Separate Domains of p21 Involved in the Inhibition of Cdk Kinase and PCNA

Nature. 1995 Mar 23;374(6520):386-8. doi: 10.1038/374386a0.

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

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Binding Sites
  • CDC2-CDC28 Kinases*
  • Cell Division / drug effects
  • Cell Line, Transformed
  • Cyclin-Dependent Kinase 2
  • Cyclin-Dependent Kinase Inhibitor p21
  • Cyclin-Dependent Kinases / antagonists & inhibitors*
  • Cyclins / pharmacology*
  • DNA Replication / drug effects
  • Escherichia coli
  • Haplorhini
  • Humans
  • Peptide Fragments / metabolism
  • Proliferating Cell Nuclear Antigen / drug effects
  • Proliferating Cell Nuclear Antigen / metabolism*
  • Protein-Serine-Threonine Kinases / antagonists & inhibitors*
  • Recombinant Fusion Proteins / metabolism
  • Simian virus 40 / genetics
  • Tumor Cells, Cultured
  • Xenopus
  • Xenopus Proteins

Substances

  • CDKN1A protein, human
  • Cyclin-Dependent Kinase Inhibitor p21
  • Cyclins
  • Peptide Fragments
  • Proliferating Cell Nuclear Antigen
  • Recombinant Fusion Proteins
  • Xenopus Proteins
  • Protein-Serine-Threonine Kinases
  • CDC2-CDC28 Kinases
  • CDK2 protein, human
  • Cdk2 protein, Xenopus
  • Cyclin-Dependent Kinase 2
  • Cyclin-Dependent Kinases