Inhibition of cyclin-dependent kinases by p21 - PubMed (original) (raw)

Inhibition of cyclin-dependent kinases by p21

J W Harper et al. Mol Biol Cell. 1995 Apr.

Free PMC article

Abstract

p21Cip1 is a cyclin-dependent kinase (Cdk) inhibitor that is transcriptionally activated by p53 in response to DNA damage. We have explored the interaction of p21 with the currently known Cdks. p21 effectively inhibits Cdk2, Cdk3, Cdk4, and Cdk6 kinases (Ki 0.5-15 nM) but is much less effective toward Cdc2/cyclin B (Ki approximately 400 nM) and Cdk5/p35 (Ki > 2 microM), and does not associate with Cdk7/cyclin H. Overexpression of P21 arrests cells in G1. Thus, p21 is not a universal inhibitor of Cdks but displays selectivity for G1/S Cdk/cyclin complexes. Association of p21 with Cdks is greatly enhanced by cyclin binding. This property is shared by the structurally related inhibitor p27, suggesting a common biochemical mechanism for inhibition. With respect to Cdk2 and Cdk4 complexes, p27 shares the inhibitory potency of p21 but has slightly different kinase specificities. In normal diploid fibroblasts, the vast majority of active Cdk2 is associated with p21, but this active kinase can be fully inhibited by addition of exogenous p21. Reconstruction experiments using purified components indicate that multiple molecules of p21 can associate with Cdk/cyclin complexes and inactive complexes contain more than one molecule of p21. Together, these data suggest a model whereby p21 functions as an inhibitory buffer whose levels determine the threshold kinase activity required for cell cycle progression.

PubMed Disclaimer

Similar articles

Cited by

References

    1. Genes Dev. 1993 Jul;7(7A):1111-25 - PubMed
    1. Cell. 1994 Jul 15;78(1):67-74 - PubMed
    1. Cell. 1992 Sep 18;70(6):993-1006 - PubMed
    1. Genes Dev. 1993 Aug;7(8):1572-83 - PubMed
    1. Proc Natl Acad Sci U S A. 1992 Apr 1;89(7):2907-11 - PubMed

Publication types

MeSH terms

Substances

LinkOut - more resources