One of the most commonly mutated gene in glioblastoma and many other cancers is the tumor suppressor TP53 (p53). The most common p53 mutations are missense mutations in the DNA binding domain that lead to the expression of full length mutant p53 protein. In addition to the loss of tumor suppressor function, these mutations can endow oncogenic gain of function abilities that allow mutant p53 to bind and regulate the promoters of aberrant target genes, driving tumorigenesis. We analyzed the prevalence of individual p53 mutations in GBM, and found that certain point mutations exhibit significant sex differences in their frequency, suggesting that these mutations may have a sex specific effect on cancer cell fitness. However, the mechanisms that control mutant p53 target genes specificity are poorly understood. In this project, we are investigating the molecular mechanisms of individual p53 mutations and their contribution to sex differences in tumorigenesis and survival.
Mutant p53 has no definable binding site, and instead relies on interactions with other proteins to mediate its localization to aberrant genes. One potential regulator of mutant p53 localization is the epigenetic reader Brd4. Brd4 binds to acetylated histones in the promoters and enhancers of target genes via its two bromodomains, and recruits transcription factors and scaffolding proteins that regulate transcription, including p53. Brd4-p53 binding is required for the regulation of WTp53 target genes, and is reliant on phosphorylation by casein kinase II (CKII) for binding to chromatin and transcription activation. Our lab has found profound sex differences in the occupation of enhancers and promoters by Brd4. Together this led us to the hypothesis that heterogeneity in Brd4 binding contributes to the targeting of mutant p53 to sex specific loci and the transcription of aberrant target genes.