Arrest of the cell cycle by the tumour-suppressor BRCA1 requires the CDK-inhibitor p21WAF1/CiP1

Nature. 1997 Sep 11;389(6647):187-90. doi: 10.1038/38291.


Much of the predisposition to hereditary breast and ovarian cancer has been attributed to inherited defects in the BRCA1 tumour-suppressor gene. The nuclear protein BRCA1 has the properties of a transcription factor, and can interact with the recombination and repair protein RAD51. Young women with germline alterations in BRCA1 develop breast cancer at rates 100-fold higher than the general population, and BRCA1-null mice die before day 8 of development. However, the mechanisms of BRCA1-mediated growth regulation and tumour suppression remain unknown. Here we show that BRCA1 transactivates expression of the cyclin-dependent kinase inhibitor p21WAF1/CIP1 in a p53-independent manner, and that BRCA1 inhibits cell-cycle progression into the S-phase following its transfection into human cancer cells. BRCA1 does not inhibit S-phase progression in p21-/- cells, unlike p21+/+ cells, and tumour-associated, transactivation-deficient mutants of BRCA1 are defective in both transactivation of p21 and cell-cycle inhibition. These data suggest that one mechanism by which BRCA1 contributes to cell-cycle arrest and growth suppression is through the induction of p21.

Publication types

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

MeSH terms

  • Animals
  • BRCA1 Protein / genetics
  • BRCA1 Protein / physiology*
  • COS Cells
  • Cell Cycle / genetics
  • Cell Cycle / physiology*
  • Cyclin-Dependent Kinase Inhibitor p21
  • Cyclin-Dependent Kinases / metabolism
  • Cyclins / genetics
  • Cyclins / physiology*
  • DNA / biosynthesis
  • Enzyme Inhibitors / pharmacology
  • Gene Expression Regulation
  • Genes, Tumor Suppressor
  • Green Fluorescent Proteins
  • HeLa Cells
  • Humans
  • Luminescent Proteins
  • Mice
  • Mutation
  • Promoter Regions, Genetic
  • Transcriptional Activation
  • Transfection
  • Tumor Cells, Cultured


  • BRCA1 Protein
  • CDKN1A protein, human
  • Cdkn1a protein, mouse
  • Cyclin-Dependent Kinase Inhibitor p21
  • Cyclins
  • Enzyme Inhibitors
  • Luminescent Proteins
  • Green Fluorescent Proteins
  • DNA
  • Cyclin-Dependent Kinases