Abstract
The widely prevailing view that the cyclin-dependent kinase inhibitors (CKIs) are solely negative regulators of cyclin-dependent kinases (CDKs) is challenged here by observations that normal up-regulation of cyclin D- CDK4 in mitogen-stimulated fibroblasts depends redundantly upon p21(Cip1) and p27(Kip1). Primary mouse embryonic fibroblasts that lack genes encoding both p21 and p27 fail to assemble detectable amounts of cyclin D-CDK complexes, express cyclin D proteins at much reduced levels, and are unable to efficiently direct cyclin D proteins to the cell nucleus. Restoration of CKI function reverses all three defects and thereby restores cyclin D activity to normal physiological levels. In the absence of both CKIs, the severe reduction in cyclin D-dependent kinase activity was well tolerated and had no overt effects on the cell cycle.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Animals
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Cell Cycle Proteins*
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Cell Line
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Cells, Cultured
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Cyclin D
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Cyclin-Dependent Kinase 4
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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 / antagonists & inhibitors
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Cyclin-Dependent Kinases / metabolism*
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Cyclins / deficiency
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Cyclins / metabolism*
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Embryo, Mammalian
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Enzyme Inhibitors / metabolism
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Fibroblasts / cytology
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Fibroblasts / physiology
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Humans
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Kinetics
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Mice
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Mice, Knockout
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Microtubule-Associated Proteins / deficiency
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Microtubule-Associated Proteins / metabolism*
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Proto-Oncogene Proteins*
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Recombinant Fusion Proteins / metabolism
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Transfection
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Tumor Suppressor Proteins*
Substances
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CDKN1A protein, human
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Cdkn1a protein, mouse
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Cdkn1b protein, mouse
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Cell Cycle Proteins
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Cyclin D
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Cyclin-Dependent Kinase Inhibitor p21
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Cyclins
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Enzyme Inhibitors
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Microtubule-Associated Proteins
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Proto-Oncogene Proteins
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Recombinant Fusion Proteins
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Tumor Suppressor Proteins
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Cyclin-Dependent Kinase Inhibitor p27
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CDK4 protein, human
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Cdk4 protein, mouse
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Cyclin-Dependent Kinase 4
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Cyclin-Dependent Kinases