Cyclin D-cdk4 is not a master regulator of cell multiplication in Drosophila embryos.
Inactivation of Cyclin E-Cdk2 is essential for a timely arrest of the epidermal cell proliferation program during Drosophila embryogenesis. E-type cyclin-cdk complexes are thought to be activated by D-types titrating away inhibitors and inducing cyclin E transcription by activating E2F transcription factors via Rb phosphorylation. Therefore, we have analyzed whether the developmentally controlled inactivation of Cyclin E-Cdk2 required for the epidermal cell proliferation arrest occurs as a consequence of Cyclin D-Cdk4 inactivation. However, preventing Cyclin D-Cdk4 inactivation by overexpression has a minimal effect on Cyclin E expression and does not interfere with the initial G1 arrest, while it readily induces the E2F target RnrS in arresting epidermal cells. Prolonged Cyclin D-Cdk4 overexpression eventually interferes with maintenance of quiescence in some cells. Moreover, in Cdk4 mutant embryos, some RnrS expression is still induced by Cyclin E overexpression, and endogenous Cyclin E expression as well as cell cycle progression is not affected, except for late aspects of the endoreduplication program. These findings argue against the proposed necessity of complete Rb inactivation by sequential phosphorylation by D- and E-type cyclin-cdk complexes. They demonstrate that Cyclin D-Cdk4 does not function as the master regulator of the embryonic cell proliferation program.
Meyer
Claas A
CA
Department of Genetics, University of Bayreuth, 95440, Bayreuth, Germany.
Jacobs
Henning W
HW
Lehner
Christian F
CF
D000818:Animals; D018797:Cell Cycle Proteins; D002455:Cell Division; D056741:Cyclin D; D019927:Cyclin E / Q000235:genetics / Q000378:metabolism; D051358:Cyclin-Dependent Kinase 4; D018844:Cyclin-Dependent Kinases / Q000235:genetics / Q000378:metabolism*; D016213:Cyclins / Q000235:genetics / Q000378:metabolism*; D004268:DNA-Binding Proteins; D004330:Drosophila / Q000166:cytology* / Q000196:embryology* / Q000235:genetics / Q000378:metabolism; D029721:Drosophila Proteins; D050684:E2F Transcription Factors; D015870:Gene Expression; D011518:Proto-Oncogene Proteins; D016196:S Phase; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism
D018797:Cell Cycle Proteins; C534694:CycD protein, Drosophila; D056741:Cyclin D; D019927:Cyclin E; D016213:Cyclins; D004268:DNA-Binding Proteins; D029721:Drosophila Proteins; D050684:E2F Transcription Factors; D011518:Proto-Oncogene Proteins; D014157:Transcription Factors; C495896:Cdk4 protein, Drosophila; D051358:Cyclin-Dependent Kinase 4; D018844:Cyclin-Dependent Kinases