Updating the Mammalian Cell Cycle: The Role of Interphase Cdks in Tissue Homeostasis and Cancer

Abstract

Genetic interrogation of the mammalian cell cycle has revealed that the essential role of interphase Cdks is not to specifically drive the various phases of the cycle, as previously proposed in widely accepted models, but to sustain proliferation of specialized cells at various times during embryonic or postnatal development. Indeed, genetic studies have indicated that Cdk1 can drive the mammalian cell cycle in the absence of interphase Cdks. The molecular bases for the essential requirement of interphase Cdks in selected cell types are still poorly understood. However, these observations have important implications for understanding the role of Cdk misregulation in cancer. Indeed, it is likely that misregulation of Cdks may only confer proliferative advantages to selected cell types. More importantly, it is also possible that certain cells may become dependent of selective interphase Cdks only when their proliferation is driven by defined oncogenes. Recent studies have illustrated the requirement for Cdk4 in HER2-overexpressed mammary adenocarcinomas and K-Ras oncogene-driven lung adenocarcinomas but not in the corresponding normal tissues. Likewise, Cdk2 plays an important role in the development of Myc-induced lymphomas. These findings may open the door to the design of novel therapeutic strategies that may benefit cancer patients.