wt1 – a complex life
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WT1 – A Complex Life. By: Chen Zhu. WT1 – Outline. Introduction Function Structure Role in development In mice In humans Role in cancer Wilm’s Tumor, related illnesses. Introduction. Wilms’ Tumor 1 (WT1) is found on human chromosome 11p13 - PowerPoint PPT PresentationTRANSCRIPT
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WT1 – A Complex Life
By: Chen Zhu
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WT1 – Outline Introduction Function Structure Role in development
In mice In humans
Role in cancer Wilm’s Tumor, related illnesses
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Introduction Wilms’ Tumor 1 (WT1) is found on
human chromosome 11p13 WT1 is important for the development of
the genitourinary system and mesothelial tissues.
The inactivation of WT1 is responsible for ~10-15% of Wilms’ tumor
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Function WT1 is a transcriptional and post-
transcriptional regulator It contains signals that allow it to localize
inside the nucleus It contains domains that can bind to
several DNA sequences
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Structure WT1 is a 50kb gene with ten exons,
together encoding a mRNA of ~3kb. The N-terminus of WT1 contains a proline
and glutamine-rich region that facilitates homodimerization
There are two alternatively spliced exons in WT1
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Exon 5 Exon 5 encodes 17 amino acids between
the N-terminus and the first Zn finger domain
Encodes a protein-protein interaction domain
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Exon 9 Encodes the sequence KTS between the
third and fourth zinc fingers of the protein WT1 (-KTS) variants have been shown to
act as transcriptional regulators1
WT1 (+KTS) may play a role in RNA processing.
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Adapted from Figure 5 in Keith W. Brown and Karim T.A. Malik, “The molecular biology of Wilms’ Tumor,” Exp. Rev. Mol. Med. 14 May, http://www.expertreviews.org/01003027h.htm
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Alternate Splicing 24 alternate isoforms of WT1 have been
described (+KTS)/(-KTS) is by far the most
important alternate splicing mechanism
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Function Many target genes of WT1 have been
identified The role of WT1 in transcriptional
regulation, however, is not well understood
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Function We do understand, however, that WH1 is
involved in many different pathways: The differentiation of leukemic cell lines The differentiation of pheochromocytoma cells Both the induction and prevention of apoptosis
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WT1 Target Genes2
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Role In Development WT1 is expressed during development in the
following systems: Urinogenital system Epicardium and subepicardial mesenchyme
(heart) Kidneys Spleen Parts of the brain Spinal chord Mesothelial organs Diaphram
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Jordan A. Kreidberg, et al., “WT-1 is required for early liver development,” Cell 74: 679-691 (1993)
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Knockout Mice WT1 (-/-) die from embryonic day 12 to the
end of gestation Many defects are evident in many of the
areas mentioned in the previous slide Mutant embryos lack kidneys and gonads
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Heterozygous Mice WT1 (+/-) mice usually die after several
months due to renal insufficiency The severity of symptoms can be
correlated with WT1 levels Symptoms are similar to the human
Frasier Syndrome
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Jordan A. Kreidberg, et al., “WT-1 is required for early liver development,” Cell 74: 679-691 (1993)
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Kidney Development
Loose mesenchyme forms epithelial condenses around ureteric bud tips
S-shaped bodies develop and eventually elongate to attach to the collecting duct
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Kidney Development -The role of WT1 Without WT1, the loose mesenchyme
becomes apoptotic WT1 may thus act as a survival factor for
populations of embryonic kidney cells during development
An antiapoptotic protein encoded by Bcl-2 may be an upstream mediator of WT1
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Heart Development
WT1(-/-) mutants show smaller hearts and thinning of muscular walls
The epicarium, especially, requires WT1 WT1 is thought to play a role in the
transformation of epicardial to mesenchymal cells
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Jordan A. Kreidberg, et al., “WT-1 is required for early liver development,” Cell 74: 679-691 (1993)
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Role In Cancer WAGR: heterozygous deletions at
chromosome 11p13 Frasier Syndrome : heterozygous point
mutations in intron 9 Leukemia: heterozygous WT1 mutations
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WAGR WAGR is a syndrome for affected children
predisposed to develop:Wilms’ tumorAniridiaGenitourinary anomaliesmental Retardation
http://bms.brown.edu/pedisurg/images/ImageBank/Abdomen/WilmsCT8yo.jpg
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WAGR Aniridia Genitourinary Anomalies Mental Retardation
http://www.abdn.ac.uk/clsm/UserFiles/Image/collinson-eye-large.jpg
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Wilms’ Tumor is a cancer of the kidney About 500 cases are diagnosed yearly Onset is early, with nearly everybody
diagnosed under the age of 25 Survival with therapy is very good: ~85% WAGR patients should undergo frequent
ultrasound testing
Wilm’s Tumor
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Wilm’s Tumor Wilm’s tumor arises from mesenchyme
that fails to differentiate into the epithelial component of the nephron
Inactivation of WT1 produces foci of primitive renal cells called nephrogenic rests
Sometimes called tri-phasic type, consisting of undifferentiated mesenchyme, stromal and epiphelial cells
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Leukemia WT1 is inappropriately expressed in many
Leukemia cell lines (~15%) WT1 is usually expressed in stem cells of
bone marrow, but not in normal mature blood cells, linking it to an immature state for leukemia cells
WT1 expression levels increase during the progression of acute myeloid leukemia
Patients with low WT1 mRNA had a better prognosis than those with high WT1 mRNA
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Questions?
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Bibliography1. Holger Scholz and Karin M. Kirschner, “A Role for the Wilms’
Tumor Protein WT1 in Organ Development,” Physiology 20: 54-59 (2005)
2. Volkher Scharnhorst, et al., “WT1 proteins: functions in growth and differentiation,” Gene 273: 141-161 (2001)
3. Kay-Dietrich Wagner, et al., “The complex life of WT1,” Journal of Cell Science 116: 1653-1658 (2003)
4. Jordan A. Kreidberg, et al., “WT-1 is required for early liver development,” Cell 74: 679-691 (1993)
5. National Cancer institute, “Wilms’ Tumor and Other Childhood Kidney Tumors,” November 27, 2006. <http://www.cancer.gov/cancertopics/pdq/treatment/wilms/Patient>
6. International WAGR Syndrome Association, “What is WAGR Syndrome?” Accessed April 27, 2007. <http://www.wagr.org/>
7. Monika L. Metzger, Jeffrey S. Dome., “Current Therapy for Wilms’ Tumor,” Oncologist 10: 815-826 (2005)