protein phosphatase 2A). SETBP1 impairs PP2A
activity via SET and promotes proliferation of acute
myeloid leukemia cells (Cristóbal et al., 2010).
Germinal mutations
In Schinzel-Giedion midface retraction syndrome.
Result of the chromosomal anomaly
Hybrid gene
Description
5' NUP98 - 3' SETBP1
Transcript
Exon 12 of NUP98 (nucleotide (nt) 1552) fused in-
frame with exon 5 of SETBP1 (nt 4015).
References Panagopoulos I, Kerndrup G, Carlsen N, Strömbeck B, Isaksson M, Johansson B. Fusion of NUP98 and the SET binding protein 1 (SETBP1) gene in a paediatric acute T cell lymphoblastic leukaemia with t(11;18)(p15;q12). Br J Haematol. 2007 Jan;136(2):294-6
Cristóbal I, Blanco FJ, Garcia-Orti L, Marcotegui N, Vicente C, Rifon J, Novo FJ, Bandres E, Calasanz MJ, Bernabeu C, Odero MD. SETBP1 overexpression is a novel leukemogenic mechanism that predicts adverse outcome in elderly patients with acute myeloid leukemia. Blood. 2010 Jan 21;115(3):615-25
This article should be referenced as such:
Huret JL. t(11;18)(p15;q12). Atlas Genet Cytogenet Oncol Haematol. 2012; 16(3): 231.
Leukaemia Section Short Communication
Atlas Genet Cytogenet Oncol Haematol. 2012; 16(3) 232
Atlas of Genetics and Cytogenetics in Oncology and Haematology
OPEN ACCESS JOURNAL AT INIST-CNRS
t(11;21)(q21;q22) Jean-Loup Huret
Genetics, Dept Medical Information, University of Poitiers, CHU Poitiers Hospital, F-86021 Poitiers,
France (JLH)
Published in Atlas Database: October 2011
Online updated version : http://AtlasGeneticsOncology.org/Anomalies/t1121q21q22ID1592.html Printable original version : http://documents.irevues.inist.fr/bitstream/DOI t1121q21q22ID1592.txt This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2012 Atlas of Genetics and Cytogenetics in Oncology and Haematology
Identity
Note
This translocation is different from the
t(11;21)(q12;q22) with MACROD1/RUNX1
involvement.
Clinics and pathology
Disease
Acute myeloid leukemia (AML)
Epidemiology
One case to date, a 65-year-old male patient with
M2-AML (Dai et al., 2007).
Evolution
The patient died 10 months after diagnosis.
Genes involved and proteins
LPXN
Protein
LPXN contains two types of protein-protein
interaction domains: leucine-aspartate (LD) repeats
in N-term, and LIM (Lin-11 Isl-1 Mec-3) domains
at the C-term. Belongs to the paxillin family (PXN,
LPXN, TGFB1I1). Protein involved in focal
adhesion. LPXN and paxillin had opposite roles in
adhesion to collagen LPXN siRNA stimulated
whereas paxillin siRNA inhibited cell adhesion.
Strongly expressed in hematopoietic cells. LPXN is
involved in bone resorption and stimulates prostate
cancer cell migration (Chen and Kroog, 2010).
RUNX1
Location
21q22.3
Protein
Transcription factor (activator) for various
hematopoietic-specific genes.
Result of the chromosomal anomaly
Hybrid gene
Description
5' RUNX1 - 3' LPXN
Transcript
Two in frame fusion transcripts -fusion of exon 5 or
6 of RUNX1 to LPXN exon 8.
Fusion protein
Description
The two variant fusion proteins RUNX1-LPXN
localized in the nucleus and inhibited RUNX1
transactivation (Dai et al., 2009). It is hypothesized
that the reciprocal LPXN-RUNX1 may also play a
role in leukemogenesis.
t(11;21)(q21;q22) Huret JL
Atlas Genet Cytogenet Oncol Haematol. 2012; 16(3) 233
References Dai H, Xue Y, Pan J, Wu Y, Wang Y, Shen J, Zhang J.. Two novel translocations disrupt the RUNX1 gene in acute myeloid leukemia. Cancer Genet Cytogenet. 2007 Sep;177(2):120-4.
Dai HP, Xue YQ, Zhou JW, Li AP, Wu YF, Pan JL, Wang Y, Zhang J.. LPXN, a member of the paxillin superfamily, is fused to RUNX1 in an acute myeloid leukemia patient with a t(11;21)(q12;q22) translocation. Genes Chromosomes Cancer. 2009 Dec;48(12):1027-36.
Chen PW, Kroog GS.. Leupaxin is similar to paxillin in focal adhesion targeting and tyrosine phosphorylation but has distinct roles in cell adhesion and spreading. Cell Adh Migr. 2010 Oct-Dec;4(4):527-40.
This article should be referenced as such:
Huret JL. t(11;21)(q21;q22). Atlas Genet Cytogenet Oncol Haematol. 2012; 16(3):232-233.
Leukaemia Section Short Communication
Atlas Genet Cytogenet Oncol Haematol. 2012; 16(3) 234
Atlas of Genetics and Cytogenetics in Oncology and Haematology
OPEN ACCESS JOURNAL AT INIST-CNRS
t(8;17)(q24;q22) ???BCL3/MYC Jean-Loup Huret
Genetics, Dept Medical Information, University of Poitiers, CHU Poitiers Hospital, F-86021 Poitiers,
France (JLH)
Published in Atlas Database: October 2011
Online updated version : http://AtlasGeneticsOncology.org/Anomalies/t0817q24q22ID1494.html Printable original version : http://documents.irevues.inist.fr/bitstream/DOI t0817q24q22ID1494.txt This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2012 Atlas of Genetics and Cytogenetics in Oncology and Haematology
Identity
Note
It is unlikely that the BCL3 gene (HGNC official
name) is involved in this translocation with a
breakpoint in 17q22, since BCL3 sits in 19q13.32
(coordonates: starts at 45251978 and ends at
45263301 bp from 19pter); the alternative would be
a cryptic translocation, involving a cryptic inserted
fragment of 19q13.32, including BCL3, within
17q22.
Clinics and pathology
Disease
Aggresive prolymphocytic leukemia
Epidemiology
Only one case to date, with no clinical data.
Cytogenetics
Cytogenetics morphological
The karyotype also showed the classical
t(14;18)(q32;q21), usually found in follicular
lymphoma, a 12q+ and a Xp+, not otherwise
described.
Genes involved and proteins
Note
As said above, it is unprobable that the MYC
partner is BCL3.
MYC
Protein
MYC regulates the transcription of genes required
to coordinate a range of cellular processes,
including those essential for proliferation, growth,
differentiation, apoptosis and self-renewal, and
protein synthesis through ribosome biogenesis (van
Riggelen et al., 2010).
BCL3
Location
19q13.32
Protein
BCL3 is mainly found in the nucleus. Protein which
contains seven ankyrin repeats. Ankyrin repeats are
found in IkB family members, including IkBa,
IkBb, and IkBe. BCL3 is a member of the IkappaB
family, whose proteins regulate the NFkappaB
family of transcription factors. Component of a
complex with a NF-kB p52-p52 homodimer Down-
regulates inflammatory responses through limiting
the transcription of NF-kB-dependent genes. Binds
to NF-kB p50 and p52, Jab1, Pirin, Tip60 and
Bard1. Bcl-3 is an adaptor protein (Dechend et al.,
1999; Kreisel et al., 2011). Regulates genes
involved in cell proliferation and apoptosis.
NFkappaB plays a major role in B-cell
development.
Result of the chromosomal anomaly
Hybrid gene
Description
Disruption of MYC close to the first intron, with
the decapitation of the first intron, replaced by a
sequence of 1.7 kb, that the authors have called
"BCL3".
t(8;17)(q24;q22) ???BCL3/MYC Huret JL
Atlas Genet Cytogenet Oncol Haematol. 2012; 16(3) 235
References Gauwerky CE, Huebner K, Isobe M, Nowell PC, Croce CM. Activation of MYC in a masked t(8;17) translocation results in an aggressive B-cell leukemia. Proc Natl Acad Sci U S A. 1989 Nov;86(22):8867-71
Dechend R, Hirano F, Lehmann K, Heissmeyer V, Ansieau S, Wulczyn FG, Scheidereit C, Leutz A. The Bcl-3 oncoprotein acts as a bridging factor between NF-kappaB/Rel and nuclear co-regulators. Oncogene. 1999 Jun 3;18(22):3316-23
van Riggelen J, Yetil A, Felsher DW. MYC as a regulator of ribosome biogenesis and protein synthesis. Nat Rev Cancer. 2010 Apr;10(4):301-9
Kreisel D, Sugimoto S, Tietjens J, Zhu J, Yamamoto S, Krupnick AS, Carmody RJ, Gelman AE. Bcl3 prevents acute inflammatory lung injury in mice by restraining emergency granulopoiesis. J Clin Invest. 2011 Jan 4;121(1):265-76
This article should be referenced as such:
Huret JL. t(8;17)(q24;q22) ???BCL3/MYC. Atlas Genet Cytogenet Oncol Haematol. 2012; 16(3):234-235.
Deep Insight Section
Atlas Genet Cytogenet Oncol Haematol. 2012; 16(3) 236
Atlas of Genetics and Cytogenetics in Oncology and Haematology
OPEN ACCESS JOURNAL AT INIST-CNRS
Plasticity and Tumorigenicity Elena Campos-Sanchez, Isidro Sanchez-Garcia, Cesar Cobaleda
Centro de Biologia Molecular "Severo Ochoa", CSIC/Universidad Autonoma de Madrid, C/Nicolas
Cabrera 1, Universidad Autonoma, Cantoblanco, 28049 Madrid, Spain (ECS, CC), Experimental
Therapeutics and Translational Oncology Program, Instituto de Biologia Molecular y Celular del
Cancer, CSIC/ Universidad de Salamanca, Campus M de Unamuno s/n, 37007-Salamanca, Spain
(ISG)
Published in Atlas Database: September 2011
Online updated version : http://AtlasGeneticsOncology.org/Deep/PluripotencyID20103.html Printable original version : http://documents.irevues.inist.fr/bitstream/DOI PluripotencyID20103.txt This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2012 Atlas of Genetics and Cytogenetics in Oncology and Haematology
Summary The research fields of developmental biology and oncology have always been tightly linked, since the times of
Rudolf Virchow's cellular theory ("omnis cellula e cellula") and embryonal rest hypothesis. On the other side,
for many years, contemporary cancer research has been mainly focused on the altered controls of proliferation in
tumoral cells. This has been reflected in the therapeutic approaches employed in the clinic to treat the patients:
with very few exceptions, anti-cancer treatments are targeted at the mechanisms of abnormal tumoral growth.
Such therapies, however, are very unspecific, highly toxic and, ultimately, inefficient in most cases. In the last
years, a new recognition of the role of aberrant differentiation at the root of cancer has arisen, mainly driven by
the coming of age of the "cancer stem cell" (CSC) theory. From this point of view, the comprehensive
knowledge of the developmental mechanisms by which normal cells acquire their identity is essential to
understand how these controls are deregulated in tumours. New insights into the mechanisms that maintain the
molecular boundaries of cell identity have been gained from the study of induced pluripotency, showing that cell
fate can be much more susceptible to change than previously thought. Applied to cancer, these findings imply
that the oncogenic events that take place in an otherwise healthy cell lead to a reprogramming of the normal
cellular fate and establish a new pathologic developmental program. Therefore, cancer reprogramming and
cellular plasticity are closely related, since only some cells possess the plasticity required to allow
reprogramming to occur, and only some oncogenic events can, in the right plastic cell, induce this change. Here
we discuss the latest findings in the fields of cellular plasticity and reprogramming and we consider their
consequences for our understanding of cancer development and treatment.
Historical perspective The search for the capacity of regenerating disease-
affected organs is probably as old as mankind
(Odelberg, 2004). The examples are abundant in
ancient religions, from the Egyptian god Osiris,
who resurrected and recomposed his maimed body
from the pieces that had been thrown into the Nile,
to the legendary Hydra that could regenerate its
severed heads. Or the mythological Prometheus,
who had his viscera eaten by an eagle every day,
only to regenerate them again. But also from a more
scientific point of view, it was already noticed by
Aristotle (384-322 BC) that lizards can regenerate
their tails after amputation. But until the 18th
century this knowledge was mainly anecdotic, and
only with the arrival of the Age of Enlightenment,
regeneration and plasticity will become the matter
of scientific research. In 1712, Réaumur describes
the regeneration of the limbs and claws of crayfish
(Réaumur, 1712); in 1744, Trembley discovers that
a part of the Hydra polyp can regenerate the
complete organism (Trembley, 1744); in 1769,
Spallanzani reports that tadpoles can regenerate
their tails and salamanders their amputated jaws,
limbs and tails (Spallanzani, 1769). The research
performed during most of the 19th
and first half of
Plasticity and Tumorigenicity Campos-Sanchez E, et al.
Atlas Genet Cytogenet Oncol Haematol. 2012; 16(3) 237
the 20th
centuries showed that, for regeneration to
occur, the cells that are normally forming part of
the organs are not sufficient, and a special type of
cells are required: the progenitor cells (Odelberg,
2004; Birnbaum and Sánchez Alvarado, 2008). The
origin of these cells was not very clear (and it is
still a matter of debate and intense research, in fact,
see (Sánchez Alvarado, 2000; Kragl et al., 2009;
Rinkevich et al., 2011)); for some tissues, like skin,
blood, muscles or bones, progenitors were shown to
exist in the tissues in small numbers, and to become
activated as a consequence of the lesions. In other
cases, the progenitors seemed to arise from mature
cells that become dedifferentiated. The best
example supporting this possibility has been
described in primitive vertebrates like the urodeles
(e.g. salamanders and axolotls). In these animals,
after a wound harms the organism, the cells from
the normal tissues form a group of cells known as
the regenerative blastema, which will generate all
the tissues in the new limb/tail (Chalkey, 1954;
Bodemer and Everett, 1959; Hay and Fischman,
1961). It has long been held that the blastema was
the result of cellular dedifferentiation to
progenitors. However, the most recent findings
seem to indicate that there is no cellular
dedifferentiation to progenitors involved in this
process, and the regeneration is always due to the
action of resident tissue-specific stem cells and
progenitors, thus questioning the role of mature
cellular plasticity in tissue regeneration (Kragl et
al., 2009; Rinkevich et al., 2011). We have
therefore seen how the study of "naturally"
occurring regeneration opened the way to a new
understanding of the stem cell-based architecture of
the organs and tissues, especially with the study of
primitive vertebrates. In 1952, amphibians also
provided the first animal model of experimentally-
induced reprogramming when Briggs and King
generated Xenopus tadpoles by transplanting the
nucleus of cells from the blastula into oocytes,
therefore reverting the cellular differentiation
program (Briggs and King, 1952). Afterwards, it
was shown that more differentiated cells, like those
from the intestinal epithelia, could also be
reprogrammed by nuclear transfer (Gurdon, 1962).
These landmark findings undoubtedly showed that
the genetic potential of cells was not lost during
differentiation, and that development did not imply
genetic changes. This principle was extended to
mammals with the cloning of Dolly the sheep in
1997 (Wilmut et al., 1997). This was the ultimate
proof showing that the changes that occur during
differentiation are totally reversible, and
demonstrated that the fate restrictions that take
place during development are the result of
epigenetic modifications. These studies also
showed that there were factors in the oocyte
cytoplasm capable of inducing a reprogramming
that led to the appearance of a totipotent phenotype.
In a parallel way, the search for the molecular
regulators responsible for establishing and
controlling cellular identity led finally to the
identification of the factors capable of
reprogramming cellular fate. In 1987, it was shown
that ectopic expression of the Antennapedia
homeotic gene lead to changes in the body plan of
Drosophila, that got extra legs instead of antennae
(Schneuwly et al., 1987). Also, Gehring et al.
showed that the ectopic expression of eyeless
controlled eye development and led to the
development of ectopic eyes in the fly's legs
(Gehring, 1996). In mammals, the first master
regulator factor to be identified was MyoD, which
was shown to be capable of transdifferentiating
fibroblasts into the myogenic lineage (Davis et al.,
1987). Other examples of factors with fate-
reprogramming capacity are C/EBPα, capable of
mediating the transdifferentiation of mouse B cells
into macrophages (Xie et al., 2004) or Pax5, whose
loss leads to the dedifferentiation of committed B
cells (Nutt et al., 1999; Cobaleda et al., 2007a;
Cobaleda and Busslinger, 2008). All these data
proved that the lack or excess of just one factor
could lead to a radical alteration of the
transcriptional profile and could cause stable fate
changes. This evidence, together with the one
coming from reprogramming by nuclear
transplantation, paved the way to the search for the
factors capable of reprogramming to full
pluripotency that led, in 2006, to the identification
of the four transcription factors capable of inducing
pluripotency in virtually every kind of terminally
differentiated cells (Takahashi and Yamanaka,
2006). We will discuss this aspect with more detail
afterwards.
On the other side, cancer has also been recognized
as a distinct pathological entity since the origins of
mankind. The first references are the Edwin Smith
and Ebers papyri from the 1600 BC and 1500 BC,
approximately (Hajdu, 2004). The Edwin Smith
papyrus contains the first mention and description
of breast cancer, and it concludes that there is no
treatment for the disease. Cancer was not so
common in ancient times, mainly because life span
was much shorter, but it was already clearly
recognized. Hippocrates (460-375 BC) realized that
growing tumors occurred typically in adults and
they reminded him of a moving crab, which led to
the terms carcinos and cancer. Celsus (25 BC-AD
50) also compared cancer with a crab, because it
penetrates the surrounding organs like if it had
claws; Celsus introduced the first classification for
breast cancer and advocated for surgical therapy.
Furthermore, he already realized that tumors could
only be cured if they were removed in their early
stages and that, even after removal and wound
healing, breast carcinomas tended to recur causing
swelling in the armpit and, finally, death by
spreading throughout the body. Galen (131-AD
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200) already recommended surgery by cutting a
wide margin of healthy tissue around the edges of
the tumor (Hajdu, 2004). If we jump now to our
days, it seems disappointing to see how little those
old critical findings have been overcome by modern
medicine, 2000 years later. Indeed, still today, clean
surgical margins and lack of lymph node invasion
are the most important prognostic markers for the
successful eradication of solid tumors, and only if
tumors are completely resected before they
metastasize (something that it is anyhow impossible
to determine with current technologies) can
curation be guaranteed. However, in the last thirty
years we have gained an enormous knowledge
about the molecular biology of the disease. In 1979,
it was shown that the phenotype of transformed
cells could be transferred to normal fibroblasts by
DNA transfection (Shih et al., 1979), a finding that
lead to the rapid molecular cloning of the first
human oncogene (the RAS gene), simultaneously by
several groups (Goldfarb et al., 1982; Lane et al.,
1982; Parada et al., 1982; Santos et al., 1982). Since
then, many genes have been described as being
either oncogenes or tumor suppressors, and the
molecular mechanisms of their transforming
capabilities have been analyzed to great detail, in
close relationship with their functions in "normal"
conditions. This is a field that has expanded
tremendously in the last decades, and a
comprehensive study of the topic falls out of the
scope of this revision. However, there are some
aspects that must be taken into account for posterior
debate. A very important one is the fact that, for
many types of tumors, specific genetic mutations
have been shown to correlate closely with the
phenotype of the tumors, suggesting that the
oncogenic alterations might be acting as new
specification factors that determine the tumor
appearance and/or phenotype. This association is
especially evident in the case of mesenchymal
tumors caused by chromosomal aberrations
(Sánchez-García, 1997; Cobaleda et al., 1998). In
2000, Hanahan and Weinberg summarized the main
features that had to be disrupted in normal cellular
behavior in order for allow a tumor to appear and
progress (Hanahan and Weinberg, 2000), and this
list has expanded with the years (Hanahan and
Weinberg, 2011). These main aspects are related
with the survival and proliferation of cancer cells,
but it must be noted that most of them are equally
shared by non-malignant tumors (Lazebnik, 2010).
However, all the aspects related to the alterations of
the normal developmental regulatory mechanisms
in tumorigenesis have received much less attention.
But in fact, if cellular fate was carved into stone,
cancer would be impossible, since no new lineages
could be generated other than the normal,
physiologic ones. Here is where the normal
mechanisms regulating cellular identity and
plasticity play an essential role in allowing cancers
to arise and hopefully, as we will discuss, they
might be the key to its eradication.
The specification of cellular identity during
development and differentiation is a dynamic
process that starts with stem and progenitor cells
and ends with terminal differentiation into each
specialized cellular type. In this progression there
can be many cellular intermediates; some of them
are transient, and some can be long-lasting, but the
maintenance of cellular identity at each stage is
determined by the signals from the environment
and, in an intrinsic manner, by specific transcription
factors and epigenetic modifiers that establish a
defined chromatin architecture and a specific gene
expression profile.
As we have seen, evidences about cellular plasticity
had being accumulating for decades (Hochedlinger
and Jaenisch, 2006; Gurdon and Melton, 2008; Graf
and Enver, 2009; Vicente-Dueñas et al., 2009a), but
the latest findings in the field of reprogramming
have definitively shown how switching to a
different phenotype can be a lot easier than
previously expected, and can have real
physiological relevance, beyond basic research.
Cancer is a perfect example of pathological
reprogramming in which, from a normal tissue, a
whole new differentiation lineage is opened with its
own hierarchy and structure (Reya et al., 2001;
Sánchez-García et al., 2007). So, without forgetting
the so well-studied aberrant proliferation,
reprogramming is an essential part of the
tumorigenesis process, and it is closely dependent
on the cellular plasticity of the cancer-initiating
cells. The term plasticity, as we will use it here,
refers to the ability of cells (stem or differentiated)
to adopt the biological properties (gene expression
profile, phenotype, etc.) of other differentiated
types of cells (belonging to the same or different
lineages). This definition comprises also the
property of competence, i.e. the ability of stem cells
and progenitors to give rise to their different
descendant lineages during normal development.
We use such an ample definition of the term
precisely to reflect the fact that the molecular
mechanisms that are important for progenitors'
competence during normal development are the
same ones responsible for the plasticity changes of
more differentiated types of cells, both in
pathological processes and in experimentally-
induced reprogramming. Here we will discuss the
vital role of cellular plasticity in the origin and
maintenance of tumoral cells. We will first revise
the latest research discoveries in the fields of
normal developmental and experimentally-induced
plasticity, and afterwards will link these findings
with what we know about cancer biology.
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Atlas Genet Cytogenet Oncol Haematol. 2012; 16(3) 239
Lineage commitment and cellular identity Adult stem cells are the responsible of generating
all the different specialized cellular types forming
the organism. The majority of them perform this
job throughout the whole life of the organism,
thanks to their self-renewal capacity. This property
allows them to divide asymmetrically, therefore
given rise to a new identical daughter stem cell and
to a multipotential progenitor, lacking self-renewal
capacity, which will give rise to all the
differentiated tissue cells. Although it is known that
there are some specific factors that are essential for
the specification and maintenance of stem cell
identity (Boyer et al., 2005), the molecular bases of
the choice that stem cells have to make between
maintaining competence (i.e. plasticity) or entering
into the differentiation programs are not yet
completely understood (Niakan et al., 2010). In this
context, a first important aspect to consider is the
fact that the stem cell population itself is
intrinsically heterogeneous. This means that the
"stemness" is not a static condition defined by
stable, constant levels of expression of intrinsic
stem factors and surface stem markers, but it is
more of a continuum that moves within certain
margins. For example, in a clonal population of
haematopoietic progenitor cells, there is a Gaussian
distribution of the levels of expression of Sca-1,
one of the most classical stem cell markers (Chang
et al., 2008). Furthermore, cells at both the low- or
high-end levels of expression can, when isolated,
regenerate the whole population with all the range
of expression levels. However, every one of these
sub-populations, defined by their levels of a surface
marker, also expresses different transcriptomes, and
has therefore distinct intrinsic differentiation
tendencies towards different lineages. Therefore,
each individual cell in the stem population
represents a metastable transitional point in a
continuum of constantly changing transcriptomes.
In fact, this is most probably the mechanism at the
basis of the stochastic choice of lineage, when some
cells approach too much to the "edges" of the
normal distribution and the transcriptome changes
become irreversible (Chang et al., 2008).
In 1957 Waddington conceptualized the irreversible
process of cellular differentiation as marbles falling
down a slope (Waddington, 1957). This
metaphorical concept has regained new momentum
with the mathematical interpretation of
transcriptional cellular states as Gene Regulatory
Networks (GRNs). In this type of analysis,
pluripotency is represented as a mathematical
attractor (a condition towards which a dynamical
system tends to progress over time), in such a way
that the points (cells) that get close enough to the
attractor remain close even if slightly disturbed.
This attractor is surrounded by a "differentiation
landscape" where other stable cellular fates are
represented by stable "valleys" and differentiation
routes towards them are "channels" through which
the cells move (Enver et al., 2009; Huang, 2009).
Under this light, pluripotency can be considered as
a dynamic state of controlled heterogeneity within a
population, where small individual fluctuations in
the levels of expression of transcription factors and
epigenetic regulators maintain a global status of
apparent stability. The cells that approach the limits
of the attractor (those who, in their random
fluctuations, go too far from the middle point of the
Gaussian curve) are therefore more prone to
differentiate, suggesting that commitment, although
rare, is an spontaneous phenomenon (unless it is
specifically triggered by an external signal that
unbalances the dynamic equilibrium) (Huang,
2009).
Maintenance of cellular identity throughout the differenciation process Although in some rare cases they are unipotent (e.g.
spermatogonial stem cells), adult stem cells are
usually multipotent, and they can give rise to a wide
range of differentiated cell types. In the first
instance, stem cells lose their self-renewal potential
(their stemness) and start the differentiation process
by becoming multipotential progenitors. We have
seen that the differentiation program can be pre-set
already by the oscillatory patterns of gene
expression at the stem cell population level, and
that cells lying at the different ends of specific
gradients of gene expression can have opposite
differentiation preferences (Chang et al., 2008). So,
once they leave the stem cell state, the cells start
making lineage choices that are usually mutually
excluding and are normally conceptualized in a
branching pattern. These alternative options are
usually controlled by the cross-antagonism between
transcription factors with competing, opposing
functions (Swiers et al., 2006; Loose et al., 2007).
A very well characterized developmental system is
hematopoietic differentiation where several models
of lineage-specification have been identified which
seem to be based on the aforementioned
mechanism. For example, the choice between
erythroid/megakaryocyte or myeloid-monocytic
fates at the level of erythromyeloid progenitors is
controlled by the reciprocal inhibition between the
transcription factors GATA-1 and PU.1, therefore
creating a binary decision for the progenitor (Laiosa
et al., 2006; Enver et al., 2009). The bipotent
progenitor itself would therefore be this
intermediate state created and maintained by the
equilibrium between the both factors. This fact
helps understanding the phenomenon of
multilineage gene priming, in which uncommitted
progenitors present low levels of simultaneous
expression of multiple transcription factors
corresponding to different mature cell types and
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Atlas Genet Cytogenet Oncol Haematol. 2012; 16(3) 240
possessing antagonistic functions (Hu et al., 1997;
Enver et al., 2009). In general, there seems to be a
progressive loss of developmental potential in a
hierarchical process that moves through sequential
differentiation options and in which, at any given
point, a progenitor would only have to choose
between two mutually exclusive options (Brown et
al., 2007; Ceredig et al., 2009). Additionally, in the
process of maturation into a given lineage, the
progenitors will receive (and react to) the necessary
extrinsic signals (for example, cytokines) that,
according to this model, would be more permissive
than instructive.
Maintenance of the cellular identity of mature differentiated cells Plasticity, in normal development, is a property that
is "intended" to be restricted to stem cells and
progenitors. In general, the final differentiated
cellular types of any given organ or tissue possesses
stable identities, in consequence with the fact that
they usually are highly specialized cells with very
specific physiological functions. Therefore, it
would not make sense, from the biological point of
view, that a specialized cell would be the source of
other differentiated cell types. This, as we have
mentioned, is the role of stem cells, with their
physiological plasticity (i.e., normal competence)
that we have previously discussed. However, the
concept of the stability of differentiated cell types
has been shaken by the discovery of the fact that the
4 Yamanaka transcription factors (4Y TFs) Oct4,
Sox2, c-Myc and Klf4 (Takahashi and Yamanaka,
2006) are enough for the reprogramming of most
differentiated cells types into induced pluripotent
stem cells (iPSCs). This finding has altered our
notion of the latent developmental potential hidden
in differentiated cells, showing how it can be
"awakened" by experimental manipulations in the
laboratory. This, as we have described, was already
known to a certain extent from the nuclear
reprogramming experiments performed in
amphibians more than 50 years ago (Briggs and
King, 1952; Gurdon, 1962). Nevertheless, although
those experiments already proved that the cell
nucleus could be reprogrammed from a
differentiated cell type into a pluripotent progenitor,
Yamanaka's experiments showed that only 4 factors
were actually enough to make the whole process
possible. We have seen that, a more modest level, it
had already been proven that the overexpression or
loss of individual transcription factors could induce
fate changes in differentiated cells (MyoD, C/EBPa,
Pax5, etc). Although these were examples of
transdifferentiation taking place between closely
related cell types, they already pointed the way for
the search of the factors capable of reprogramming
to full pluripotency. Since the differentiated state is
the more stable one (indicating that the GRNs are
less subject to fluctuation), where the cells have
reached after "rolling down" the differentiation
pathway in the normal process of development,
therefore an "activation energy" is required to move
the cells "uphill" to become again pluripotent.
Conceptually, there are at least two main possible
scenarios to explain the population dynamics in the
process of reprogramming to pluripotency
(Yamanaka, 2009): one possibility (the so-called
elite model) is that only some cells can be
reprogrammed, and these are the ones that are
selected among the entire population, since they are
the only ones that are receptive to the action of the
reprogramming factors. Alternatively, it might
happen that all the differentiated cells are equally
capable of undergoing reprogramming, and it is
only due to technical or methodological reasons
that we are not able to reveal this potential in all of
them (stochastic model). According to the
accumulating evidences, it would seem that the
stochastic model is the one that is closer to reality
and that, given the right combination of factors; any
cell could be reprogrammed to pluripotency
(Yamanaka, 2009). However, as we have
mentioned, this is a developmentally and
energetically unfavourable process, a fact that is
evidenced by several details. The most obvious one
is the very low efficiency of the reprogramming
process, even in the most favourable conditions.
This fact clearly indicates that, independently on
how many cells of the population are initially
responsive to the reprogramming factors, very few
of them can complete the path towards full
reprogramming (Yamanaka, 2009). Also, this is a
gradual process in which several non-physiological
cellular intermediates can be isolated (Mikkelsen et
al., 2008; Stadtfeld et al., 2008). The study of these
incompletely reprogrammed intermediates has
revealed that they have re-activated the self-renewal
and maintenance stem cell genes, but not yet those
of pluripotency; also, these stages of aborted
reprogramming have not been able to completely
repress the expression of lineage-specific
transcription factors and retain persistent DNA
hypermethylation marks as a proof of their failure
in achieving complete epigenetic remodelling
(Mikkelsen et al., 2008). But perhaps the most
patent proof of the difficulty of the process of full
reprogramming to pluripotency is the persistence of
an epigenetic memory in the iPCs that makes them
more prone to re-differentiate into the lineages from
which they were initially derived, indicating that a
complete elimination of the initial epigenetic
program cannot yet be achieved (Kim et al., 2010;
Bar-Nur et al., 2011).
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Atlas Genet Cytogenet Oncol Haematol. 2012; 16(3) 241
Tumoral reprogramming and induction of pluripotency: similarities The role of transcription factors in the control of
tumoral reprogramming and induction of
pluripotency
We have seen in the initial section of this review
that both cancer research and developmental
biology have been the focus of intense attention
since ancient times. What's more, they have always
been closely related from the conceptual point of
view. The cellular theory of Rudolf Virchow is
clearly essential for the understanding of both
development and tumorigenenesis. But he went
further, since he already proposed the embryonal
rest hypothesis of tumour origin, after realising the
histological similarities between tumours and
embryonic tissues (Virchow, 1855). This concept
was afterwards expanded by Julius Conheim, who
suggested that tumours arise from residual
embryonic remnants "lost" during normal
development (Cohnheim, 1867). This hypothesis
actually connects with the current theory of the
cancer stem cells (CSCs) in which progenitors are
situated at the root of cancer maintenance (see
below). Another example of the influence of cancer
research in the progress of the fields of stem cell
biology and developmental biology is the fact that
embryonic stem (ES) cells were identified in a
search that has been initiated in the study of
teratocarcinomas (Solter, 2006; Morange, 2007;
Hochedlinger and Plath, 2009).
In the field of cancer research it has traditionally
been postulated that more than one molecular hit is
required to generate a tumour cell, because several
aspects of cellular biology must be altered in the
progress towards a full-blown tumour (Hanahan
and Weinberg, 2000). Therefore, in order to achieve
tumoral reprogramming (although this was not the
terminology traditionally used), more than one
single molecular alteration had to happen. We have
mentioned before that for a "simple"
transformation, like a lineage switch, the change in
the levels of expression of a single transcription
factor could be enough (Davis et al., 1987; Nutt et
al., 1999; Xie et al., 2004; Cobaleda et al., 2007a).
Similarly, a single initial oncogenic lesion may
contribute to just a part of the tumoral phenotype,
by causing a block in differentiation, or an
alteration in the control of cell cycle. In
oncogenesis, many factors and routes have been
shown to be altered, and their individual
contributions to the tumoral phenotype are clear,
although their synergy and interactions are less
known. In the case of reprogramming to
pluripotency, the discovery of Takahashi and
Yamanaka (Takahashi and Yamanaka, 2006)
revealed the nature of these factors. Before,
reprogramming to pluripotency was only possible
by the use of nuclear transplantation, but it was not
known which of the factors present in the zygote
possessed the required reprogramming capacity.
Interestingly enough, the 4 Yamanaka factors are
known to be involved in tumorigenesis in different
contexts, and both c-Myc and Klf4 are well-known
oncogenes (Rowland et al., 2005; Okita et al., 2007;
Tanaka et al., 2007; Chen et al., 2008), thus further
linking reprogramming to tumorigenesis.
In summary, the experimental results show that the
maintenance of cellular identity is essential for
differentiated cells, and that only strong
transcriptional or epigenetic regulators can subvert
it. In this way, the multistep nature of tumorigenesis
is paralleled by reprogramming to pluripotency in
the series of "uphill" steps required and in the need
for the sum of the effects of several factors to
overcome the built-in safety mechanisms designed
to protect cells from transformation or, in other
words, to prevent cells from changing their identity.
In the case of the reprogramming factors, the
precise role of each of them is not yet clear, but
their experimental introduction at different times
during the process of reprogramming is shedding
some light on this issue (Sridharan et al., 2009), by
identifying distinct contributions of the different
factors along the reprogramming progression. In the
early stages of reprogramming, the most important
process happening is the silencing of the gene
expression programs of the differentiated cells. This
aspect is previous to the induction of the ES-like
expression program, and the main molecular
responsible for this function seems to be c-Myc.
However, it has also been shown that treatment
with histone deacetylase inhibitors like valproic
acid (VPA) can substitute for c-Myc, because of
their capacity for repressing the gene expression
programs of differentiated cells (Huangfu et al.,
2008). Therefore, it would seem that the action of c-
Myc takes place mainly before the activation of the
regulators of the pluripotent state and,
consequently, ectopic expression of c-Myc is
required only during the first few days of the
reprogramming process (Sridharan et al., 2009). In
fact, c-Myc is dispensable for reprogramming, but
in its absence there is an enormous drop in the
efficiency of the procedure (Nakagawa et al., 2008;
Wernig et al., 2008). The other three factors, Oct4,
Sox2, and Klf4, need to act together to achieve the
entry into the pluripotent condition, as evidenced by
the fact that, when they are used individually, they
cannot bind their pluripotent target genes in cells
that are sill incompletely reprogrammed, most
likely because the pattern of epigenetic
modifications at these loci is not permissive for
their binding (Sridharan et al., 2009). Indeed, Oct4,
Sox2, and also Nanog co-bind to a plethora of
genes in overlapping genomic sites (Boyer et al.,
2005; Loh et al., 2006), in such a way that the
transcriptional program required for pluripotency is
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Atlas Genet Cytogenet Oncol Haematol. 2012; 16(3) 242
maintained by the coordinated action of these key
genes.
In general, for the reprogramming of almost every
cell type to pluripotency, the 4 Yamanaka
transcription factors are enough. However, there are
some exceptional cases in which additional
alterations are required. For example, in the case of
mature B cells it is necessary to interfere with the
activity of the transcription factor Pax5, which is
the master regulator of B cell identity (Cobaleda et
al., 2007a; Hanna et al., 2008). Previous
experiments had revealed that the elimination of
Pax5, in the absence of any other genetic
manipulation, allowed mature B cells to
dedifferentiate to early haematopoietic
multipotential progenitors (Cobaleda et al., 2007b).
These findings again correlate reprogramming with
cancer development, since it has also been shown
that the elimination of Pax5 function in mature B
cells induces a process of pathological
dedifferentiation that gives rise to progenitor cell
lymphomas (Cobaleda et al., 2007a). Therefore, the
loss of a transcription factor that is required for the
maintenance of cellular identity can be a tumour-
inducing lesion. However, and contrary to mature B
cells, earlier stages of B cell development can be
reprogrammed to pluripotency in the presence of
functional Pax5, just with the 4 Yamanaka
transcription factors (Hanna et al., 2008), thus
supporting the intuitive idea that the degree of
differentiation of the target cell has an effect on the
final efficiency of reprogramming (see below).
In the genetic landscape, the oncogenic mutations
alter the architecture of the whole gene regulatory
network, since it modifies one of the nodes. This
leads to an alteration in the landscape that gives rise
to new abnormal attractors (new "valleys") where
cancer cells reside (Huang et al., 2009).
Furthermore, this alteration in the landscape gives
the cell a new momentum to move towards new
directions, and this effect can persist even when the
initial stimulus has disappeared. From the point of
view of tumoral reprogramming, this implies that
the expression of a tumour-promoting gene, even if
it is transient, can by itself trigger a durable
malignant phenotype that does not require anymore
of the initial mutation for its maintenance (Huang et
al., 2009).
The role of epigenetic factors in the control of
tumoral reprogramming and induction of
pluripotency
In the previous section we have seen that either the
gain or the loss of function of transcription factors
plays an essential role in reprogramming to
pluripotency, in the same way as how oncogene
overexpression or loss of tumour suppressors
promote tumorigenesis. Also, similarly to tumour
progression, large-scale epigenetic changes are
required for full reprogramming to happen. Today,
it is clearly established that not only genetic
alterations are responsible for cancer development,
but there is also an important role of epigenetic
alterations (Esteller and Herman, 2002; Esteller,
2007; Esteller, 2008) that lead to the specification
of an heritable, abnormal pattern of gene expression
that plays an essential role in cancer initiation and
progression (Ting et al., 2006). All the relevant
epigenetic marks, from DNA methylation to histone
modifications, are perturbed in tumour progression.
The subsequent changes in gene expression patterns
are especially relevant when they affect the levels
of expression of specific oncogenes or tumour
suppressors, but they affect in fact the whole
epigenome, and therefore condition all cellular
identity. All these epigenetic alterations are usually
secondary, and they can be just due to tumour
progression and therefore independent from (i.e.,
not directly caused by) the initiating oncogenic
mutation, but they can also be directly induced by
the first oncogenic event, like it happens when
chromosomal aberrations deregulate histone
modification genes (Esteller, 2008). In the process
of reprogramming to pluripotency, epigenetic
modifications are intrinsically required for the
process to take place, and they have to occur all
throughout the genome, not being just restricted to
the activation or repression of individual genes,
something that is already achieved by the
transcription factors. This explains why the
efficiency of reprogramming is significantly
superior in the presence of chemicals that can
globally interfere with epigenetic marks. For
example, the DNA methyltransferase inhibitor 5-
aza-cytidine (AZA) causes a rapid and stable
transition to a fully reprogrammed iPS state
(Huangfu et al., 2008; Mikkelsen et al., 2008).
Similarly, treatment with valproic acid (VPA), a
histone deacetylase (HDAC) inhibitor, considerably
improves the induction to pluripotency (Huangfu et
al., 2008). Other example is provided by the use of
the compound BIX-01294, an inhibitor of G9a
methyltransferase that makes it possible to achieve
reprogramming to pluripotency using only Oct4 and
Klf4 transcription factors, with an efficiency
comparable to the one obtained when using the four
factors (Shi et al., 2008). In normal development,
the biological role of G9a is to terminate the
pluripotencial state as the progenitors exit to the
differentiation process (Feldman et al., 2006;
Epsztejn-Litman et al., 2008). This is achieved by
its histone methylation activity, that prevents the
reactivation of its target genes (for example
embryonic genes like Oct4) when their
transcriptional repressors are no longer present
(Feldman et al., 2006). Also, at the same time, G9a
promotes DNA methylation, that stops reversion
towards the undifferentiated state (Feldman et al.,
2006; Epsztejn-Litman et al., 2008). Therefore,
genome-wide epigenetic changes affecting many
still unknown loci, are essential in the late stages of
Plasticity and Tumorigenicity Campos-Sanchez E, et al.
Atlas Genet Cytogenet Oncol Haematol. 2012; 16(3) 243
direct reprogramming, and inhibition of the proteins
responsible for generating or maintaining these
marks lowers the "activation energy" required for
the transition to pluripotency. Therefore, it makes
sense that several of the chemical inhibitors that we
have just mentioned are in fact already in use, or in
clinical trials to be used as therapeutic agents
against cancer. AZA was approved by the FDA in
2004 for the treatment of myelodysplastic
syndromes, being the first drug into the new class
of demethylating agents (Kaminskas et al., 2005).
Its mechanism of action is very unspecific, aimed at
the restoration of the normal levels of expression of
genes whose expression has been lost due to
promoter hypermethylation during tumoral
progression, and that might be necessary for the
control of proliferation and differentiation. Like in
the case of most antitumoral drugs, AZA is
expected to affect primarily the tumoral cells and
leave non-proliferative cells unaffected (Sacchi et
al., 1999; Kaminskas et al., 2005). Something
similar happens for HDAC inhibitors (Dey, 2006;
Lane and Chabner, 2009). All these findings
underscore once more the concept of cancer as a
reprogramming disease and a case of wrong
differentiation.
Instructive and permissive factors in the
progression and selection of the processes of
tumoral reprogramming and induction of
pluripotency
We have seen how both genome-wide changes in
epigenetic marks and the loss and/or gain of
transcriptional regulators are essential components
of the processes of tumour generation and
reprogramming to pluripotency. However, it is clear
that these changes are clearly unwanted from the
points of view of normal development and cellular
function. Therefore, cells have developed many
built-in protection mechanisms to maintain their
identity against these transcriptional, genetic and
epigenetic changes. Nevertheless, all these
mechanisms are bypassed, in one way or another
(Hanahan and Weinberg, 2000; Hanahan and
Weinberg, 2011), and cancer appears. How this
happens in "progression to pluripotency" (in
analogy to tumoral progression) is still to be
discovered. However, it has recently been shown by
several groups (Zhao et al., 2008; Banito et al.,
2009; Hong et al., 2009; Kawamura et al., 2009;
Krizhanovsky and Lowe, 2009; Li et al., 2009;
Marión et al., 2009; Utikal et al., 2009) that, exactly
as it happens in cancer progression, the elimination
of the DNA damage control checkpoint (p53-p21)
greatly improves the efficiency of the
reprogramming process, making it possible that
many of the starting cells become successfully
reprogrammed. This is done at the expense of an
increased level of genetic instability, and most of
the iPSCs obtained in the absence of a functional
p53-p21 axis carry genetic aberrations of different
kinds. This is in connection with what we have
mentioned before about reprogramming being an
"uphill", unfavourable process, which most of the
cells fail to complete (Mikkelsen et al., 2008).
Therefore, eliminating the DNA damage checkpoint
diminishes the selection and allows a larger number
of cells to survive until pluripotency. These results
support the idea of cancer as a disease of cellular
differentiation and, furthermore, reinforce the idea
that suggests that the driving forces behind the
tumoral process are aberrantly expressed
transcription factors, epigenetic regulators and
signalling molecules, while the role of many of the
other alterations found in tumours (for example, the
loss of p53) is mainly permissive.
Role of the cell of origin in tumoral reprogramming
and induction of pluripotency
In the study of oncogenesis, it has traditionally been
assumed that the phenotype of the tumour cells was
a reflection of that of the normal cell that gave rise
to the tumour in the first place. There were some
classical examples in which this what not the case
like, for example, chronic myelogenous leukaemia
(CML), where the t(9;22) chromosomal
translocation could be found in most types of
differentiated haematopoietic cells, therefore
indicating that a common, earlier progenitor, should
be the cell of origin (Melo and Barnes, 2007). But,
in general, since most cancerous cells are
reminiscent of some differentiated cell type, for
every type of tumour, the cell of origin was
postulated to be the corresponding normal
differentiated cell. However, the cancer stem cell
(CSC) theory has led to a change in our perspective
(Cobaleda and Sánchez-García, 2009; Vicente-
Dueñas et al., 2009a; Vicente-Dueñas et al., 2009b).
The CSC theory proposes that tumours are stem
cell-based tissues just like any other, and this has
several radical consequences for our understanding
of cancer. The most important one is the fact that
not all the tumoral cells are equally capable of
regenerating the tumour. This means that, when
tumoral cells are experimentally transplanted into a
new host, or when some tumour cells remain in the
patient after incomplete tumour excision, the
reappearance of the tumour is caused by just a
certain tumoral cellular subpopulation. Only those
cells, possessing stem cell characteristics, can give
rise to the whole tumour with all its cellular
heterogeneity. Although there can be a big range of
variability in the percentage of CSCs within a
tumour, from very few to 25% (Quintana et al.,
2008; Cobaleda and Sánchez-García, 2009;
Vicente-Dueñas et al., 2009a; Vicente-Dueñas et
al., 2009b), the fact is that, like in any other stem-
cell based tissue, the majority of cells composing
the tumour mass lack this capacity. Hence, if
tumours are maintained by aberrant cells possessing
stem cell characteristics, then what is the origin of
these cells? This cancer cell-of-origin (not to be
Plasticity and Tumorigenicity Campos-Sanchez E, et al.
Atlas Genet Cytogenet Oncol Haematol. 2012; 16(3) 244
confused with the CSC, which would be the cancer-
maintaining cell of the already developed tumour)
is initially a normal cell (not necessarily a stem cell)
that will be reprogrammed by the oncogenic events
in order to finally originate (or convert into) a
tumoral cell with stem properties. There are two
main mechanisms that could be invoked in this
scenario. One option is that the cell-of-origin
suffering the oncogenic mutation(s) is already a
stem cell, which therefore becomes reprogrammed
to give rise to a new pathological tissue instead of
the normal one. In the case of CML, it has recently
been demonstrated, using genetically modified
mice, that the restricted expression of the oncogenic
alteration in the stem cell/progenitor compartment
is enough to generate a human-like tumour with all
the variety of differentiated tumour cells (Pérez-
Caro et al., 2009; Vicente-Dueñas et al., 2009b). In
mouse models of intestinal cancer it has also been
found that tumours originate in the crypt stem cell,
since when the oncogenic stimulus (activation of
the Wnt signalling pathway) is targeted to the stem
cell compartment, intestinal adenomas develop in
which a developmental hierarchy is maintained. On
the contrary, when the oncogenic lesions are
targeted at the non-stem intestinal epithelial cells,
they only generate short-lived, small
microadenomas (Barker et al., 2008; Zhu et al.,
2008). In the nervous system, targeting
astrocytoma-associated oncogenic lesions to
progenitors (in this case in the subventricular zone)
results in tumour development, while targeting
them to the differentiated cells of the adult
parenchyma does not result in tumours, only in
local astrogliosis (Alcantara Llaguno et al., 2009).
Therefore, there are many examples (Dirks, 2008;
Joseph et al., 2008; Zheng et al., 2008) where it has
been proven that the initiating event takes place in a
normal stem cell, even if the mature tumour is
composed by differentiated cells, indicating a true
tumoral reprogramming mediated by the oncogenic
lesions (Vicente-Dueñas et al., 2009b).
The other alternative is that the cancer cell-of-origin
can be a differentiated cell that regains stem cell
characteristics in the process of tumoral
reprogramming. This option relies on two
requirements: first, the oncogenic alteration must be
capable of conferring or programming these
characteristics in the target cell and, second, the cell
must be plastic enough so as to be reprogrammed
by this precise oncogenic alteration. It has been
shown that some oncogenes, like MOZ-TIF2
(Huntly et al., 2004), MLL-AF9 (Krivtsov et al.,
2006; Somervaille and Cleary, 2006), MLL-ENL
(Cozzio et al., 2003), MLL-GAS (So et al., 2003) or
PML-RARα (Guibal et al., 2009; Wojiski et al.,
2009) can generate CSCs when they are introduced
into committed target cells. Gene expression arrays
have revealed that MLL-AF9 can activate a stem
cell-like program in committed granulocyte-
macrophage progenitors, therefore conferring them
the property of self-renewal (Krivtsov et al., 2006).
Also c-Myc can induce a transcriptional program
reminiscent of that of embryonic stem cells in
differentiated epithelial cells, and originate
epithelial CSCs (Wong et al., 2008). However,
other oncogenes are unable of conferring self-
renewal properties, like for example BCR-
ABLp190 (Huntly et al., 2004). In these cases the
oncogene, since it cannot immediately confer stem
cell properties, could give rise to a precancerous
cell that can afterwards, with the presence of
additional alterations conferring "stemness", give
rise to the cancer stem cell (Chen et al., 2007). In
any case, the cellular origin where the cancer-
initiating lesions take place is difficult to determine
since, in many cases, the functional impact of the
oncogenic lesion (i.e. the tumour clonal expansion)
can present with phenotypes mimicking
differentiation stages that can be either upstream or
downstream of the initiating cell. For example, the
translocations that are the initiating lesions of many
childhood B acute lymphoblastic leukaemias (ALL)
originate in utero during embryonic haematopoiesis
and promote the conversion of partially committed
cells into preleukaemic cells with altered self-
renewal and survival properties, that will require a
second postnatal hit to develop into full leukemias
(Hong et al., 2008). Also, in leukemias carrying the
AML1-ETO translocation, this aberration can be
detected in stem cells in patients in remission.
These stem cells behave apparently normal during
the remission phase, indicating that they can remain
dormant and, with time, some of their descendants
can become tumorigenic and originate the relapse
(Miyamoto et al., 2000). We have described
previously that, in mice, the loss of Pax5 in mature
B cells leads to the dedifferentiation to multipotent
progenitors and the appearance of progenitor B cell
lymphomas (Cobaleda et al., 2007a). In human
Hodking lymphomas, the overexpression of specific
antagonists leads to the functional inactivation of
the B cell factor E2A, which in turn causes the loss
of B cell markers and induces the expression of
lineage-inappropriate genes characteristic of the
Reed-Sternberg Hodking lymphoma cells (Mathas
et al., 2006). Also in children's B-ALLs, the CSCs
can present with the phenotypes of different stages
of early B cell development that, on top of that, can
apparently interconvert among them, therefore
complicating even more the task of identifying the
cancer-cell of origin (le Viseur et al., 2008). A
genomic analysis of samples from relapsed ALL
patients, when compared with the samples at
diagnosis, has shown that the same ancestral clone
can be found at both stages of the disease
(Mullighan et al., 2008). So, clearly in many cases
the cancer-maintaining cell evolves over time and
adapts to treatment to finally lead to relapse, and
therefore the characteristics of the CSC population
Plasticity and Tumorigenicity Campos-Sanchez E, et al.
Atlas Genet Cytogenet Oncol Haematol. 2012; 16(3) 245
in a certain moment may not relate at all any more
to those of the initial cancer cell-of-origin (Barabé
et al., 2007).
As we already mentioned when we described the
view of reprogramming to pluripotency from the
perspective of the GRNs, the inducing factors are
not required anymore once the cells have reached
the pluripotent condition and the new identity
(however plastic this is) has been established. If
cancer stem cells are generated by a tumoral
reprogramming process, then maybe the oncogenes
that initiate tumour formation might be not be
required for tumour progression (Krizhanovsky and
Lowe, 2009). If this were the case, it would explain
the aforementioned examples in which a pre-
cancerous lesion exists stably in an aberrant cell
population that does only evolve to an open tumour
when secondary mutations occur. In this scenario,
the initiating lesion would be the driving force in
the reprogramming process, but once this has been
completed, it would only be a passenger mutation,
or could even perform a different role that would be
independent from its reprogramming capacity, like
for example in tumour expansion/proliferation. A
mechanism of this kind would explain why some
targeted therapies fail in spite of their initial
apparent efficacy: for example, imatinib, a drug
targeted against the deregulated kinase activity of
BCR-ABL, successfully eliminates differentiated
tumour cells, but it fails to kill the BCR-ABL+
CSCs, since it does not seem to interfere with the
function of the chimeric oncogene in this cellular
context (Graham et al., 2002; Barnes and Melo,
2006).
The fact that CSCs can originate from differentiated
cells represents the last and most patent similarity
between tumorigenesis and reprogramming to
pluripotency. Also in iPSCs generation, the nature
of the cell of origin is key in determining the global
success. In this way, it has been described that, in
the haematopoietic system, the capacity of
reprogramming cells decreases as they differentiate,
since HSC are 300 times more likely to be
reprogrammed than B or T cells (Eminli et al.,
2009). In the case of the nervous system, when the
starting cells are adult neural stem cells (NSCs),
then pluripotency can be achieved using only Oct4
(Kim et al., 2009), probably because of the high
similarity of NSCs transcriptional profile to that of
ES cells. Similarly, in a liver model of
transdetermination it has been demonstrated that
Neurogenin3 can convert hepatic progenitor cells
into neo-islets but it cannot transdifferentiate
mature hepatocytes (Yechoor et al., 2009).
Outlook The knowledge obtained in the research of the
molecular and cellular mechanisms that control
cellular plasticity, pluripotency and reprogramming
will also have a profound impact in our
understanding of tumorigenesis and, in a more
distant future, in the treatment of cancer. It is clear
that the two fields of research will continue being
mutually interdependent. By way of example, the
main obstacle for the future use of iPSCs in the
clinic is precisely the generation of tumours as a
result of uncontrolled growth or differentiation of
the cells, once they are in the patient. Therefore, the
knowledge and control of the narrow limits of gene
expression that mark the difference between normal
and tumoral differentiation and reprogramming will
be required before this problem can be overcome.
Assuming the role that reprogramming plays in
cancer generation makes it possible to initiate the
development of new therapeutic strategies aimed at
re-directing the wrong differentiation program
towards a new outcome (ideally, in most cases,
terminal non-tumoral differentiation and cellular
death). Differentiation therapies are already in use
in some cases, like the administration of retinoic
acid to differentiate tumoral cells in PML-RARα+
positive acute promyelocytic leukemias. We have
described how reprogramming to pluripotency, due
to its inefficiency, can get caught up at several
points before reaching the iPSC state (Mikkelsen et
al., 2008). Tumoral cells are probably very close to
these incompletely reprogrammed intermediates,
and the study of the latter should help us in
understanding how to get the former ones out of
their pathologic block. In fact, epigenetic therapies
are most probably going to be on the rise in the
coming years for the treatment of many types of
tumours, since our knowledge about the molecular
mechanisms controlling the epigenetic marks and
their role in self-renewal, differentiation and
maintenance is increasing very quickly, and this
should help us to obtain more and better (more
specific) epigenetic drugs (Jones, 2007; Shen et al.,
2009).
The discovery of reprogramming to pluripotency
has transfigured the research in the field of cellular
plasticity. It is nowadays possible, using just three
ectopic factors, to reprogram fibroblasts into
functional neurons (Vierbuchen et al., 2010), to
convert in vivo pancreatic exocrine cells to β cells
(Zhou et al., 2008) or to directly transdifferentiate
mouse mesoderm into heart tissue (Takeuchi and
Bruneau, 2009). One of the most remarkable
examples in this context is the phenotype caused by
the deletion of a single gene, Foxl2, in adult ovarian
follicles. This inactivation immediately upregulates
testis-specific genes and leads to a full organ
reprogramming (Uhlenhaut et al., 2009) that shows
that the maintenance of the identity of the ovarian
cells requires the active and constant presence of a
specific gene. This is therefore an active process
that resembles very much what we have described
for Pax5 and B cells, but affecting a whole organ
with all its cellular diversity.
Our increasing knowledge and technical control
over cellular identity should help us in the
Plasticity and Tumorigenicity Campos-Sanchez E, et al.
Atlas Genet Cytogenet Oncol Haematol. 2012; 16(3) 246
development of strategies for the reprogramming of
tumoral cells. In fact, several experimental
evidences seem to suggest that this is perfectly
possible. For example, melanoma cells can be
reprogrammed by nuclear transplantation
(Hochedlinger et al., 2004). Also, embryonal
carcinoma cells or mouse brain tumours have been
used as a valid starting material for nuclear cloning
experiments (Li et al., 2003; Blelloch et al., 2004).
Therefore, maybe in a not so distant future we
might have the knowledge and tools to manipulate
tumoral cell identity to force cancer cells to
differentiate, or to make them vulnerable to therapy.
Acknowledgments Research in C.C. lab was partially supported by
FEDER, Fondo de Investigaciones Sanitarias
(PI080164), CSIC P.I.E. 200920I055 and
201120E060, from the ARIMMORA project (FP7-
ENV-2011, European Union Seventh Framework
Program) and from an institutional grant from the
"Fundación Ramón Areces". Research in ISG group
was partially supported by FEDER and by MICINN
(SAF2009-08803 to ISG), by Junta de Castilla y
León (REF. CSI007A11-2 and Proyecto
Biomedicina 2009-2010), by MEC OncoBIO
Consolider-Ingenio 2010 (Ref. CSD2007-0017), by
NIH grant (R01 CA109335-04A1), by Sandra
Ibarra Foundation, by Group of Excellence Grant
(GR15) from Junta de Castilla y Leon, and the
ARIMMORA project (FP7-ENV-2011, European
Union Seventh Framework Program) and by
"Proyecto en Red de Investigación en Celulas
Madre Tumorales en Cancer de Mama", supported
by Obra Social Kutxa y Conserjería de Sanidad de
la Junta de Castilla y León. All Spanish funding is
co-sponsored by the European Union FEDER
program. ISG is an API lab of the EuroSyStem
project. ECS is the recipient of a JAE-predoc
Fellowship from CSIC and a "Residencia de
Estudiantes" Fellowship. The authors declare no
conflict of interest.
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This article should be referenced as such:
Campos-Sanchez E, Sanchez-Garcia I, Cobaleda C. Plasticity and Tumorigenicity. Atlas Genet Cytogenet Oncol Haematol. 2012; 16(3):236-250.
Deep Insight Section
Atlas Genet Cytogenet Oncol Haematol. 2012; 16(3) 251
Atlas of Genetics and Cytogenetics in Oncology and Haematology
OPEN ACCESS JOURNAL AT INIST-CNRS
Vacuolar H(+)-ATPase in Cancer Cells: Structure and Function Xiaodong Lu, Wenxin Qin
School of Medical Science and Laboratory Medicine, Jiangsu University, China (XL), State Key
Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai
Jiao Tong University School of Medicine, China (WQ)
Published in Atlas Database: September 2011
Online updated version : http://AtlasGeneticsOncology.org/Deep/V-ATPaseInCancerID20104.html Printable original version : http://documents.irevues.inist.fr/bitstream/DOI V-ATPaseInCancerID20104.txt This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2012 Atlas of Genetics and Cytogenetics in Oncology and Haematology
Vacuolar H+-ATPase (V-ATPase) is a highly
evolutionarily conserved enzyme, which is
distributed within the plasma membranes and the
membranes of some organelles such as endosome,
lysosome and secretory vesicle. The mayor function
of V-ATPase is to pump protons across the cell
membrane to extracellular milieu or across the
organelle membrane to intracellular compartments.
V-ATPases located in cell surface act as important
proton transporters that regulate the cytosolic pH to
~7.0 which is essential for most physiological
processes, whereas V-ATPases within intracellular
membrane are involved in cellular processes as
receptor-mediated endocytosis, membrane
trafficking, protein processing or degradation, and
nutrients uptake (Nishi et al., 2002; Forgac et al.,
2007; Toei et al., 2010; Cruciat et al., 2010).
Malfunctioned V-ATPase is closely related to
several diseases including tumor. More and more
evidences indicate that V-ATPase is an enhancer
for carcinogenesis and cancer progression, such as
malignant transformation, growth and proliferation,
invasion and metastasis, acquirement of multi-drug
resistance, etc., which strongly supports that V-
ATPase should be an effective target of anticancer
strategy (Fais et al., 2007).
The structure of V-ATPases and its expression in tumor cells The molecular structure of normal V-ATPase of
yeast and mammalian cells has been well studied.
V-ATPase is a delicate complex which is composed
of a cytosolic catalytic domain V1 and an integral
domain V0, the former responsible for ATP
hydrolysis and the latter providing
transmembraneous proton channel (Nishi et al.,
2002; Yokoyama et al., 2005; Wang al., 2007). The
core of the V1 section is composed of a hexameric
arrangement of alternating A and B subunits, which
participate in ATP binding and hydrolysis. Other
subunits of V1 include three copies of E and G
subunits which are the stator, one copy of the
regulatory C and H subunits, one copy of subunits
D and F which form a central rotor axle. The V0
section includes a ring of proteolipid subunits (c, c'
and c") that are adjacent to subunits a and e.
Subunits D and F of V1 and subunit a of V0 form
the central stalk, whereas the multiple peripheral
stalks are composed of subunits C, E, G, H and the
N-terminal domain of subunit a. V1 and V0 is
connected by both stalks. Several subunits like a, d,
e, C, G, H, D and F contain slice variants as to
spatial and temporal expression pattern in different
cell types (Forgac et al., 2007; Miranda et al.,
2010). As for tumor cells, especially those with
high metastatic potential, the V-ATPases are
usually excessively agitated. The altered structures
of V-ATPase of tumor cells may include the
increased level of subunit expressions and unique
spliced variants of some subunits.
The level of the subunit c expression was found to
be related to the metastasis potentials in tumors.
One of the studies is the comparison of subunit c
expression between normal and pancreatic
carcinoma tissues and between invasive and non-
invasive pancreatic cancers, which
immunohistochemical data showed the notable
difference - 92% invasive ductal cancers (42/46)
Vacuolar H(+)-ATPase in Cancer Cells: Structure and Function
Lu X, Qin W
Atlas Genet Cytogenet Oncol Haematol. 2012; 16(3) 252
were mild to marked subunit c positive in the
cytoplasm, whereas neither non-invasive ductal
cancers nor benign cystic neoplasms expressed
detectable immunoreactive proteins (Ohta et al.,
1996). Subunit c seems to be one of the V-ATPase
subunit which significantly influence the
proliferation and metastasis of tumor cells. The
inhibition of the V-ATPase subunit c via siRNA
resulted in the suppression of growth and metastasis
of a hepatocellular carcinoma cell line in vitro and
in mice model (Lu et al., 2005), which is according
to another result of the suppression of subunit c in
Hela cell via antisense oligonucleotides (Zhan et al.,
2003). But in oral squamous cell carcinoma cells,
subunit C1 was the most strongly over-expressed
gene at the mRNA level compared to other genes of
the V-ATPase complex (Otero-Rey et al., 2008).
Specific spliced variants of subunit have been
observed in tumors. A study of expression of
subunit a of V-ATPase in breast cancer cell lines
displayed the metastasis-specific subunit a isoform
expression profile. In highly metastatic breast
cancer cell line compared with its lowly metastatic
parallel, levels of a3 and a4 were much higher
although all the four a isoforms - a1-4 can be
detectable. They distribute differently, and
especially, a4-containing v-ATPases were located
mainly in the plasma membrane of higher
metastatic breast cancer cell, seeming to be
involved in the formation of the leading surface of
the cells due to the combination with F-actin and
closely correlated to the potency of invasion. a3-
containing V-ATPases were located in intracellular
compartment membrane, which regulated the pH of
the cytosol and intracellular compartments and also
involved in invasion (Hinton et al., 2009). In
accordance with this data, the strongly expressed a3
isoform were observed in high-metastatic
melanoma cells and in bone metastases (Nishisho et
al., 2011). Other tumor-relevant spliced variants are
yet to be found.
The roles of the v-ATPase in the growth, proliferation or apoptosis in tumor cells One of cancer hallmarks is the shift in energy
production from oxidative phosphorylation to
aerobic glycolysis, ie "Warburg effect", which
produces excess intracellular acidosis (Gillies et al.,
2008). However, cancer cells usually have neutral
to alkaline intracellular pH in the acidized
extracellular microenvironment. The V-ATPase is
among the four major types of pH regulators (the
other three are: Na+/H+ exchangers, bicarbonate
transporters, proton/lactate symporters). Much data
implies proton pump is essential in tumors and cells
seem to render V-ATPases more than any other
three transporters to regulate pH in cytosol (Torigoe
et al., 2002). The ability to extrude intracellular
protons and maintain the cytosol pH is critical for
cancer cell survival from a cascade of self-digestion
triggered by acidosis.
The inhibition of v-ATPase may induce apoptotic
cell death in several human cancer cell lines
including pancreatic cancer (Ohta et al., 1998;
Hayash et al., 2006), liver cancer (Morimura et al.,
2008), gastric cancer (Nakashima et al., 2003), B-
cell hybridoma cells (Nishihara et al., 1995; De
Milito et al., 2007) and breast cancer (McHenry et
al., 2010).The deficiency of V-ATPase will
decrease cytosol pH and increased lysosome pH,
both of which might influence lysosome function.
The apoptosis induced by V-ATPase inhibitors
were in either lysosome-mediated or non-lysosome-
mediated manner. In the first case, when lysosomal
V-ATPase was defected, lysosomal pH and
permeability will be increased, resulted in the
release of cathepsin D and activation of caspase,
with no significant impact on mitochondrial
transmembrane potential (Nakashima et al., 2003).
In the other case, mitochondria and lysosome might
be together involved in V-ATPase-inhibitor-
induced apoptosis via capsase pathway or ROS-
dependant manner (Ishisaki et al., 1999; De Milito
et al., 2007). The inhibition of V-ATPase could also
induce apoptosis by suppressing anti-apoptotic Bcl-
2 or Bcl-xL and facilitate the caspase-independent
apoptotic pathway (Sasazawa et al., 2009). In order
to survive from the apoptosis induced by acidosis
resulted from glycolysis, tumor cells needs to
extrude excessive acid, in which processes V-
ATPase plays a crucial role. It is reasonable to
postulate that the inhibition of proton extrusion may
be more susceptible or vulnerable to cell death of
cancer cells than normal cells.
Moreover, the slightly alkalized cytosolic pH favors
the growth and proliferation of the cells. Some
glycolysis-related enzymes or oncogenes are
sensitive the narrow range of pH alteration.
Alkalization of cytosol, which mainly regulated by
V-ATPase in tumor cells, could activate glycolysis
whereas repress oxidative phosphorylation,
meanwhile also promote the transcription of
oncogenes like HIF-1, akt, myc, ras, etc (Gillies et
al., 2008; López-Lázaro, 2008). The cytosol pH of
tumor cells was found to be higher than in
untransformed controls (Busa et al.,1984; Casey et
al., 2010) and increasing cytosol pH was sufficient
to confer tumourigenicity to cultured fibroblasts
(Perona et al., 1988). On the contrast, p53, the
important tumor suppressor could be inactivated in
the condition of alkalization (Xiao et al., 2003). It is
much likely that the glucose metabolism shift and
mutant V-ATPase may be the co-selectors in
selecting those "adaptive phenotype", which may
take the advantages for survival and proliferation
during the initial stage of carcinogenesis.
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Lu X, Qin W
Atlas Genet Cytogenet Oncol Haematol. 2012; 16(3) 253
The functions of the v-ATPase in cellular signals processing V-ATPase is the important factor that regulates the
process of internization and activation of cellular
signals. It is mainly due that the V-ATPase is the
main contributor of low intracellular vesicles pH,
which is essential for various membrane traffic
processes. V-ATPase activity influence endocytosis
and degradation of molecule-receptor complex,
recycling of the released receptor, recruitment of
signal molecules, and their proper spatial
intracellular distributions (Hurtado-Lorenzo et al.,
2006; Marshansky et al., 2008), therefore exerts a
profound effect on cell behavior such as growth,
proliferation or metastasis via the modulated signals
and their pathways. It has been reported that tumor-
associated m-TOR (mammalian target of
rapamycin) (O'Callaghan et al., 2009), Notch
(Fortini and Bilder, 2009; Vaccari et al., 2010) or
Wnt (Cruciat et al., 2010; Buechling et al., 2010)
could be regulated by V-ATPase.
Early endosomes are important sites for signal
molecules internalization and activation in
mammalian cells. Studies of the effects of V-
ATPases inhibitors on isolated rat hepatocytes and
rat sinusoidal endothelial cells suggested that the
pH gradient between the endocytic compartments
and the cytoplasm was necessary for the receptor-
mediated endocytosis (Harada et al., 1996; Harada
et al., 1997). Inhibition of V-ATPases can retard
recycling of transferrin receptor (Presley et al.,
1997), impair the formation of endosomal carrier
vesicle (Clague et al., 1994), and inhibit late
endosome-lysosome fusion (van Weert et al.,
1995). Although the significance of active V-
ATPase in signal molecules endocytosis and
processing on the behavior of tumor cells is not yet
full elucidated for most data was gained from yeast
or normal mammalian cells, it could be
hypothesized that V-ATPase might regulate some
signal pathways via modulating the recycling rate
of receptor, which would be responsible for the
sensitivity of tumor cells to some signal molecules,
ie, the faster rate at which the receptor cycling in a
V-ATPase-regulated membrane trafficking, the
more efficiently the cells render the receptors, the
more signal molecules could be recruited, and the
stronger or more lasting response to the stimulation
by the signal molecules could be expected.
For example, the activation of Notch, a common
hallmark of an increasing number of cancers (Miele
et al., 2006; Roy et al., 2007), is involved in V-
ATPase-associated endosomal system (Yan et al.,
2009; Vaccari et al., 2010). V-ATPase activity is
required for Notch signaling. In V-ATPase mutant
cells, Notch and its receptors are trapped in an
expanded lysosome-like compartment, where they
accumulate rather than being degraded and a
substantial reduction expression in downstream
gene of notch. V-ATPase regulates Notch via: i)
endocytosis of Notch, for acidification of earlier
endosomal compartments is required in this process
and a reduced rate of Notch endocytosis was found
in V-ATPase mutant cells ii) endosomal cleavage
patterns of the protease that degrade the Notch in
the accordingly forms, each of which process
exerting its own activating potency (Vaccari et al.,
2010) iii) regulating endosome-lysosome fusion
and Notch intracellular re-distribution or the
targeting to cell surface.
The V-ATPase-associated signal molecules
processing itself may also be regulated by
endosomal protein, for example, HRG-1(heme-
regulated genes), a downstream gene of IGF-I
(insulin-like growth factor) and having an
interaction with subunit c. HRG-1 could promote
endosomal acidification and receptor trafficking,
enhance the proliferative and invasive phenotype of
cancer cells. It was implied that the increased active
V-ATPase by HRG-1 not only regulate the
endocytosis and degradation of receptors that
promote signaling for survival, growth, and
migration of cancer tumor, but also facilitate
micronutrient uptake necessary for tumor cellular
metabolism (O'Callaghan et al., 2009).
The contributions of the V-ATPase in cancer metastasis Invasion and metastasis is the relatively late event
of development of malignant cells, which is the
continuous process of breaking through the
basement membrane, degrading extracellular
matrix, angiogenesis, invading vascular system and
redistributing in the distinct host sites. The
activation of the proteases which break down
extracellular matrix is required during the
procedure. The invasive phenotype is closely
related to its highly active V-ATPase. It has been
reported that the improper activated V-ATPases
correlates with an invasive phenotype of several
types of tumors, including breast cancer (Sennoune
et al., 2004; Hinton et al., 2009), pancreatic cancer
(Chung et al., 2011) and melanoma (Nishisho et al.,
2011). The tumor metastasis can be suppressed in
vitro or in animal model by the inhibition of V-
ATPase inhibitors or siRNA (Lu et al., 2005;
Hinton et al., 2009; Supino et al., 2008). Subunit a
isoform and c seem to be important factors in
regulating the metastasis of cancer.
The main mechanisms by which overly active V-
ATPases enhance the tumor invasion and metastasis
may be that the extracellular milieu is acidized and
it is suitable for optimal pH of proteases that
degenerate extracellular matrix (ECM). The plasma
membrane V-ATPases is responsible for pumping
cytosol protons to the extracellular space resulting
in a low extracelluar pH, which is required for the
activation of several types of proteases including
cathepsins, metalloproteases, and gelatinases. V-
ATPase may influence the expression of proteases
Vacuolar H(+)-ATPase in Cancer Cells: Structure and Function
Lu X, Qin W
Atlas Genet Cytogenet Oncol Haematol. 2012; 16(3) 254
directly independent of the whole enzyme V-
ATPase function. For example, transfectants which
over express V-ATPase subunit c at the mRNA
level showed an enhance invasiveness in vitro with
a concomitant increases in secretion of matrix
metalloproteinase-2 (Kubota et al., 2000). V-
ATPase may also regulate metastasis by enhancing
proteases activation. Cathepsin is an example,
which is secreted by several types of tumor cells
and related to invasion. Once the extracellular
cathepsin is activated, it can both degrade
extracellular matrix proteins and activate other
secreted proteases involved in invasion, such as
matrix metalloprotease (Joyce et al., 2004; Gocheva
et al., 2007) and gelatinases (Martínez-Zaguilá et
al., 1996). The plasma membrane V-ATPase
appeared to be recruited at the proceeding edge of
the cancer cell by the interaction with F-actin so as
to give rise an acidic microenvironment by the edge
(Hinton et al., 2009). Moreover, intracellular V-
ATPases, the major contributor of acidity of
intracellular compartment and membrane
trafficking regulator, also facilitate in the invasion
and metastasis, which is due to possible modulating
proteolytic activation of cathepsins or matrix
metalloproteases within lysosomes or secretory
vesicles and targeting the proteases-containing
secretory vesicles to the cell surface to be
extracytosed (Hinton et al., 2009). The
accumulation of acidity, concentration of plasma
membrane V-ATPase and activated protease crown
the proceeding surface of a metastatic cell,
conferring the tumor cell a "cutting edge".
Mobility is crucial for spread of tumor cells to the
distant sites. NiK-12192, one of V-ATPase
inhibitor was shown able to reduce the
migration/invasion of human lung cancer cells in
vitro and significantly reduce the number of
spontaneous metastases in the lung of nude mice
implanted with a human lung carcinoma. After the
treatment of NiK-12192, the lung cancer cells in
vitro showed that actin fibers were broken, spots of
aggregation were evident and no pseudopodia and
regular structure for actin filaments could be seen,
comparing to the control cells with long and regular
fibers of tubulin in the cell cytoplasm and filaments
of actin forming pseudopodia. NiK-12192-treated
cells also demonstrate a reduction in the experiment
of wound healing assay due to the retard of
migration (Supino et al., 2008). V-ATPase subunit
B and C appear to contain the binding sites to the
actin cytoskeleton (Vitavska et al., 2003; Vitavska
et al., 2005; Zuo et al., 2006). The interactions
between V-ATPase and cytoskeleton implicate their
involvement and regulation of cell mobility and
membrane trafficking (Sun-Wada et al., 2009).
Angiogenesis, a consequence of the mutual
interaction between cancer cells and the stoma cells
of extracellular microenvironments, is another
important step during metastasis, during which
process, endothelial cells is mainly involved. It was
documented that V- ATPases play a crucial role in
growth and phenotypic modulation of
myofibroblasts that contribute to neointimal
formation in cultured human saphenous vein (Otani
et al., 2000) The microvascular endothelial cells in
tumor tissue also incline to render plasma
membrane V-ATPase to cope with the acidic
extracellular environment. The ability of migration
of endothelial cell toward the adjacent tissue is
required during angiogenesis, in which process V-
ATPase plays a role, shown in the result that the
penetration of basement membrane of endothelial
cell was suppressed by bafilomycin treatment
(Rojas et al., 2006).
The relations of V-ATPase and drug resistance in cancer Acquired multidrug resistance (MDR) can limit
therapeutic potential and one of the reasons of
relapse. It is well known that MDR is correlate to
the evolutionarily conserved family of the ATP
binding cassette (ABC) proteins pg, yet it is
documented that V-ATPase plays a role in MDR in
a pg-independent manner, and the inhibition of V-
ATPase could not only suppress tumor cells
directly, but also sensitize the tumor cells to the
chemical therapy (De Milito et al., 2005). It was
documented that proton pump inhibitor (PPI)
pretreatment sensitized tumor cell lines to the
effects of cisplatin, 5-fluorouracil, and vinblastine
significantly. PPI treatment will increases both
extracellular pH and the pH of lysosomal
organelles, which induced a marked increase in the
cytoplasmic retention of the cytotoxic drugs, with
clear targeting to the nucleus in the case of
doxorubicin. In vivo experiments, oral pretreatment
with omeprazole was able to induce sensitivity of
human solid tumors to cisplatin (Lucian et al.,
2004).
V-ATPase renders several mechanisms of
multidrug resistance including: neutralized drug
extracellularly or intracellularly, decreased drug
internalization, altered DNA repair and inhibition of
apoptosis. The pH of the tumor microenvironment
may influence the uptake of anticancer drugs.
Molecules diffuse passively across the cell
membrane most efficiently in the uncharged form.
Because the extracellular pH in tumors is low and
the intracellular pH of tumor cells is neutral to
alkaline, weakly basic drugs that have an acid
dissociation constant of 7.5-9.5, such as
doxorubicin, mitoxantrone, vincristine, and
vinblastine, are protonated and display decreased
cellular uptake (Raghunand et al., 1999; Gerweck et
al., 2006; McCarty and Whitaker, 2010). The data
in vitro or in animal models indicates that
extracellular alkalinization leads to substantial
improvement in the therapeutic effectiveness of
antitumor drugs via enhanced the cellular drug
Vacuolar H(+)-ATPase in Cancer Cells: Structure and Function
Lu X, Qin W
Atlas Genet Cytogenet Oncol Haematol. 2012; 16(3) 255
The roles of V-ATPase in cancer cells. 1) Protons produced by glycolysis are pumped by plasma membrane V-ATPase (green
circle: V0; blue circle: V1) which prevents the cell from acidosis-induced apoptosis and the slightly basic of cytosolic pH enhanced cell growth and proliferation; 2) Acidification of secretary vesicle, which is maintained by intracellular V-ATPase, is essential for protease secretion and activation (orange bars: active form; orange-red bars: inactive forms of protease). The
interaction between V-ATPase and actin (green wave line) may contribute the recruitment of V-ATPase on plasma membrane. The accumulation of V-ATPase on the plasma membrane, the extracellular acidic-microenvironment and activated-protease
appear to crown the tumor cell, conferring it a "cutting edge" at the proceeding surface which facilitates invasion and metastasis. Moreover, in acidic microenvironment, angiogenesis is enhanced; 3) V-ATPases might regulate signal pathway via controlling
international of signal molecules (red circle), releasing and recycling the receptors, and processing signal molecules. Therefore, V-ATPases may exert effects on cell behavior via signal pathway; 4) V-ATPases contributes to acquirement of resistance of
anticancer drug (green square) supported by the data that inhibition of V-ATPase sensitize the tumor cells to chemical therapy, which is partly due to the increased influx of anticancer drug when in a basic extracellular condition.
uptake and cytotoxicity (Gerweck et al., 2006;
Trédan et al., 2007).The reduced intracellular
accumulation of anticancer drugs may also be due
that V-ATPase has a role as cooperating factor of
ATP-dependent membrane proteins that function as
drug efflux pumps (Raghunand et al., 1999).
Interestingly, the levels of V-ATPase subunit
expressions can be up-regulated by anticancer drug.
The treatment of cisplatin on human epidermoid
cancer KB cells increased the protein levels of the
majority of the subunits such as c, c", D, a, A, C
and E, which indicates it may stimulate the
expression of the V-ATPase complex as a whole. It
is suggested that the V-ATPase expression may be
a defensive response to the anticancer drug
(Murakami et al., 2001; Torigoe et al., 2002). Still,
there are also some controversial results on the
relationship between the cationic drugs uptake and
V-ATPase - the inhibition of V-ATPase decreased
the uptake of the cationic drugs (Morissette et al.,
2009; Marceau et al., 2009), which might be
explained that the influence of V-ATPase on the
drug uptake may also be depend upon the
characteristics of the drugs and its relation to
membrane trafficking.
That the defects of V-ATPase increase the
sensitivity to drugs may be partly due to the
decreased cytosolic pH, which were observed in the
influence of cisplatin on the V-ATPase mutant
yeast Saccharomyces cerevisiae (Liao et al., 2006)
or increased toxicity of combined treatment of V-
ATPase inhibition and anticancer drug on lung
cancer cell, breast cancer or liver cancer cell lines
(Wong et al., 2005; Farina et al., 2006; You et al.,
2009). At low cytosolic pH, sensitivity to DNA
damaging drugs or UV irradiation in V-ATPase
mutants may be associated with altered DNA
conformation or defective DNA damage repair
mechanisms, rendering DNA more prone to
damage (Robinson et al., 1992; Petrangolini et al.,
2006; Liao et al., 2006).
Conclusions According to the roles V-ATPase in tumor cells, we
conclude that alteration of V-ATPase is much likely
the necessary initial step of transformation of the
malignant cells and the malfunctional V-ATPase
acts as a continual enhancer of carcinogenesis and
tumor progression. Tumor cells take the advantages
of disfunctioned plasma and intracellular V-ATPase
in these aspects: enhanced proliferation and growth,
Vacuolar H(+)-ATPase in Cancer Cells: Structure and Function
Lu X, Qin W
Atlas Genet Cytogenet Oncol Haematol. 2012; 16(3) 256
evading apoptosis, facilitating metastasis and
angiogenesis, and acquirement of the drug
resistance. V-ATPase will be a prospective
candidate for cancer diagnosis and treatment.
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Hinton A, Sennoune SR, Bond S, Fang M, Reuveni M, Sahagian GG, Jay D, Martinez-Zaguilan R, Forgac M. Function of a subunit isoforms of the V-ATPase in pH homeostasis and in vitro invasion of MDA-MB231 human breast cancer cells. J Biol Chem. 2009 Jun 12;284(24):16400-8
Marceau F, Bawolak MT, Bouthillier J, Morissette G. Vacuolar ATPase-mediated cellular concentration and retention of quinacrine: a model for the distribution of lipophilic cationic drugs to autophagic vacuoles. Drug Metab Dispos. 2009 Dec;37(12):2271-4
Morissette G, Ammoury A, Rusu D, Marguery MC, Lodge R, Poubelle PE, Marceau F. Intracellular sequestration of amiodarone: role of vacuolar ATPase and macroautophagic transition of the resulting vacuolar cytopathology. Br J Pharmacol. 2009 Aug;157(8):1531-40
Sasazawa Y, Futamura Y, Tashiro E, Imoto M. Vacuolar H+-ATPase inhibitors overcome Bcl-xL-mediated chemoresistance through restoration of a caspase-independent apoptotic pathway. Cancer Sci. 2009 Aug;100(8):1460-7
Sun-Wada GH, Tabata H, Kawamura N, Aoyama M, Wada Y. Direct recruitment of H+-ATPase from lysosomes for phagosomal acidification. J Cell Sci. 2009 Jul 15;122(Pt 14):2504-13
Yan Y, Denef N, Schüpbach T. The vacuolar proton pump, V-ATPase, is required for notch signaling and endosomal trafficking in Drosophila. Dev Cell. 2009 Sep;17(3):387-402
You H, Jin J, Shu H, Yu B, De Milito A, Lozupone F, Deng Y, Tang N, Yao G, Fais S, Gu J, Qin W. Small interfering RNA targeting the subunit ATP6L of proton pump V-
Vacuolar H(+)-ATPase in Cancer Cells: Structure and Function
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Atlas Genet Cytogenet Oncol Haematol. 2012; 16(3) 258
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Buechling T, Bartscherer K, Ohkawara B, Chaudhary V, Spirohn K, Niehrs C, Boutros M. Wnt/Frizzled signaling requires dPRR, the Drosophila homolog of the prorenin receptor. Curr Biol. 2010 Jul 27;20(14):1263-8
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Cruciat CM, Ohkawara B, Acebron SP, Karaulanov E, Reinhard C, Ingelfinger D, Boutros M, Niehrs C. Requirement of prorenin receptor and vacuolar H+-ATPase-mediated acidification for Wnt signaling. Science. 2010 Jan 22;327(5964):459-63
McCarty MF, Whitaker J. Manipulating tumor acidification as a cancer treatment strategy. Altern Med Rev. 2010 Sep;15(3):264-72
McHenry P, Wang WL, Devitt E, Kluesner N, Davisson VJ, McKee E, Schweitzer D, Helquist P, Tenniswood M. Iejimalides A and B inhibit lysosomal vacuolar H+-ATPase (V-ATPase) activity and induce S-phase arrest and apoptosis in MCF-7 cells. J Cell Biochem. 2010 Mar 1;109(4):634-42
Miranda KC, Karet FE, Brown D. An extended nomenclature for mammalian V-ATPase subunit genes and splice variants. PLoS One. 2010 Mar 10;5(3):e9531
O'Callaghan KM, Ayllon V, O'Keeffe J, Wang Y, Cox OT, Loughran G, Forgac M, O'Connor R. Heme-binding protein HRG-1 is induced by insulin-like growth factor I and associates with the vacuolar H+-ATPase to control endosomal pH and receptor trafficking. J Biol Chem. 2010 Jan 1;285(1):381-91
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Chung C, Mader CC, Schmitz JC, Atladottir J, Fitchev P, Cornwell ML, Koleske AJ, Crawford SE, Gorelick F. The vacuolar-ATPase modulates matrix metalloproteinase isoforms in human pancreatic cancer. Lab Invest. 2011 May;91(5):732-43
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This article should be referenced as such:
Lu X, Qin W. Vacuolar H(+)-ATPase in Cancer Cells: Structure and Function. Atlas Genet Cytogenet Oncol Haematol. 2012; 16(3):251-258.
Case Report Section Paper co-edited with the European LeukemiaNet
Atlas Genet Cytogenet Oncol Haematol. 2012; 16(3) 259
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A case of Acute Lymphoblastic Leukemia with rare t(11;22)(q23;q13) Jill D Kremer, Anwar N Mohamed
Cytogenetics Laboratory, Pathology Department, Wayne State University School of Medicine, Detroit
Medical Center, Detroit MI, USA (JDK, ANM)
Published in Atlas Database: October 2011
Online updated version : http://AtlasGeneticsOncology.org/Reports/t1122q23q13MohamedID100059.html Printable original version : http://documents.irevues.inist.fr/bitstream/DOI t1122q23q13MohamedID100059.txt This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2012 Atlas of Genetics and Cytogenetics in Oncology and Haematology
Clinics
Age and sex
14 months old male patient.
Previous history
No preleukemia, no previous malignancy, inborn
condition of note. Patient has hemoglobin S trait.
Organomegaly
Hepatomegaly, splenomegaly, enlarged lymph
nodes, central nervous system involvement.
Blood WBC : 33 X 10
9/l
HB : 2.6g/dl
Platelets : 1 X 109/l
Blasts : 72%
Bone marrow : 100 bone marrow blast
replacement.
Cyto-Pathology Classification
Cytology
Acute lymphoblastic leukemia (ALL) with L1
morphology
Immunophenotype
Flow cytometry of bone marrow aspirate identified
a dim CD45 lymphoblast population (85%)
expressing HLA-DR, CD19 and partially
expressing CD10, CD22, CD9 and CD40.
Rearranged Ig Tcr
Not performed.
Pathology
Bone marrow aspirate appeared hypocellular with
95% lymphoblasts of L1 morphology, 2% myeloid
series, and 3% erythroid series.
Electron microscopy
Not performed.
Diagnosis
CD34 negative B-precursor ALL.
Survival
Date of diagnosis: 01-2011
Treatment: Methotrexate, Cytarabine, Vincristine,
Dexamethasone, PEG-aspargase
Complete remission : no
Treatment related death : no
Relapse : no
Status: Alive. Last follow up: 10-2011
Survival: 9 months
Karyotype
Sample: Bone marrow aspirate
Culture time: 24hr without stimulant and 48hr
with 10% conditioned medium.
Banding: GTG
Results
46,Y,der(X)t(X;9)(p11.1;q11),add(9)(q11),t(11;22)(
q23;q13)[20] (see Figure 1). Post induction bone
marrow study demonstrated a normal 46,XY
karyotype.
A case of Acute Lymphoblastic Leukemia with rare t(11;22)(q23;q13)
Kremer JD, Mohamed AN
Atlas Genet Cytogenet Oncol Haematol. 2012; 16(3) 260
Figure 1: G-banded karyotype showing 46,Y,der(X)t(X;9)(p11.1;q11),add(9)(q11),t(11;22)(q23;q13). Arrows pointed to t(11;22).
Figure 2: FISH. A. Interphase hybridized with LSI MLL dual-color break apart probe showed a split signal pattern of MLL
(1O1G1F). B. Metaphase hybridized with BCR/ABL dual-fusion probe showed 2O2G signaling. C. For identification of chromosome 22, the same metaphase subsequently hybridized with LSI MLL probe showing relocation of the telomeric side
(orange signal) of MLL to 22q confirming t(11;22)(q23;q13) (arrows). Note: G= green; O= orange; F= fusion.
Other Molecular Studies
Technics:
Fluorescence in situ hybridization (FISH) using the
ALL panel DNA probes including CEP 4, 10, and
17 alpha satellite probes, LSI MLL dual-color break
apart probe, BCR/ABL and TEL/AML1 dual-fusion
translocation probes was performed (Abbott
Molecular, Downers Grove, IL).
Results:
Hybridization with MLL probe produced a
split/translocation pattern in 61% of interphase
cells. Metaphase FISH showed that the telomeric
region of MLL gene was translocated to 22q13
distal to BCR (Figure 2). The hybridization with the
BCR/ABL probe showed two signals each
(unfused), however on a previously G-banded
metaphase it appeared that the BCR signals
remained on chromosome 22 while one ABL signal
was translocated to der(X). The remaining probes
produced a normal hybridization pattern.
Comments The patient described here is a 14 month-old-male
presented with an upper respiratory tract infection
unresponsive to antibiotics. Subsequently he was
diagnosed with high risk B-precursor ALL due to
the positivity of MLL/11q23 rearrangement. The
patient was started on a Children's Oncology Group
induction chemotherapy protocol. Secondary to his
high risk status, the patient is being evaluated for a
bone marrow transplant. At time of diagnosis
A case of Acute Lymphoblastic Leukemia with rare t(11;22)(q23;q13)
Kremer JD, Mohamed AN
Atlas Genet Cytogenet Oncol Haematol. 2012; 16(3) 261
Table 1: AML cases with t(11;22)(q23;q13) reported in literature.
Patient Primary
Malignancy Leukemia Karyotype Gene
4 Y/M [2] Non-Hodgkin
Lymphoma AML M1 48,XY,+8,+8,t(11;22)(q23;q13) MLL-EP300
5 Y/F [3] Neuroblastoma AML M2 46,XX,t(1;22;11)(q44;q13;q23),t(10;17)(q22;q21) MLL-EP300
65 Y/M [4] AML with MDS AMML 46,XY,t(11;22)(q23;q13)[15]/47,idem,+8[2] MLL-EP300
chromosome analysis revealed the presence
t(11;22)(q23;q13) in all 20 metaphases and
rearrangement of the MLL gene.
Translocations involving the MLL/11q23 region are
the most common genomic aberrations in infant
ALL seen in ~80% of cases (Raimondi, 2004).
Generally leukemia harboring MLL translocation is
clinically aggressive and associated with poor
prognosis. The most common chromosomes
involved in 11q23 translocations are t(4;11)
followed by t(11;19) and t(9;11). Additionally,
leukemia with MLL/11q23 translocations are
frequently associated with over expression of
FLT3, therefore, targeted therapy inhibitors of
FLT3 (a tyrosine kinase) may be beneficial for
those patients. Currently there are only three
reported cases in the literature with
t(11;22)(q23;q13), unlike our case all having
secondary acute myeloid leukemia with prior
therapy of topoisomerase II inhibitor (table 1).
Moreover, rearrangement of the MLL gene and
MLL-EP300 fusion gene were demonstrated in
those three cases (Ida et al., 1997; Ohnishi et al.,
2008; Duhoux et al., 2011). The clinical
presentation of our case is quit different from these
three cases. Although our case had a rearrangement
of the MLL/11q23 gene, the MLL-EP300 fusion
gene was not tested. Because the partner genes
involved in MLL/11q23 translocations are
markedly heterogeneous, it remains unclear
whether EP300 or other gene is involved in the
present case which may be responsible for the
different phenotype of this leukemia.
References Ida K, Kitabayashi I, Taki T, Taniwaki M, Noro K, Yamamoto M, Ohki M, Hayashi Y. Adenoviral E1A-associated protein p300 is involved in acute myeloid leukemia with t(11;22)(q23;q13). Blood. 1997 Dec 15;90(12):4699-704
Raimondi SC.. 11q23 rearrangements in childhood acute lymphoblastic leukemia. Atlas Genet Cytogenet Oncol Haematol. February 2004. URL : http://AtlasGeneticsOncology.org/Anomalies/11q23ChildALLID1321.html .
Ohnishi H, Taki T, Yoshino H, Takita J, Ida K, Ishii M, Nishida K, Hayashi Y, Taniwaki M, Bessho F, Watanabe T.. A complex t(1;22;11)(q44;q13;q23) translocation causing MLL-p300 fusion gene in therapy-related acute myeloid leukemia. Eur J Haematol. 2008 Dec;81(6):475-80. Epub 2008 Sep 6.
Duhoux FP, De Wilde S, Ameye G, Bahloula K, Medves S, Lege G, Libouton JM, Demoulin JB, A Poirel H.. Novel variant form of t(11;22)(q23;q13)/MLL-EP300 fusion transcript in the evolution of an acute myeloid leukemia with myelodysplasia-related changes. Leuk Res. 2011 Mar;35(3):e18-20. Epub 2010 Oct 25.
This article should be referenced as such:
Kremer JD, Mohamed AN. A case of Acute Lymphoblastic Leukemia with rare t(11;22)(q23;q13). Atlas Genet Cytogenet Oncol Haematol. 2012; 16(3):259-261.
Case Report Section Paper co-edited with the European LeukemiaNet
Atlas Genet Cytogenet Oncol Haematol. 2012; 16(3) 262
Atlas of Genetics and Cytogenetics in Oncology and Haematology
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Insertion as an alternative mechanism of CBFB-MYH11 gene fusion in a new case of acute myeloid leukemia with an abnormal chromosome 16 Yaser Hussein, Vandana Kulkarni, Anwar N Mohamed
Cytogenetics Laboratory, Pathology Department, Wayne State University School of Medicine, Detroit
Medical Center, Detroit MI, USA (YH, VK, ANM)
Published in Atlas Database: October 2011
Online updated version : http://AtlasGeneticsOncology.org/Reports/ins16q22p13p13MohamID100058.html Printable original version : http://documents.irevues.inist.fr/bitstream/DOI ins16q22p13p13MohamID100058.txt This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2012 Atlas of Genetics and Cytogenetics in Oncology and Haematology
Clinics
Age and sex
17 years old female patient.
Previous history
No preleukemia, no previous malignancy, inborn
condition of note. Thalassemia trait carrier.
Organomegaly
Hepatomegaly, splenomegaly, enlarged lymph
nodes, no central nervous system involvement.
Blood WBC : 138.7 X 10
9/l
HB : 6.9g/dl
Platelets : 51 X 109/l
Blasts : 76%
Bone marrow : 100 Bone marrow biopsy was
hypercellular (100%) and replaced by myeloblasts
and monoblasts. Normal hematopoiesis was greatly
decreased and there was prominent
hemophagocytosis. The majority of the blasts were
myeloperoxidase positive however another smaller
component of blasts was nonspecific esterase
positive.
Cyto-Pathology Classification Cytology: Acute myeloid leukemia with abnormal
eosinophils (AML-M4eos).
Immunophenotype
Flow cytometry of bone marrow aspirate identified
a significant population of myeloblasts (49%)
expressing CD34, HLA-DR, CD9, CD13, CD33,
CD117 and partially expressing CD15, CD11b, and
CD64. A second population of monocytes is also
identified (37%) expressing CD4, CD14, CD15,
CD36 and CD64.
Rearranged Ig Tcr: Not performed.
Pathology
Bone marrow aspirate revealed myeloblasts,
monoblasts, monocytes, and increased eosinophils
many of which had abnormal granules (FAB AML-
M4eos).
Electron microscopy: Not performed.
Diagnosis
Acute myelomonocytic leukemia with abnormal
eosinophils (AML-M4eos) and CBFB/16q22
rearrangement.
Survival
Date of diagnosis: 03-2011
Treatment: Intrathecal methotrexate,
hydrocortisone, and cytarabine.
Treatment related death : no
Relapse : no
Status: Alive. Last follow up: 09-2011
Survival: 6 months
Insertion as an alternative mechanism of CBFB-MYH11 gene fusion in a new case of acute myeloid leukemia with an abnormal chromosome 16
Hussein Y, et al.
Atlas Genet Cytogenet Oncol Haematol. 2012; 16(3) 263
Karyotype
Sample: Bone marrow
Culture time: 24 hrs without stimulating agents
and 48 hrs with 10% conditioned medium.
Banding: GTG
Results
At time of diagnosis abnormal metaphase cells with
the following karyotype was found;
46,XX,ins(16)(q22p13p13)[20] (see Figure 1).
Remission bone marrow on 4/20/2011 and
9/13/2011 revealed a normal female karyotype;
46,XX[20].
Other Molecular Studies
Technics:
Fluorescence in situ hybridization (FISH) using LSI
CBFB dual color break-apart rearrangement DNA
probes (Abbott Molecular IL, USA), and
CBFB/MYH11 dual fusion translocation DNA
probe (Cytocell Inc. Cambridge, UK) were
performed.
Results:
The hybridization with the CBFB break-apart probe
produced a split pattern in 62% of interphase cells.
On metaphase cells, the 5'CBFB (SepctrumRed)
and 3'CBFB (SepctrumGreen) signals stayed on the
16q, instead of 5'CBFB being relocated to 16p as
seen in the standard inv(16). The CBFB signals
were separated but maintained the orientation
pattern of the 5' and 3' probe, suggesting they were
split by an insertion (Figure 2A). Subsequently,
using the CBFB-MYH11 probe on metaphases
showed that MYH11 signal on 16p moved and
juxtaposed to CBFB on 16q, confirming the
insertion of MYH11 into CBFB (Figure 2B).
Figure 1. G-Banded karyotype from the diagnostic bone marrow sample demonstrating the ins(16)(q22p13p13) (arrowed).
Insertion as an alternative mechanism of CBFB-MYH11 gene fusion in a new case of acute myeloid leukemia with an abnormal chromosome 16
Hussein Y, et al.
Atlas Genet Cytogenet Oncol Haematol. 2012; 16(3) 264
Figure 2. A. Metaphase FISH using LSI CBFB/q22 breakapart rearrangement probe showing one normal fusion signal and split signals (red and green) on 16q (arrow). B. Metaphase hybridized with CBFB/MYH11 probe showing insertion of MYH11 green
signal (appearing yellow) within CBFB/16q22 red signal (arrow).
Comments The patient described here is a 17 year old female
presented with upper respiratory tract infection and
bruises for 2 weeks. Subsequently she was
diagnosed with AML (FAB M4 eos). Cytogenetics,
performed on bone marrow aspirate revealed a
unique structural abnormality of chromosome 16
which was interpreted as insertion; 46, XX,
ins(16)(q22p13p13). FISH confirmed that the
MYH11/p13 gene was inserted into the
CBFB/16q22 gene region (Figure 2B). The result of
this unusual structural rearrangement was the fusion
of CBFB /MYH11 genes commonly seen in
inv(16)(p13q22) bearing leukemia.
The CBFB/MYH11 gene fusion is strongly
associated with AML-M4 with abnormal
eosinophils. Generally, the fusion is generated from
inv(16)(p13q22) or t(16;16) with the inversion
being much more common than translocation (Le
Beau et al., 1983; Tobal et al., 1995). The case
presented here demonstrates that insertion is
another mechanism in producing CBFB/MYH11
gene fusion in AML-M4eos. To our best
knowledge, there is only one reported case of
AML-M4 having similar structural abnormality of
chromosome 16 and CBFB/MYH11 fusion
(O'Reilly et al., 2000). These two cases suggest that
insertion represents a variant rare rearrangement for
the formation of this fusion. FISH is highly
recommended to characterize unusual abnormalities
of chromosome 16 and to confirm the CBFB-
MYH11 fusion.
References Le Beau MM, Larson RA, Bitter MA, Vardiman JW, Golomb HM, Rowley JD. Association of an inversion of chromosome 16 with abnormal marrow eosinophils in acute myelomonocytic leukemia. A unique cytogenetic-clinicopathological association. N Engl J Med. 1983 Sep 15;309(11):630-6
Tobal K, Johnson PR, Saunders MJ, Harrison CJ, Liu Yin JA. Detection of CBFB/MYH11 transcripts in patients with inversion and other abnormalities of chromosome 16 at presentation and remission. Br J Haematol. 1995 Sep;91(1):104-8
O'Reilly J, Chipper L, Springall F, Herrmann R. A unique structural abnormality of chromosome 16 resulting in a CBF beta-MYH11 fusion transcript in a patient with acute myeloid leukemia, FAB M4. Cancer Genet Cytogenet. 2000 Aug;121(1):52-5
This article should be referenced as such:
Hussein Y, Kulkarni V, Mohamed AN. Insertion as an alternative mechanism of CBFB-MYH11 gene fusion in a new case of acute myeloid leukemia with an abnormal chromosome 16. Atlas Genet Cytogenet Oncol Haematol. 2012; 16(3):262-264.
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