Cks1 Promotion of S Phase Entry and Proliferation Is Independent of p27Kip1 Suppression

Cks1 is an activator of the SCFSkp2 ubiquitin ligase complex that targets the cell cycle inhibitor p27Kip1 for degradation. The loss ofCks1 results in p27Kip1 accumulation and decreased proliferation and inhibits tumorigenesis. We identify here a function of Cks1 in mammalian cell cycle regulation that is independent of p27Kip1 . Specifically,Cks1 −/− ;p27 Kip1−/− mouse embryonic fibroblasts retain defects in the G1 -S phase transition that are coupled with decreased Cdk2-associated kinase activity and defects in proliferation that are associated withCks1 loss. Furthermore, concomitant loss ofCks1 does not rescue the tumor suppressor function of p27Kip1 that is manifest in various organs ofp27 Kip1−/− mice. In contrast, defects in mitotic entry and premature senescence manifest inCks1 −/− cells are p27Kip1 dependent. Collectively, these findings establish p27Kip1 -independent functions of Cks1 in regulating the G1 -S transition.