INVESTIGADORES
VAZQUEZ Elba Susana
congresos y reuniones científicas
Título:
BRCA1 regulates GADD153-mediated apoptosis in prostate cancer
Autor/es:
DE LUCA PAOLA; CHAMORRO JULIAN; RUIZ GRECCO MARINA; GUERON GERALDINE; ZALAZAR FLORENCIA; GARDNER KEVIN; VAZQUEZ ELBA; DE SIERVI ADRIANA
Lugar:
San Diego, California, USA
Reunión:
Congreso; Annual Meeting American Association for Cancer Research; 2008
Institución organizadora:
American Association for Cancer Research
Resumen:
Inherited mutations of BRCA1, a tumor suppressor, confer a high risk for breast, ovarian and other type of human tumors, including prostate cancer. BRCA1 regulates the DNA damage response, cell cycle progression, apoptosis, steroid hormone responses, and the maintenance of genomic integrity. Recently we determined that BRCA1 is a central component in the regulation of its own promoter via a novel negative feedback mechanism in leukemia cells. In this study we found by chromatin immunoprecipitation that BRCA1 is highly enriched at the BRCA1 promoter in prostate cancer cells. Following exposure to genotoxic agents BRCA1 is released from it own promoter in order to be recruit to other genes or sites of DNA damage. This release leads to derepression of BRCA1 transcription. Strikingly, we found that the release of BRCA1 from its own promoter is accompanied by an increase in its occupancy at the GADD153 and an increase in GADD153 transcription. Thus, we identified a new BRCA1 target: GADD153, a growth arrest and DNA damage response transcription factor. We determined that BRCA1 binds GADD153 promoter with higher affinity after DNA damage and BRCA1 overexpression increased GADD153 transcription. Accordingly, silencing BRCA1 levels caused marked repression of GADD153 transcription. Furthermore, GADD153 mediated apoptosis induced by DNA damage was significantly diminished after decrease BRCA1 protein levels with siRNA transfections. This mechanism was reverted by the presence of p53 suggesting that GADD153 regulation by BRCA1 in response to DNA damage is a p53 dependent pathway. All together these results show a new mechanism for the DNA damage response in prostate cancer involving BRCA1 and GADD153. It suggests that BRCA1 and GADD153 show coordinate upregulation through promoter exchange of BRCA1 protein following DNA damage. Further elucidation of the mechanism of this novel form of regulation will facilitate the design and development of new therapeutic tools against androgen independent prostate cancer.