One mechanism for cell type-specific regulation of the bax promoter by thetumor 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 cycl in-dependent kinase inhibitor p21 and the proapoptotic Bar protein. In cont rast to Saos-2 cells in which p53 activated both the p21 and bar promoters, in MDA-MB-453 cells p53 activated the p21 promoter, but failed to activate the bar 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 effec t was not due to either p73 or other identified cellular factors competing with p53 for binding to its response element in the bar promoter. p53 expre ssed in MDA-MB-453 cells also failed to activate transcription through the p53 response element of the bar promoter in isolation, demonstrating that t he defect is at the level of the interaction between p53 and its response e lement. In contrast to other p53 target genes, like p21, in which p53-depen dent transcriptional activation is mediated by a response element containin g two consensus p53 half-sites, activation by p53 of the bax element was me diated by a cooperative interaction of three adjacent half-sites. In additi on, the interaction of p53 with its response element from the bax promoter, as compared with its interaction with its element from the p21 promoter, i nvolves a conformationally distinct form of the protein. Together, these da ta suggest a potential mechanism for the differential regulation of p53-dep endent transactivation of the bar and p21 genes.