Abstract
The mechanism by which p53 modulates apoptosis in cancer therapy is incompletely understood. Here, cell-free extracts from irradiated tumor cells are described in which endogenous p53 protein is shown to participate in caspase activation. This apoptotic activity is also oncogene-dependent, but independent of transcription in general or the presence of Bax or cytochrome c. A general use for this system is as a cell-free screen for apoptosis modulators. In this way, profound effects of protein kinase A were identified and corroborated in vivo by the protection conferred by cAMP against diverse triggers of p53-dependent apoptosis. This system provides direct biochemical evidence that p53 protein can transduce apoptotic signals through protein-protein interactions and reveals a modulator kinase pathway capable of regulating p53-dependent caspase activation.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Adenylyl Imidodiphosphate / pharmacology
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Animals
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Apoptosis*
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Caspases / metabolism*
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Cell Line, Transformed / radiation effects
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Cell Transformation, Neoplastic*
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Cell-Free System
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Cyclic AMP / metabolism
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Cyclic AMP-Dependent Protein Kinases / metabolism
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Cytochrome c Group / metabolism
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Enzyme Activation / drug effects
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Enzyme Repression
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Gamma Rays
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Mice
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Oncogenes*
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Proto-Oncogene Proteins
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Proto-Oncogene Proteins c-bcl-2*
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Rats
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Tumor Cells, Cultured
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Tumor Suppressor Protein p53 / metabolism*
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bcl-2-Associated X Protein
Substances
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Bax protein, mouse
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Bax protein, rat
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Cytochrome c Group
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Proto-Oncogene Proteins
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Proto-Oncogene Proteins c-bcl-2
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Tumor Suppressor Protein p53
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bcl-2-Associated X Protein
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Adenylyl Imidodiphosphate
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Cyclic AMP
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Cyclic AMP-Dependent Protein Kinases
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Caspases