The Drosophila Cyclin D-Cdk4 complex promotes cellular growth

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Abstract
Mammalian cyclin D–Cdk4 complexes have been characterized as growth factor‐responsive cell cycle regulators. Their levels rise upon growth factor stimulation, and they can phosphorylate and thus neutralize Retinoblastoma (Rb) family proteins to promote an E2F‐dependent transcriptional program and S‐phase entry. Here we characterize the in vivo function of Drosophila Cyclin D (CycD). We find that Drosophila CycD–Cdk4 does not act as a direct G1/S‐phase regulator, but instead promotes cellular growth (accumulation of mass). The cellular response to CycD–Cdk4‐driven growth varied according to cell type. In undifferentiated proliferating wing imaginal cells, CycD–Cdk4 caused accelerated cell division (hyperplasia) without affecting cell cycle phasing or cell size. In endoreplicating salivary gland cells, CycD–Cdk4 caused excessive DNA replication and cell enlargement (hypertrophy). In differentiating eyes, CycD–Cdk4 caused cell enlargement (hypertrophy) in post‐mitotic cells. Interaction tests with a Drosophila Rb homolog, RBF, indicate that CycD–Cdk4 can counteract the cell cycle suppressive effects of RBF, but that its growth promoting activity is mediated at least in part via other targets.