The requirement for the p53 proline-rich functional domain for mediation of apoptosis is correlated with specific PIG3 gene transactivation and with transcriptional repression.
Wild-type p53 is a tumor suppressor gene which can activate or repress transcription, as well as induce apoptosis. The human p53 proline-rich domain localized between amino acids 64 and 92 has been reported to be necessary for efficient growth suppression. This study shows that this property mainly results from impaired apoptotic activity. Although deletion of the proline-rich domain does not affect transactivation of several promoters, such as WAF1, MDM2 and BAX, it does alter transcriptional repression, reactive oxygen species production and sequence-specific transactivation of the PIG3 gene, and these are activities which affect apoptosis. Whereas gel retardation assays revealed that this domain did not alter in vitro the specific binding to the p53-responsive element of PIG3, this domain plays a critical role in transactivation from a synthetic promoter containing this element. To explain this discrepancy, evidence is given for a proline-rich domain-mediated cellular activation of p53 DNA binding.
Venot
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Centre de Recherche de Vitry-Alfortville, Rhône-Poulenc Rorer, 13 quai Jules Guesde, 94403 Vitry sur Seine Cedex, France.
Maratrat
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Dureuil
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Conseiller
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E
Bracco
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Debussche
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D000911:Antibodies, Monoclonal / Q000378:metabolism; D017209:Apoptosis / Q000235:genetics*; D001483:Base Sequence; D002453:Cell Cycle / Q000235:genetics; D002460:Cell Line; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins / Q000235:genetics; D017931:DNA Primers; D004268:DNA-Binding Proteins / Q000378:metabolism; D006801:Humans; D009687:Nuclear Proteins; D011392:Proline / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D011518:Proto-Oncogene Proteins / Q000235:genetics; D019253:Proto-Oncogene Proteins c-bcl-2; D051736:Proto-Oncogene Proteins c-mdm2; D017382:Reactive Oxygen Species; D012097:Repressor Proteins / Q000378:metabolism; D017384:Sequence Deletion; D016385:TATA Box; D015533:Transcriptional Activation; D016159:Tumor Suppressor Protein p53 / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D051028:bcl-2-Associated X Protein
D000911:Antibodies, Monoclonal; C494826:BAX protein, human; C493956:CDKN1A protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D017931:DNA Primers; D004268:DNA-Binding Proteins; D009687:Nuclear Proteins; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D017382:Reactive Oxygen Species; D012097:Repressor Proteins; D016159:Tumor Suppressor Protein p53; D051028:bcl-2-Associated X Protein; D011392:Proline; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2