Abstract
It is still unclear whether the BH3-only protein Puma (p53 up-regulated modulator of apoptosis) can prime cells to death and render antiapoptotic BH3-binding Bcl-2 homologues necessary for survival through its ability to directly interact with proapoptotic Bax and activate it. In this study, we provide further evidence, using cell-free assays, that the BH3 domain of Puma binds Bax at an activation site that comprises the first helix of Bax. We also show that, in yeast, Puma interacts with Bax and triggers its killing activity when Bcl-2 homologues are absent but not when Bcl-xL is expressed. Finally, endogenous Puma is involved in the apoptotic response of human colorectal cancer cells to the Bcl-2/Bcl-xL inhibitor ABT-737, even in conditions where the expression of Mcl-1 is down-regulated. Thus, Puma is competent to trigger Bax activity by itself, thereby promoting cellular dependence on prosurvival Bcl-2 family members.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Apoptosis / physiology
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Apoptosis Regulatory Proteins / genetics
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Apoptosis Regulatory Proteins / metabolism*
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Biphenyl Compounds / metabolism
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Cell Line, Tumor
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Colorectal Neoplasms / metabolism
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Cyclin-Dependent Kinase Inhibitor p21 / genetics
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Cyclin-Dependent Kinase Inhibitor p21 / metabolism
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Gene Knockdown Techniques
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Humans
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Myeloid Cell Leukemia Sequence 1 Protein
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Nitrophenols / metabolism
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Piperazines / metabolism
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Protein Binding
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Proto-Oncogene Proteins / genetics
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Proto-Oncogene Proteins / metabolism*
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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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Sulfonamides / metabolism
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Yeasts / physiology
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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*
Substances
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ABT-737
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Apoptosis Regulatory Proteins
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BBC3 protein, human
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Biphenyl Compounds
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Cyclin-Dependent Kinase Inhibitor p21
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Myeloid Cell Leukemia Sequence 1 Protein
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Nitrophenols
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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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Sulfonamides
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bcl-2-Associated X Protein