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Two p53 mutants display differential gain-of-function effects on tumorigenesis in vivo

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dc.contributor.advisor Zong, Wei-Xing en_US
dc.contributor.author Hanel, Walter George en_US
dc.contributor.other Department of Genetics en_US
dc.date.accessioned 2013-05-24T16:38:21Z
dc.date.accessioned 2015-04-24T14:47:52Z
dc.date.available 2013-05-24T16:38:21Z
dc.date.available 2015-04-24T14:47:52Z
dc.date.issued 2012-08-01 en_US
dc.identifier.uri http://hdl.handle.net/1951/60285 en_US
dc.identifier.uri http://hdl.handle.net/11401/71548 en_US
dc.description 106 pg. en_US
dc.description.abstract p53 is a transcription factor which promotes cell cycle arrest, DNA damage repair, and apoptosis in the presence of DNA damage or oncogenic signaling. It is mutated in more than half of all human cancers demonstrating its clinical significance. Most studies have shown mutation of p53 to be associated with a poor clinical outcome for a broad variety of tumors. Unlike most other tumor suppressors which undergo genomic loss or silencing during tumor progression, p53 undergoes missense mutation within its coding region with retention of expression of the mutated protein in tumors. More importantly, mutant p53 proteins undergo drastic stabilization and accumulate to high levels in neoplastic tissue. These observations led to extensive studies detailing the tumorigenic activities of these mutant proteins in promoting the neoplastic transition and progression of tumors independent of their loss of function of wild type tumor suppressor activity. Study of these gain-of-function (GOF) activities will lead to novel therapeutic interventions for these clinically aggressive neoplasms. My dissertation studies involved three projects which have each led to important discoveries of mutant p53 GOF. In my first project, phenotyping of two novel mutant p53 knockin mouse models indicates a powerful gain-of-function effect of the specific p53 mutation, R248Q, in the earlier initiation of a wild variety of tumor in vivo. In my second project, I identify the presence of enhanced oncogenic signaling in tumors derived from p53 mutant mice as an important gain of function activity. In my third project, I show that mutant p53R248Q results in expansion of the steady state levels of the early stem/progenitor hematopoietic cells, potentially implicating this GOF activity in the increased tumorigenic activity of this p53 mutant. These models add to the growing body of evidence supporting the gain-of-function of p53 mutants and will serve as useful tools to investigate genotype-phenotype correlations of germline and spontaneous mutant p53 tumors. en_US
dc.description.sponsorship This work is sponsored by the Stony Brook University Graduate School in compliance with the requirements for completion of degree. en_US
dc.format Monograph en_US
dc.format.medium Electronic Resource en_US
dc.language.iso en_US en_US
dc.publisher The Graduate School, Stony Brook University: Stony Brook, NY. en_US
dc.subject.lcsh Genetics en_US
dc.subject.other Gain-of-function, HUPKI, LSK, MSC en_US
dc.title Two p53 mutants display differential gain-of-function effects on tumorigenesis in vivo en_US
dc.type Dissertation en_US
dc.mimetype Application/PDF en_US
dc.contributor.committeemember Hayman, Michael en_US
dc.contributor.committeemember Hearing, Patrick en_US
dc.contributor.committeemember Lin, Richard. en_US


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