Sunday, November 24, 2024
11/24/2024
Project Summary It is now well accepted that tumor-derived mutant forms of p53 are potently oncogenic. Silencing mutant p53, or inducing the degradation of this protein, can markedly impair tumor growth in vitro and tumor progression in vivo. The ability of mutant p53 to drive tumor progression is frequently mediated by protein- protein interaction, and this is often referred to as the “gain of function” (GOF) activity of mutant p53. One of our gaps in knowledge has been the identification of key GOF activities of mutant p53. Another has been investigation into how coding region SNPs (single nucleotide polymorphisms) in p53 influence the mutant p53 GOF. One of the Holy Grails of cancer biology has been the identification of compounds that can reactivate the p53 pathway in tumors containing mutant p53, by refolding mutant forms of p53 into wild type conformation and activity. Several groups have reported the identification of compounds that act in these ways. Another key gap in our knowledge has been how coding region SNPs (single nucleotide polymorphisms) in p53 impact the folding of mutant p53, and the efficacy of compounds that refold mutant p53. In this application, we take aim at two coding region SNPs in p53: Pro72Arg and Tyr107His. We recently published that the codon 72 variation is a potent intragenic modifier of mutant p53 GOF. Specifically, the Arg (R72) variant of mutant p53 is a superior mediator of tumor cell invasiveness and is associated with poor prognosis in women with breast cancer. We will delve into an investigation of the influence of this SNP on mutant p53 GOF, using novel mouse models for the R175H mutation, containing either P72 or R72. We will learn their impact on p53 structure using NMR, and on their influence on the efficacy of p53- refolding compounds. This aim constitutes a structural, molecular and in vivo analysis of the codon 72 SNP of mutant p53. We have obtained data that the Y017H variant of p53 alters the structure and activity of this protein. We will explore the effect of this African-specific SNP on p53 function in a novel mouse model. We have identified genes with impaired transactivation by Y107H, including the chromatin modifier PADI4;; we will explore its impact on p53 function and tumor suppression. In sum, for both aims we employ a combination of gene expression, protein-protein interaction, cytotoxicity and novel mouse models. We have recruited expert collaborators like Donna George (Penn), John Karanicolas (Fox Chase Cancer Center) and Darren Carpizo (Rutgers-Cancer Institute of New Jersey). These Investigators bring to bear their complimentary expertise to address an important and clinically-relevant question: how can we better harness p53 to eradicate cancer.
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