Abstract
The protein p21 (WAF1, CIP1 or sdi1), induced by the tumour-suppressor protein p53, interacts with and inhibits two different targets essential for cell-cycle progression. One of these is the cyclin-Cdk family of kinases and the other is the essential DNA replication factor, proliferating-cell nuclear antigen (PCNA). We report here that separate domains of p21 are responsible for interacting with and inhibiting the two targets. An amino-terminal domain inhibits cyclin-Cdk kinases and a carboxy-terminal domain inhibits PCNA. Using these separated domains, we have determined that p21 inhibits different biological systems through different targets. The PCNA-binding domain is sufficient for inhibition of DNA replication based on simian virus 40, whereas the Cdk2-binding domain is sufficient for inhibition of DNA replication based on Xenopus egg extract and for growth suppression in transformed human cells.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, Non-P.H.S.
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Animals
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Binding Sites
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CDC2-CDC28 Kinases*
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Cell Division / drug effects
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Cell Line, Transformed
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Cyclin-Dependent Kinase 2
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Cyclin-Dependent Kinase Inhibitor p21
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Cyclin-Dependent Kinases / antagonists & inhibitors*
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Cyclins / pharmacology*
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DNA Replication / drug effects
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Escherichia coli
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Haplorhini
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Humans
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Peptide Fragments / metabolism
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Proliferating Cell Nuclear Antigen / drug effects
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Proliferating Cell Nuclear Antigen / metabolism*
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Protein Serine-Threonine Kinases / antagonists & inhibitors*
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Recombinant Fusion Proteins / metabolism
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Simian virus 40 / genetics
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Tumor Cells, Cultured
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Xenopus
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Xenopus Proteins
Substances
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CDKN1A protein, human
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Cyclin-Dependent Kinase Inhibitor p21
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Cyclins
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Peptide Fragments
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Proliferating Cell Nuclear Antigen
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Recombinant Fusion Proteins
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Xenopus Proteins
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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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Cdk2 protein, Xenopus
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Cyclin-Dependent Kinase 2
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Cyclin-Dependent Kinases