Cks1 Promotion of S Phase Entry and Proliferation Is Independent of p27^Kip1 Suppression

Cks1 is an activator of the SCF^Skp2 ubiquitin ligase complex that targets the cell cycle inhibitor p27^Kip1 for degradation. The loss of Cks1 results in p27^Kip1 accumulation and decreased proliferation and inhibits tumorigenesis. We identify here a function of Cks1 in mammalian cell cycle regulation that is independent of p27^Kip1. 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 with Cks1 loss. Furthermore, concomitant loss of Cks1 does not rescue the tumor suppressor function of p27Kip1 that is manifest in various organs of p27^Kip1-/- mice. In contrast, defects in mitotic entry and premature senescence manifest in Cks1^-/- cells are p27^Kip1 dependent. Collectively, these findings establish p27^Kip1-independent functions of Cks1 in regulating the G1-S transition.