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BRCA1 shifts p53-mediated cellular outcomes towards irreversible growth arrest

Oncogene volume 22, pages 3749–3758 (2003)Cite this article

Abstract

The tumor suppressor protein BRCA1 has been shown to enhance p53 transcription, whereas activated p53 represses BRCA1 transcription. To further understand the functional interaction of these proteins, we investigated the role of BRCA1 in p53-induced phenotypes. We found that BRCA1 when subjected to forced expression acts synergistically with wild-type p53, resulting in irreversible growth arrest, as shown by VhD mouse fibroblast cells expressing a temperature-sensitive mutant of p53. Furthermore, reintroduction of both BRCA1 and p53 into BRCA1(−/−)/p53(−/−) mouse embryonic fibroblasts markedly increased the senescence phenotype compared to that induced by p53 alone. In particular, we found that BRCA1 expression attenuated p53-mediated cell death in response to γ-irradiation. Moreover, microarray screening of 11 000 murine genes demonstrated that a set of genes upregulated by p53 is enhanced by coexpression of BRCA1 and p53, suggesting that BRCA1 and p53 exert a promoter selectivity leading to a specific phenotype. Taken together, our results provide evidence that BRCA1 is involved in p53-mediated growth suppression rather than apoptosis.

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Abbreviations

FACS:

Fluorescence-activated cell sorting

FBS:

fetal bovine serum

GFP:

Green fluorescence protein

MEF:

Mouse embryonic fibroblast

PAGE:

Polyacrylamide gel electrophoresis

SA-β-gal:

Senescence-associated β-galactosidase

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Acknowledgements

We thank K-P Lu for useful comments and suggestions, M Ouchi for technical assistance, and M Meyer for proofreading of the manuscript. We thank R Scully for HCC1937-IRES BRCA1 cells, A Levine and X Wu for providing VhD cells, B Vogelstein for the adenovirus expression system and J Yu for PUMA antibodies. This work was supported in part by Grants CA78356, CA85214, and CA80058 from the National Institutes of Health.

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  1. Contributed equally to the work

Authors and Affiliations

  1. Hematology/Oncology Division, Cancer Biology Program, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, 02115, MA, USA

    Pat P Ongusaha, Kyung-tae Kim, Emily Nytko, Jennifer C Kwak & Sam W Lee

  2. Derald H Ruttenberg Cancer Center, Mount Sinai School of Medicine, New York, 10029, NY, USA

    Toru Ouchi

  3. Department of Surgery, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, 02115, MA, USA

    Rosemary B Duda

  4. Genetics of Development and Disease Branch, National Institute of Diabetes, Digestive and Kidney Diseases, National Institutes of Health, Bethesda, 20892, MD, USA

    Chu-Xia Deng

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  1. Pat P Ongusaha
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Correspondence to Sam W Lee.

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Ongusaha, P., Ouchi, T., Kim, Kt. et al. BRCA1 shifts p53-mediated cellular outcomes towards irreversible growth arrest. Oncogene 22, 3749–3758 (2003). https://doi.org/10.1038/sj.onc.1206439

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