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The cyclin-dependent kinase (Cdk) inhibitor p21 is induced by the tumor suppressor p53 and is required for the G1-S block in cells with DNA damage. We report that there are two copies of a cyclin-binding motif in p21, Cy1 and Cy2, which interact with the cyclins independently of Cdk2. The cyclin-binding motifs of p21 are required for optimum inhibition of cyclin-Cdk kinases in vitro and for growth suppression in vivo. Peptides containing only the Cy1 or Cy2 motif partially inhibit cyclin-Cdk kinase activity in vitro and DNA replication in Xenopus egg extracts. A monoclonal antibody which recognizes the Cy1 site of p21 specifically disrupts the association of p21 with cyclin E-Cdk2 and with cyclin D1-Cdk4 in cell extracts. Taken together, these observations suggest that the cyclin-binding motif of p21 is important for kinase inhibition and for formation of p21-cyclin-Cdk complexes in the cell. Finally, we show that the cyclin-Cdk complex is partially active if associated with only the cyclin-binding motif of p21, providing an explanation for how p21 is found associated with active cyclin-Cdk complexes in vivo. The Cy sequences may be general motifs used by Cdk inhibitors or substrates to interact with the cyclin in a cyclin-Cdk complex.
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Radiation-induced cell cycle arrest compromised by p21 deficiency.
1995,
Pubmed
Chen,
Separate domains of p21 involved in the inhibition of Cdk kinase and PCNA.
1995,
Pubmed
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Xenbase
Chen,
Characterization of p21Cip1/Waf1 peptide domains required for cyclin E/Cdk2 and PCNA interaction.
1996,
Pubmed
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Mice lacking p21CIP1/WAF1 undergo normal development, but are defective in G1 checkpoint control.
1995,
Pubmed
Dutta,
Inhibition of DNA replication factor RPA by p53.
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Pubmed
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WAF1/CIP1 is induced in p53-mediated G1 arrest and apoptosis.
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Pubmed
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WAF1, a potential mediator of p53 tumor suppression.
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Pubmed
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Cdk-interacting protein 1 directly binds with proliferating cell nuclear antigen and inhibits DNA replication catalyzed by the DNA polymerase delta holoenzyme.
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Pubmed
Goubin,
Identification of binding domains on the p21Cip1 cyclin-dependent kinase inhibitor.
1995,
Pubmed
Gu,
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Pubmed
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Pubmed
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Pubmed
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p15INK4B is a potential effector of TGF-beta-induced cell cycle arrest.
1994,
Pubmed
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The p21 Cdk-interacting protein Cip1 is a potent inhibitor of G1 cyclin-dependent kinases.
1993,
Pubmed
Harper,
Inhibition of cyclin-dependent kinases by p21.
1995,
Pubmed
Hengst,
A cell cycle-regulated inhibitor of cyclin-dependent kinases.
1994,
Pubmed
Jackson,
Early events in DNA replication require cyclin E and are blocked by p21CIP1.
1995,
Pubmed
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Xenbase
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Pubmed
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Pubmed
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Pubmed
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Xenbase
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Pubmed
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1995,
Pubmed
Lees,
Sequences within the conserved cyclin box of human cyclin A are sufficient for binding to and activation of cdc2 kinase.
1993,
Pubmed
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Xenbase
Li,
Differential effects by the p21 CDK inhibitor on PCNA-dependent DNA replication and repair.
1994,
Pubmed
Lin,
Analysis of wild-type and mutant p21WAF-1 gene activities.
1996,
Pubmed
Luo,
Cell-cycle inhibition by independent CDK and PCNA binding domains in p21Cip1.
1995,
Pubmed
Matsuoka,
p57KIP2, a structurally distinct member of the p21CIP1 Cdk inhibitor family, is a candidate tumor suppressor gene.
1995,
Pubmed
Morgan,
Principles of CDK regulation.
1995,
Pubmed
Nakanishi,
Identification of the active region of the DNA synthesis inhibitory gene p21Sdi1/CIP1/WAF1.
1995,
Pubmed
Nobori,
Deletions of the cyclin-dependent kinase-4 inhibitor gene in multiple human cancers.
1994,
Pubmed
Noda,
Cloning of senescent cell-derived inhibitors of DNA synthesis using an expression screen.
1994,
Pubmed
Pan,
Inhibition of nucleotide excision repair by the cyclin-dependent kinase inhibitor p21.
1995,
Pubmed
Parker,
p53-independent expression of p21Cip1 in muscle and other terminally differentiating cells.
1995,
Pubmed
Polyak,
Cloning of p27Kip1, a cyclin-dependent kinase inhibitor and a potential mediator of extracellular antimitogenic signals.
1994,
Pubmed
Polyak,
p27Kip1, a cyclin-Cdk inhibitor, links transforming growth factor-beta and contact inhibition to cell cycle arrest.
1994,
Pubmed
Serrano,
A new regulatory motif in cell-cycle control causing specific inhibition of cyclin D/CDK4.
1993,
Pubmed
Sewing,
Alternative splicing of human cyclin E.
1994,
Pubmed
Sherr,
G1 phase progression: cycling on cue.
1994,
Pubmed
Shivji,
Cip1 inhibits DNA replication but not PCNA-dependent nucleotide excision-repair.
1994,
Pubmed
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Xenbase
Steinman,
Induction of p21 (WAF-1/CIP1) during differentiation.
1994,
Pubmed
Strausfeld,
Cip1 blocks the initiation of DNA replication in Xenopus extracts by inhibition of cyclin-dependent kinases.
1994,
Pubmed
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Xenbase
Toyoshima,
p27, a novel inhibitor of G1 cyclin-Cdk protein kinase activity, is related to p21.
1994,
Pubmed
Waga,
The p21 inhibitor of cyclin-dependent kinases controls DNA replication by interaction with PCNA.
1994,
Pubmed
Xiong,
p21 is a universal inhibitor of cyclin kinases.
1993,
Pubmed
Zhang,
p21-containing cyclin kinases exist in both active and inactive states.
1994,
Pubmed
Zhu,
p107 uses a p21CIP1-related domain to bind cyclin/cdk2 and regulate interactions with E2F.
1995,
Pubmed
