1

EXPERIMENTAL CANCERRESEARCH 2006

Posttranscriptional Mechanisms inOncogenesis

21.4.2006

Christoph MoroniInstitut für Med. Mikrobiologie

Universität Basel

PROTO-ONKOGENE

SUPPRESSOR-GENE

VERLUST

AKTIVIERUNG

KREBS

N = Synthesis - Degradation

NmRNA = Transcription - RNA decay

cis-ElementsRNA-binding ProteinsRNases

Promotor/ EnhancerTranscription FactorsPol-II

2

3

4

(W. Filipowicz)Sherr, Nat. Rev. MCB, 2001

5

Arnold J. Levine et al. Genes Dev. 2006; 20: 267-275

Figure 2

Primary cells Transformed cells

hTERT Oncogenic ras

p53

pRB PP2A

Viral LT sT

The tumor-suppressive functions of the human INK4A locusVoorhoeve and AgamiCancer Cell, 4, 311. 2003

A MicroRNA signature associated with prognosis and progressionin chronic lymphocytic leukemia.N Engl J Med 353, 1793-1801, 2005.

MicroRNA profiling reveals distinct signatures in B cell chroniclymphocytic leukemias.Proc Natl Acad Sci U S A 101, 11755-11760, 2004.

Human microRNA genes are frequently located at fragile sites andgenomic regions involved in cancers.Proc Natl Acad Sci U S A 101, 2999-3004, 2004.

MicroRNAs as oncogenes and tumor suppressors.N Engl J Med 353, 1768-1771, 2005.

microRNA and Cancer (I)

miR-15 and miR-16 induce apoptosis by targeting BCL2.Proc Natl Acad Sci U S A 102, 13944-13949, 2005.

RAS is regulated by the let-7 microRNA family. Cell 120, 635-647, 2005.

MicroRNA expression profiles classify human cancers. Nature 435, 834-838, 2005.

A genetic screen implicates miRNA-372 and miRNA-373 asoncogenes in testicular germ cell tumors. Cell 124, 1169-1181, 2006

microRNA and Cancer (II)

Cell, 124, 1169, 2006 Cell, 124, 1169, 2006

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Cell, 124, 1169, 2006

Cell, 124, 1169, 2006

Cell, 124, 1169, 2006

Cell, 124, 1169, 2006

Cell, 124, 1169, 2006

Summary and Conclusion

• miR372 and miR 373 are regulators ofthe oncogenic stress response pathway

• Overcome ras-induced senescence• Expressed in p53-wt seminomas• Acts in part via LATS2 (a tumor

suppressor gene