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
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Research Support, Non-U.S. Gov't
MeSH terms
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3T3 Cells
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Animals
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Cell Adhesion / physiology
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Cell Cycle Proteins*
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Cell Division / physiology
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Contact Inhibition / physiology
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Cyclin D3
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Cyclin-Dependent Kinase 6
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Cyclin-Dependent Kinase Inhibitor p21
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Cyclin-Dependent Kinase Inhibitor p27
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Cyclin-Dependent Kinases*
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Cyclins / antagonists & inhibitors
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Cyclins / metabolism
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Cyclins / physiology*
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G1 Phase / physiology
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Mice
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Mice, Inbred BALB C
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Mice, Inbred C3H
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Microtubule-Associated Proteins / metabolism
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Microtubule-Associated Proteins / physiology
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Platelet-Derived Growth Factor / pharmacology
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Precipitin Tests
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Protein Serine-Threonine Kinases / antagonists & inhibitors
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Protein Serine-Threonine Kinases / metabolism
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Protein Serine-Threonine Kinases / physiology*
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Rats
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Tetradecanoylphorbol Acetate / pharmacology
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Tumor Suppressor Proteins*
Substances
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Ccnd3 protein, mouse
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Ccnd3 protein, rat
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Cdkn1a protein, mouse
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Cdkn1a protein, rat
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Cdkn1b protein, mouse
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Cdkn1b protein, rat
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Cell Cycle Proteins
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Cyclin D3
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Cyclin-Dependent Kinase Inhibitor p21
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Cyclins
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Microtubule-Associated Proteins
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Platelet-Derived Growth Factor
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Tumor Suppressor Proteins
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Cyclin-Dependent Kinase Inhibitor p27
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Protein Serine-Threonine Kinases
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Cdk6 protein, mouse
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Cdk6 protein, rat
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Cyclin-Dependent Kinase 6
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Cyclin-Dependent Kinases
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Tetradecanoylphorbol Acetate