title: pRb/E2F-1-mediated caspase-dependent induction of Noxa amplifies the apoptotic effects of the Bcl-2/Bcl-xL inhibitor ABT-737.
abstract: Although Bcl-2 family members control caspase activity by regulating mitochondrial permeability, caspases can, in turn, amplify the apoptotic process upstream of mitochondria by ill-characterized mechanisms. We herein show that treatment with a potent inhibitor of Bcl-2 and Bcl-xL, ABT-737, triggers caspase-dependent induction of the BH3-only protein, Mcl-1 inhibitor, Noxa. RNA interference experiments reveal that induction of Noxa, and subsequent cell death, rely not only on the transcription factor E2F-1 but also on its regulator pRb. In response to ABT-737, pRb is cleaved by caspases into a p68Rb form that still interacts with E2F-1. Moreover, pRb occupies the noxa promoter together with E2F-1, in a caspase-dependent manner upon ABT-737 treatment. Thus, caspases contribute to trigger the mitochondrial apoptotic pathway by coupling Bcl-2/Bcl-xL inhibition to that of Mcl-1, via the pRb/E2F-1-dependent induction of Noxa.
authors: UMR 892 INSERM/6299 CNRS/Université de Nantes, Team 8 Cell survival and tumor escape in breast cancer, Institut de Recherche en Santé de l'Université de Nantes, Nantes, France.
authors: J
authors: J
authors: Bertin-Ciftci
authors: B
authors: B
authors: Barré
authors: J
authors: J
authors: Le Pen
authors: L
authors: L
authors: Maillet
authors: C
authors: C
authors: Couriaud
authors: P
authors: P
authors: Juin
authors: F
authors: F
authors: Braun
mesh_terms: D017209:Apoptosis / Q000187:drug effects*; D051017:Apoptosis Regulatory Proteins / Q000235:genetics; D001713:Biphenyl Compounds / Q000494:pharmacology*; D001943:Breast Neoplasms; D020169:Caspases / Q000378:metabolism; D045744:Cell Line, Tumor; D004268:DNA-Binding Proteins / Q000235:genetics; D050687:E2F1 Transcription Factor / Q000235:genetics / Q000378:metabolism*; D005260:Female; D006801:Humans; D008928:Mitochondria / Q000378:metabolism; D033681:Mitochondrial Membrane Transport Proteins; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D009596:Nitrophenols / Q000494:pharmacology*; D009687:Nuclear Proteins / Q000235:genetics; D010879:Piperazines / Q000494:pharmacology; D011401:Promoter Regions, Genetic; D011518:Proto-Oncogene Proteins / Q000235:genetics; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D034622:RNA Interference; D034741:RNA, Small Interfering; D016160:Retinoblastoma Protein / Q000235:genetics / Q000378:metabolism*; D013449:Sulfonamides / Q000494:pharmacology*; D014158:Transcription, Genetic; D000072160:Tumor Protein p73; D025521:Tumor Suppressor Proteins / Q000235:genetics; D051028:bcl-2-Associated X Protein / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D051020:bcl-X Protein / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism
chemical_list: C501332:ABT-737; D051017:Apoptosis Regulatory Proteins; C494826:BAX protein, human; C438378:BBC3 protein, human; C494811:BCL2L1 protein, human; D001713:Biphenyl Compounds; D004268:DNA-Binding Proteins; D050687:E2F1 Transcription Factor; D033681:Mitochondrial Membrane Transport Proteins; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D009596:Nitrophenols; D009687:Nuclear Proteins; C498702:PMAIP1 protein, human; D010879:Piperazines; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D034741:RNA, Small Interfering; C581062:RTL10 protein, human; D016160:Retinoblastoma Protein; D013449:Sulfonamides; D000072160:Tumor Protein p73; D025521:Tumor Suppressor Proteins; D051028:bcl-2-Associated X Protein; D051020:bcl-X Protein; D020169:Caspases