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.