One mechanism for cell type-specific regulation of the bax promoter by the tumor suppressor p53 is dictated by the p53 response element.
Key to the function of the tumor suppressor p53 is its ability to activate the transcription of its target genes, including those that encode the cyclin-dependent kinase inhibitor p21 and the proapoptotic Bax protein. In contrast to Saos-2 cells in which p53 activated both the p21 and bax promoters, in MDA-MB-453 cells p53 activated the p21 promoter, but failed to activate the bax promoter. Neither phosphorylation of p53 on serines 315 or 392 nor an intact C terminus was required for p53-dependent activation of the bax promoter, demonstrating that this differential regulation of bax could not be explained solely by modifications of these residues. Further, this effect was not due to either p73 or other identified cellular factors competing with p53 for binding to its response element in the bax promoter. p53 expressed in MDA-MB-453 cells also failed to activate transcription through the p53 response element of the bax promoter in isolation, demonstrating that the defect is at the level of the interaction between p53 and its response element. In contrast to other p53 target genes, like p21, in which p53-dependent transcriptional activation is mediated by a response element containing two consensus p53 half-sites, activation by p53 of the bax element was mediated by a cooperative interaction of three adjacent half-sites. In addition, the interaction of p53 with its response element from the bax promoter, as compared with its interaction with its element from the p21 promoter, involves a conformationally distinct form of the protein. Together, these data suggest a potential mechanism for the differential regulation of p53-dependent transactivation of the bax and p21 genes.
Thornborrow
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EC
Derald H. Ruttenberg Cancer Center, Mount Sinai School of Medicine, New York, New York 10029, USA.
Manfredi
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D001483:Base Sequence; D001665:Binding Sites; D017931:DNA Primers; D005786:Gene Expression Regulation; D016158:Genes, p53; D006801:Humans; D009687:Nuclear Proteins / Q000378:metabolism; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D011518:Proto-Oncogene Proteins / Q000235:genetics*; D019253:Proto-Oncogene Proteins c-bcl-2; D020218:Response Elements; D015533:Transcriptional Activation; D014407:Tumor Cells, Cultured; D051028:bcl-2-Associated X Protein
C494826:BAX protein, human; D017931:DNA Primers; D009687:Nuclear Proteins; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D051028:bcl-2-Associated X Protein