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

Oncogene. 2001 Apr 12;20(16):2000-9. doi: 10.1038/sj.onc.1204375.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 3T3 Cells
  • Animals
  • Cell Adhesion / physiology
  • Cell Cycle Proteins*
  • Cell Division / physiology
  • Contact Inhibition / physiology
  • Cyclin D3
  • Cyclin-Dependent Kinase 6
  • Cyclin-Dependent Kinase Inhibitor p21
  • Cyclin-Dependent Kinase Inhibitor p27
  • Cyclin-Dependent Kinases*
  • Cyclins / antagonists & inhibitors
  • Cyclins / metabolism
  • Cyclins / physiology*
  • G1 Phase / physiology
  • Mice
  • Mice, Inbred BALB C
  • Mice, Inbred C3H
  • Microtubule-Associated Proteins / metabolism
  • Microtubule-Associated Proteins / physiology
  • Platelet-Derived Growth Factor / pharmacology
  • Precipitin Tests
  • Protein-Serine-Threonine Kinases / antagonists & inhibitors
  • Protein-Serine-Threonine Kinases / metabolism
  • Protein-Serine-Threonine Kinases / physiology*
  • Rats
  • Tetradecanoylphorbol Acetate / pharmacology
  • Tumor Suppressor Proteins*

Substances

  • Ccnd3 protein, mouse
  • Ccnd3 protein, rat
  • Cdkn1a protein, mouse
  • Cdkn1a protein, rat
  • Cdkn1b protein, mouse
  • Cdkn1b protein, rat
  • Cell Cycle Proteins
  • Cyclin D3
  • Cyclin-Dependent Kinase Inhibitor p21
  • Cyclins
  • Microtubule-Associated Proteins
  • Platelet-Derived Growth Factor
  • Tumor Suppressor Proteins
  • Cyclin-Dependent Kinase Inhibitor p27
  • Protein-Serine-Threonine Kinases
  • Cdk6 protein, mouse
  • Cdk6 protein, rat
  • Cyclin-Dependent Kinase 6
  • Cyclin-Dependent Kinases
  • Tetradecanoylphorbol Acetate