The function of the Cyclin D-dependent protein kinase Cdk4/6 in Drosophila Die Funktion der Cyclin D-abhängigen Proteinkinase Cdk4/6 in Drosophila

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Drosophila is an ideal system for the in vivo analysis of the molecular mechanisms which regulate the extensive cell proliferation during development of complex multicellular organisms. As in essentially all other organisms, terminal differentiation is preceded by a cell cycle arrest during a G1/0 phase in most Drosophila tissues. In the epidermis, where cell proliferation is stopped after the sixteenth round of cell division, we have been able to demonstrate that this arrest is dependent on the timely inactivation of Cyclin E/Cdk2(Cdc2c)- and Cdk1(Cdc2)complexes. During the final cell division cycle, Cyclin E (CycE) expression is down-regulated, on the one hand, and dacapo(dap)- as well as fizzy-related(fzr)-expression are up-regulated on the other hand. The CIP/KIP-related protein Dacapo(DAP) inhibits Cyclin E/Cdk2-complexes; FZR-protein induces the degradation of the Cdk1-activating Cyclins A, B and B3. Which mechanisms are responsible for the precisely timed changes of CycE, dap and fzr expression? Current knowledge would suggest an involvement of Cyclin D/Cdk4/6-complexes. Thus, our project aims at an elucidation of the role of Cyclin D/Cdk4/6complexes specifically during the termination of the epidermal cell proliferation as well as more generally during growth and proliferation in Drosophila development. We will characterise phenotypes resulting from genetic Cdk4/6-inactivation and Cyclin D/Cdk4/6 overexpression, and we will identify genes interacting with Cdk4/6.