INVESTIGADORES
DE SIERVI Adriana
congresos y reuniones científicas
Título:
BRCA1 regulates GADD153-mediated apoptosis in prostate cancer cells.
Autor/es:
DE LUCA P; CHAMORRO J; RUIZ GRECCO M; GUERON G; ZALAZAR F; GARDNER K; NAVONE N; VAZQUEZ E; DE SIERVI A
Lugar:
San Diego, California, USA
Reunión:
Congreso; 99th AACR Annual Meeting; 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, like 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 its own promoter in vivo in prostate cancer cells. However, following treatment with genotoxic agents, BRCA1 is released, its transcription is triggered and key promoters in the DNA damage response are recruited. 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 suggest a new mechanism for the DNA damage response in prostate cancer that involves BRCA1 and GADD153. Improvement of the knowledge of these processes can facilitate new therapeutic tools for androgen independent prostate cancer.