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(KIP1) and p21(CIP1) 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.
Lin
J
J
Department of Biochemistry and Molecular Biology, Graduate School of Medicine, The University of Tokyo, Hongo, Bunkyo-ku, Tokyo 113-0033, Japan.
Jinno
S
S
Okayama
H
H
D016475:3T3 Cells; D000818:Animals; D002448:Cell Adhesion / Q000502:physiology; D018797:Cell Cycle Proteins; D002455:Cell Division / Q000502:physiology; D003260:Contact Inhibition / Q000502:physiology; D056743:Cyclin D3; D051361:Cyclin-Dependent Kinase 6; D050759:Cyclin-Dependent Kinase Inhibitor p21; D050760:Cyclin-Dependent Kinase Inhibitor p27; D018844:Cyclin-Dependent Kinases; D016213:Cyclins / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000502:physiology*; D016193:G1 Phase / Q000502:physiology; D051379:Mice; D008807:Mice, Inbred BALB C; D008809:Mice, Inbred C3H; D008869:Microtubule-Associated Proteins / Q000378:metabolism / Q000502:physiology; D010982:Platelet-Derived Growth Factor / Q000494:pharmacology; D011233:Precipitin Tests; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000502:physiology*; D051381:Rats; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D025521:Tumor Suppressor Proteins
C534697:Ccnd3 protein, mouse; C534698:Ccnd3 protein, rat; C493957:Cdkn1a protein, mouse; C493958:Cdkn1a protein, rat; C493961:Cdkn1b protein, mouse; C493962:Cdkn1b protein, rat; D018797:Cell Cycle Proteins; D056743:Cyclin D3; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D008869:Microtubule-Associated Proteins; D010982:Platelet-Derived Growth Factor; D025521:Tumor Suppressor Proteins; D050760:Cyclin-Dependent Kinase Inhibitor p27; D017346:Protein Serine-Threonine Kinases; C495912:Cdk6 protein, mouse; C495913:Cdk6 protein, rat; D051361:Cyclin-Dependent Kinase 6; D018844:Cyclin-Dependent Kinases; D013755:Tetradecanoylphorbol Acetate