Cdk6-cyclin D3 complex evades inhibition by inhibitor proteins and uniquely controls cell's proliferation competence

Mammalian cells require a cyclin D-dependent kinase for the cell cycle star t, yet many mesenchymal cells express three seemingly redundant D cyclins a nd similarly, seemingly redundant Cdk4 and Cdk6 as their kinase partners, W e have found that the Cdk6-cyclin D3 complex is unique among the D cyclin a nd kinase combinations in the ability to promote the cell cycle start. In a n anchorage-minus G(1)-arrested rat fibroblast, only Cdk6-D3 retains kinase activity due mainly to its ability to evade inhibition by p27(KIPI) and p2 1(CIPI) with a resemblance to viral cyclin-bound Cdk6, Rodent fibroblasts e ngineered to overexpress both Cdk6 and cyclin D3 highly resist serum starva tion- or cell-cell contact-imposed G(1)-arrest, In BALB/c 3T3 cells, D3 is constitutively expressed, but Cdk6 is markedly induced with concomitant act ivation upon stimulation with a growth-promoting factor. These results sugg est a role for the Cdk6-D3 complex in regulating cell's proliferation abili ty in response to external stimuli.