A FUNCTIONAL P53-RESPONSIVE INTRONIC PROMOTER IS CONTAINED WITHIN THE HUMAN MDM2 GENE

The mdm2 gene is a target for transcriptional activation by the p53 tumor suppressor gene product, Previous work has revealed that the mouse mdm2 gene contains two promoters: one is located upstream to the gene and is active in the absence of p53, the other resides within the first intron and requires p53 for transcriptional activity, To determine whether this unique promoter activation pattern is biologically important, we investigated the structure and function of the corresponding region of the human mdm2 (hmdm2) gene. We report here that the hmdm2 gene also contains an intronic, p53-dependent promoter, The structural features of this promoter are highly conserved between mouse and man, as opposed to the lack of conservation of the first exon, This promoter is triggered in vivo in the presence of activated wild type p53, leading to the production of novel mRNA species. The intronic hmdm2 promoter contains two tandem p53 binding elements, Deletion analysis suggests that optimal promoter activity requires the simultaneous binding of p53 to both elements; this may serve to prevent premature triggering of the promoter by p53.