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Defense Date


Document Type


Degree Name

Doctor of Philosophy


Human Genetics


p53 is an important tumor suppressor gene which is mutated in ~50% of all human cancers. Some of the p53 mutants appear to have acquired novel functions beyond merely losing wild-type functions. To investigate these gain-of-function effects in vivo, we interbred MMTV-v-Ha-ras transgenic mice to either p53-/- knock-out mice or p53R172H/+ knock-in mice to generate mice of three different genotypes: MMTV-ras, MMTV-ras/p53-/-, and MMTV-ras/p53R172H/R172H. Male mice of each of these genotypes were characterized with regard to age of salivary tumor onset and the tumors were characterized with regard to mean growth rates, proliferation fraction, apoptotic levels, and tumor histopathology, as well as responses to doxorubicin treatment. Microarray analysis was also performed to profile gene expression.The MMTV-ras/p53-/- and MMTV-ras/p53R172H/R172H mice display similar properties in age of tumor onset, tumor growth rates, and tumor histopathology, as well as response to doxorubicin. However, a subset of genes show differential expression between the two groups of tumor , and do not appear to be regulated by wild-type p53. At the same time, the MMTV-ras/p53R172H/R172H and MMTV-ras/p53+/+ tumors share similar expression levels of a group of genes that are differentially expressed in the MMTV-ras/p53-/- tumors. Thus, the gain-of-function effects may be caused in part by perturbed regulation of genes not normally regulated by wild-type p53, in addition to imbalances in the regulation of normal p53 target genes.


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VCU Theses and Dissertations

Date of Submission

June 2008