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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Apoptosis / drug effects*
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Apoptosis Regulatory Proteins / genetics
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Biphenyl Compounds / pharmacology*
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Breast Neoplasms
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Caspases / metabolism
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Cell Line, Tumor
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DNA-Binding Proteins / genetics
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E2F1 Transcription Factor / genetics
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E2F1 Transcription Factor / metabolism*
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Female
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Humans
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Mitochondria / metabolism
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Mitochondrial Membrane Transport Proteins
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Myeloid Cell Leukemia Sequence 1 Protein
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Nitrophenols / pharmacology*
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Nuclear Proteins / genetics
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Piperazines / pharmacology
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Promoter Regions, Genetic
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Proto-Oncogene Proteins / genetics
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Proto-Oncogene Proteins c-bcl-2 / antagonists & inhibitors
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Proto-Oncogene Proteins c-bcl-2 / genetics
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Proto-Oncogene Proteins c-bcl-2 / metabolism*
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RNA Interference
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RNA, Small Interfering
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Retinoblastoma Protein / genetics
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Retinoblastoma Protein / metabolism*
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Sulfonamides / pharmacology*
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Transcription, Genetic
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Tumor Protein p73
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Tumor Suppressor Proteins / genetics
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bcl-2-Associated X Protein / antagonists & inhibitors
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bcl-2-Associated X Protein / genetics
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bcl-2-Associated X Protein / metabolism
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bcl-X Protein / antagonists & inhibitors
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bcl-X Protein / genetics
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bcl-X Protein / metabolism
Substances
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ABT-737
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Apoptosis Regulatory Proteins
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BAX protein, human
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BBC3 protein, human
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BCL2L1 protein, human
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Biphenyl Compounds
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DNA-Binding Proteins
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E2F1 Transcription Factor
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Mitochondrial Membrane Transport Proteins
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Myeloid Cell Leukemia Sequence 1 Protein
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Nitrophenols
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Nuclear Proteins
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PMAIP1 protein, human
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Piperazines
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Proto-Oncogene Proteins
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Proto-Oncogene Proteins c-bcl-2
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RNA, Small Interfering
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RTL10 protein, human
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Retinoblastoma Protein
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Sulfonamides
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Tumor Protein p73
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Tumor Suppressor Proteins
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bcl-2-Associated X Protein
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bcl-X Protein
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Caspases