Biology Department Seminar

The p53 "guardian of the genome" is a master regulatory transcription factor that directs cellular response through direct regulation of hundreds of target genes. The transcription targets are response element sequences that are variants of a 20 base consensus sequence. Given its broad importance, we have investigated the diversity and depth of the p53 network. Diversity in the network can result from changes in the p53 gene/protein, the response elements and/or levels of p53 expression, as well as changes in the many factors that interact with p53. While mutations in p53 are associated with ~ 50% of cancers, many are not loss-of-function mutation but instead change the spectrum of genes targeted by p53, as found for some Li Fraumeni patients, leading to network diversity in a manner that can depend on the amount of cellular p53. Diversity could also arise through variation in the response elements themselves, which we have demonstrated through evolution analyses and identification of SNPs in target REs. Using a combination of yeast and human model cell systems, we established that noncanoncal sequences composed of 1/2 and 3/4 response element sites could also be targeted by p53 for transactivation. A nearby estrogen receptor target response element can greatly enhance the p53 response at a noncanonical site. Thus, the depth of genomic influence of p53 is much larger than originally anticipated due to the expanding universe of genes directly targeted by p53. Within that universe, there can be considerable diversity in p53 responses.