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Role of BRCA1 in heat shock response

Oncogene volume 22, pages 10–27 (2003)Cite this article

Abstract

The heat shock response is an evolutionarily conserved response to heat and other stresses that promotes the maintenance of key metabolic functions and cell survival. We report that exposure of human prostate (DU-145) and breast (MCF-7) cancer cells to heat (42°C) caused a rapid disappearance of the breast cancer susceptibility gene-1 (BRCA1) protein, starting at ≈1 h after the onset of heating and slightly lagging behind the increase in heat shock protein 70 (HSP70) levels. The heat-induced loss of BRCA1 occurred at the protein level, since: (1) BRCA1 mRNA expression was unaffected; and (2) the BRCA1 protein loss was also observed in DU-145 cells that expressed exogenous wild-type BRCA1 (wtBRCA1). In addition to heat regulation of BRCA1 protein levels, we also found that BRCA1 could modulate the heat shock response. Thus, wtBRCA1 overexpressing DU-145 cell clones showed significantly decreased sensitivity to heat-induced cytotoxicity; and Brca1 mutant mouse embryo fibroblasts showed increased sensitivity to heat. The DU-145 wtBRCA1 clones also showed increased expression of the small heat shock protein HSP27; and reporter assays revealed that wtBRCA1 stimulated a two to four-fold increase in HSP27 promoter activity, consistent with its ability to upregulate HSP27 mRNA and protein levels. In studies using epitope-tagged truncated BRCA1 proteins, the ability to stimulate the HSP27 promoter and to mediate heat-induced degradation required the amino-terminus but not the carboxyl-terminus of BRCA1. Although the heat-induced loss of BRCA1 appeared to be due to protein degradation, various protein metabolic agents (or combinations) failed to block this event, including: MG132 (a 26S proteasomal inhibitor), N-acetyl-leucyl-leucyl-norleucinal (a calpain inhibitor), z-VAD-fmk (a pan-caspase inhibitor), and ammonium chloride and chloroquine (which stabilize lysosomes). These findings suggest that in addition to its other functions, BRCA1 may participate in mammalian heat shock response pathways.

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Acknowledgements

This research was supported, in part, by research grants from the USPHS (R01-ES09169, RO1-CA80000, and R01-CA82599), the Susan G Komen Breast Cancer Foundation (BASIC-003255), and the US Army Breast Cancer Research Program (DAMD17-99-1-9254).

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Authors and Affiliations

  1. Department of Radiation Oncology, Long Island Jewish Medical Center, The Long Island Campus for the Albert Einstein College of Medicine, 270-05 76th Avenue, New Hyde Park, 11040, NY, USA

    Yong Xian Ma, Saijun Fan, Jingbo Xiong, Ren-qi Yuan, Qinghui Meng, Min Gao, Itzhak D Goldberg & Eliot M Rosen

  2. Department of Radiation Oncology, Albert Einstein College of Medicine, Bronx, 10461, NY, USA

    Saijun Fan, Itzhak D Goldberg & Eliot M Rosen

  3. Breast Center, Baylor College of Medicine, One Baylor Plaza Houston, 77030, TX, USA

    Suzanne A Fuqua

  4. Department of Developmental and Molecular Biology, Albert Einstein College of Medicine, Bronx, 10461, NY, USA

    Richard G Pestell & Eliot M Rosen

  5. Department of Medicine, Albert Einstein College of Medicine, Bronx, 10461, NY, USA

    Richard G Pestell

  6. Division of Hormone Dependent Tumor Biology, Albert Einstein College of Medicine, 1300 Morris Park Aveneu, Bronx, 10461, USA

    Richard G Pestell & Eliot M Rosen

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Xian Ma, Y., Fan, S., Xiong, J. et al. Role of BRCA1 in heat shock response. Oncogene 22, 10–27 (2003). https://doi.org/10.1038/sj.onc.1206061

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