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 start, yet many mesenchymal cells express three seemingly redundant D cyclins and similarly, seemingly redundant Cdk4 and Cdk6 as their kinase partners, We have found that the Cdk6-cyclin D3 complex is unique among the D cyclin and kinase combinations in the ability to promote the cell cycle start. In an 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 p21(CIPI) with a resemblance to viral cyclin-bound Cdk6, Rodent fibroblasts engineered to overexpress both Cdk6 and cyclin D3 highly resist serum starvation- or cell-cell contact-imposed G(1)-arrest, In BALB/c 3T3 cells, D3 is constitutively expressed, but Cdk6 is markedly induced with concomitant activation upon stimulation with a growth-promoting factor. These results suggest a role for the Cdk6-D3 complex in regulating cell's proliferation ability in response to external stimuli.