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Impact of Cyclin A2 Deregulation in mouse physiology, cellular transformation and cancer

Objective

The cell cycle is a complex process that is highly regulated by cyclin-dependent kinases (CDKs). CDKs function at different phases of the cell cycle and are regulated by their association with specific cofactors, the cyclins. Different cyclins exhibit distinct expression patterns that contribute to the temporal coordination of each cell cycle event.

Two forms of cyclin A exist in mammals. Cyclin A2 is ubiquitously expressed, and activates CDK2 or CDK1 kinases to promote both S phase progression and G2/M transition, respectively. In contrast, cyclin A1 pairs with CDK1 only, and is present in germ cells undergoing meiosis in the testis.

The essential role of cyclin A1 in meiosis was confirmed by the observation that cyclin A1-deficient male germ cells arrest a t the G2/M transition of meiotic prophase I and exhibit some apoptotic phenotypes. Cyclin A2 whose expression is more ubiquitous, is essential for embryonic development, the null embryos dying at around day 5.5 pc.

This early embryonic lethality has prevented the elucidation of cyclin A2 function in whole mammalian organisms. In order to address the physiological role of cyclin A2 in mammalian growth and health, we will generate mouse models with tissue-specific and/or time-specific inactivation of cyclin A 2.

This mouse model will serve as natural readouts of the regulation and function of cyclin A2 in life and growth of a mammalian organism, and will provide several useful cellular models for cell cycle studies. Cyclin A2 over-expression causes premature cell cycle entry into the S phase and over-expression of cyclin A2 was shown to promote cellular transformation.

However, the precise role of cyclin A2 in the cell transformation process, and in the development of cancer is not known. We wish to address the impact of cyclin A2 deletion on cellular transformation in vitro and cancer incidence in vivo, the ultimate goal being to determine whether inhibitors of cyclin A2 could improve cancer treatment.

Call for proposal

FP6-2004-MOBILITY-12
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Funding Scheme

IRG - Marie Curie actions-International re-integration grants

Coordinator

CENTRE NATIONAL DE LA RECHERCHE SCIENTIFIQUE-DELEGATION LANGUEDOC-ROUSSILLON
Address
1919 Route De Mende
Montpellier
France