Differential Activation of p53 Target Genes in Breast Cancer
Annual summary rept. 1 May 2000-1 May 2001
MOUNT SINAI SCHOOL OF MEDICINE NEW YORK
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A significant percentage of breast tumors are resistant to apoptotic stimuli. This resistance has been correlated with decreased expression of the proapoptotic protein bax. A major regulator of bax expression is the tumor suppressor p53. Unlike other well characterized p53 response elements, like the p21-5 element, which consist of two consensus p53 half-sites, the response element of the human bax promoter consists of three half-sites that cooperate in mediating p53-dependent transactivation. Within this unique response element are six GC-rich base pairs that mediate an interaction with Sp1 both in vitro and in cells. These bases were found to be required for p53-dependent activation, and mutations that inhibited Sp1 binding also blocked the ability of p53 to activate transcription through this element, suggesting a model in which p53 requires the cooperation of Sp1 or a Sp1-like factor to mediate transcriptional activation of the human bax promoter. In addition, I recently identified a novel p53 response element conserved in the first intron of both the human and the murine box genes. This element is required for the p53-dependent transcriptional activation of both the human and murine bax genes, demonstrating that box is a direct and evolutionarily conserved transcriptional target of p53.
- Medicine and Medical Research