Understanding the divergent functions of mutant p53

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PROJECT SUMMARY/ABSTRACT Mutation of the TP53 tumor suppressor gene is the most common genetic alteration in cancer, and over 100 distinct and recurrent missense mutations in TP53 have been identified. Virtually all p53 mutants studied to date have lost the ability to bind to DNA, thereby impairing its function as a transcription factor, and it seems likely that this molecular function largely explains its role in tumor formation. Additionally, many studies have uncovered gain-of-function or oncogenic properties of individual mutants that extend beyond loss of wild type function, most notably the ability to promote invasion and metastasis. Nevertheless, which specific TP53 mutations drive differential tumor development and the molecular mechanisms responsible for these phenotypes remain poorly understood. Given that p53 is a transcription factor and that a significant fraction of cancer- associated mutations, including C132Y, occur in the DNA binding domain, I hypothesize that p53 mutants promote differential tumor formation and progression by profoundly altering the cellular transcriptome in a mutant-specific manner. Aim 1: Characterize the metastatic potential of p53 C132Y mutant. In preliminary studies, I identified the cancer associated mutation, C132Y, as an allele that has greater metastatic potential than other mutants. In this aim, I propose in vitro and in vivo functional characterization of this mutant with the goal of determining: 1) whether the mutant is necessary for metastasis and 2) the molecular mechanisms by which the mutant promotes metastasis. Aim 2: Systematic characterization of p53 missense mutants. Many studies, including some from our own lab, have produced data to suggest that there may be differences in the function of unique missense mutant p53 proteins. What these functions are and to what extent they are conserved between mutants is still poorly understood. To address this question, I propose: 1) a systematic characterization of the transcriptome of cells harboring different mutant p53 proteins and 2) a detailed characterization of the top two mutants from each transcriptional cluster to probe the mechanisms by which the mutants are functioning. Training Plan: The applicant will work with an interdisciplinary team of mentors and collaborators to gain expertise in cell and molecular biology, precision mouse models of disease, and generation and analysis of transcriptomic data. The skills that the applicant will develop during this project will serve her well over the course of her career in biomedical research.