Artículo
BRCA1 loss induces GADD153-mediated doxorubicin resistance in prostate cancer
de Luca, Paola
; Vazquez, Elba Susana
; Moiola, Cristian Pablo
; Zalazar, Florencia
; Cotignola, Javier Hernan
; Gueron, Geraldine
; Gardner, Kevin; de Siervi, Adriana
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Fecha de publicación:
08/2011
Editorial:
American Association for Cancer Research
Revista:
Molecular Cancer Research
ISSN:
1541-7786
Idioma:
Inglés
Tipo de recurso:
Artículo publicado
Clasificación temática:
Resumen
BRCA1 plays numerous roles in the regulation of genome integrity and chemoresistance. Although BRCA1 interaction with key proteins involved in DNA repair is well known, its role as a coregulator in the transcriptional response to DNA damage remains poorly understood. In this study, we show that BRCA1 plays a central role in the transcriptional response to genotoxic stress in prostate cancer. BRCA1 expression mediates apoptosis, cell-cycle arrest, and decreased viability in response to doxorubicin treatment. Xenograft studies using human prostate carcinoma PC3 cells show that BRCA1 depletion results in increased tumor growth. A focused survey of BRCA1- regulated genes in prostate carcinoma reveals that multiple regulators of genome stability and cell-cycle control, including BLM, FEN1, DDB2, H3F3B, BRCA2, CCNB2, MAD2L1, and GADD153, are direct transcriptional targets of BRCA1. Furthermore, we show that BRCA1 targets GADD153 promoter to increase its transcription in response to DNA damage. Finally, GADD153 depletion significantly abrogates BRCA1 influence on cell-cycle progression and cell death in response to doxorubicin treatment. These findings define a novel transcriptional pathway through which BRCA1 orchestrates cell fate decisions in response to genotoxic insults, and suggest that BRCA1 status should be considered for new chemotherapeutic treatment strategies in prostate cancer. ©2011 AACR.
Palabras clave:
Brca1
,
Prostate Cancer
,
Gadd153
,
Dna Damage
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Articulos(IQUIBICEN)
Articulos de INSTITUTO DE QUIMICA BIOLOGICA DE LA FACULTAD DE CS. EXACTAS Y NATURALES
Articulos de INSTITUTO DE QUIMICA BIOLOGICA DE LA FACULTAD DE CS. EXACTAS Y NATURALES
Articulos(OCA CIUDAD UNIVERSITARIA)
Articulos de OFICINA DE COORDINACION ADMINISTRATIVA CIUDAD UNIVERSITARIA
Articulos de OFICINA DE COORDINACION ADMINISTRATIVA CIUDAD UNIVERSITARIA
Articulos(SEDE CENTRAL)
Articulos de SEDE CENTRAL
Articulos de SEDE CENTRAL
Citación
de Luca, Paola; Vazquez, Elba Susana; Moiola, Cristian Pablo; Zalazar, Florencia; Cotignola, Javier Hernan; et al.; BRCA1 loss induces GADD153-mediated doxorubicin resistance in prostate cancer; American Association for Cancer Research; Molecular Cancer Research; 9; 8; 8-2011; 1078-1090
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