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

Nature volume 389, pages 187–190 (1997)Cite this article

Abstract

Much of the predisposition to hereditary breast and ovarian cancer has been attributed to inherited defects in the BRCA1 tumour-suppressor gene1,2,3. The nuclear protein BRCA1 has the properties of a transcription factor4,5,6,7, and can interact with the recombination and repair protein RAD51 (ref. 8). Young women with germline alterations in BRCA1 develop breast cancer at rates 100-fold higher than the general population3, and BRCA1-null mice die before day 8 of development9,10. 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.

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Figure 1: BRCA1 transfection inhibits DNA synthesis in human cancer cells.
Figure 4: BRCA1 fails to inhibit DNA synthesis in p21−/− human cancer cells.
Figure 2: BRCA1 transactivates the human and mouse p21-promoter and upregulates endogenous p21 protein expression.
Figure 3: BRCA1 mutants are defective for activation of p21.

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Acknowledgements

This work was supported by grants from the NIH and the Breast Cancer Research Foundation to B.L.W. W.S.E.-D. is an assistant investigator of the Howard Hughes Medical Institute.

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Author notes

  1. Kumaravel Somasundaram and Hongbing Zhang: These authors contributed equally to this study.

Authors and Affiliations

  1. Laboratory of Molecular Oncology and Cell Cycle Regulation, Howard Hughes Medical Institute, University of Pennsylvania School of Medicine, Philadelphia, 19104, Pennsylvania, USA

    Kumaravel Somasundaram, Yi-Xin Zeng, Gen Sheng Wu & Wafik S. El-Deiry

  2. Departments of Medicine, University of Pennsylvania School of Medicine, Philadelphia, 19104, Pennsylvania, USA

    Kumaravel Somasundaram, Hongbing Zhang, Yi-Xin Zeng, Yi Peng, Hongxiang Zhang, Gen Sheng Wu, Barbara L. Weber & Wafik S. El-Deiry

  3. Departments of Genetics, University of Pennsylvania School of Medicine, Philadelphia, 19104, Pennsylvania, USA

    Barbara L. Weber & Wafik S. El-Deiry

  4. Departments of Cancer Center, University of Pennsylvania School of Medicine, Philadelphia, 19104, Pennsylvania, USA

    Barbara L. Weber & Wafik S. El-Deiry

  5. Brookdale Center for Developmental and Molecular Biology and Department of Medicine, The Mount Sinai School of Medicine, New York, 10029, New York, USA

    Yariv Houvras & Jonathan D. Licht

Authors
  1. Kumaravel Somasundaram
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  2. Hongbing Zhang
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  10. Wafik S. El-Deiry
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Correspondence to Wafik S. El-Deiry.

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Somasundaram, K., Zhang, H., Zeng, YX. et al. Arrest of the cell cycle by the tumour-suppressor BRCA1 requires the CDK-inhibitor p21WAF1/CiPl. Nature 389, 187–190 (1997). https://doi.org/10.1038/38291

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