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Synthetic lethality of PARP inhibition in BRCA-network disrupted tumor cells is associated with interferon pathway activation and enhanced by interferon-γ.
Warrener, Paul; Kim, Sammy; Williams, Sybil M G; Biery, Matthew; Gordon, Marcia; Toniatti, Carlo; Cleary, Michele A; Linsley, Peter S; Carleton, Michael.
Afiliación
  • Warrener P; Rosetta Inpharmatics LLC, A Wholly Owned Subsidiary of Merck & Co., Inc, Seattle, WA 98109, USA.
Apoptosis ; 17(7): 691-701, 2012 Jul.
Article en En | MEDLINE | ID: mdl-22392482
Tumor suppressor genes BRCA1 and BRCA2 function in a complex gene network that regulates homologous recombination and DNA double-strand break repair. Disruption of the BRCA-network through gene mutation, deletion, or RNAi-mediated silencing can sensitize cells to small molecule inhibitors of poly (ADP-ribose) polymerase (PARPi). Here, we demonstrate that BRCA-network disruption in the presence of PARPi leads to the selective induction and enhancement of interferon pathway and apoptotic gene expression in cultured tumor cells. In addition, we report PARPi cytotoxicity in BRCA1-deficient tumor cells is enhanced >10-fold when combined with interferon-γ. These findings establish a link between synthetic lethality of PARPi in BRCA-network disrupted cells and interferon pathway activation triggered by genetic instability.
Asunto(s)

Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Transducción de Señal / Interferón gamma / Proteína BRCA1 / Redes Reguladoras de Genes / Inhibidores de Poli(ADP-Ribosa) Polimerasas Tipo de estudio: Risk_factors_studies Límite: Humans Idioma: En Revista: Apoptosis Año: 2012 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Países Bajos

Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Transducción de Señal / Interferón gamma / Proteína BRCA1 / Redes Reguladoras de Genes / Inhibidores de Poli(ADP-Ribosa) Polimerasas Tipo de estudio: Risk_factors_studies Límite: Humans Idioma: En Revista: Apoptosis Año: 2012 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Países Bajos