Abstract
Progression of cells through the G1 phase of the cell cycle requires cyclin D:Cdk4/6 and cyclin E:Cdk2 complexes; however, the duration and ordering of these complexes remain unclear. To address this, we synthesized a peptidyl mimetic of the Cdk4/6 inhibitor, p16INK4a that contained an NH2-terminal TAT protein transduction domain. Transduction of TAT-p16 wild-type peptides into cells resulted in the loss of active, hypophosphorylated pRb and elicited an early G1 cell cycle arrest, provided cyclin E:Cdk2 complexes were inactive. We conclude that cyclin D:Cdk4/6 activity is required for early G1 phase cell cycle progression up to, but not beyond, activation of cyclin E:Cdk2 complexes at the restriction point and is thus nonredundant with cyclin E:Cdk2 in late G1.
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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CDC2-CDC28 Kinases*
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Cell Line
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Cyclin D
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Cyclin E / physiology
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Cyclin-Dependent Kinase 2
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Cyclin-Dependent Kinase 4
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Cyclin-Dependent Kinase 6
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Cyclin-Dependent Kinase Inhibitor p16 / physiology*
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Cyclin-Dependent Kinases / physiology*
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Cyclins / physiology*
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G1 Phase / physiology*
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Humans
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Keratinocytes
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Phosphorylation
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Protein Serine-Threonine Kinases / physiology*
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Proto-Oncogene Proteins*
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Retinoblastoma Protein / metabolism*
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Transfection
Substances
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Cyclin D
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Cyclin E
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Cyclin-Dependent Kinase Inhibitor p16
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Cyclins
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Proto-Oncogene Proteins
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Retinoblastoma Protein
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Protein Serine-Threonine Kinases
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CDC2-CDC28 Kinases
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CDK2 protein, human
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CDK4 protein, human
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CDK6 protein, human
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Cyclin-Dependent Kinase 2
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Cyclin-Dependent Kinase 4
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Cyclin-Dependent Kinase 6
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Cyclin-Dependent Kinases