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p53  is an important tumor suppressor gene which is mutated in ~50% of all human cancers. Some of these mutants appear to have acquired novel functions beyond merely losing wild-type functions. To investigate these gain-of-function effects  in vivo , we generated mice of three different genotypes: MMTV- Hras/p53 +/+  , MMTV- Hras/p53 -/-  , and MMTV- Hras/p53 R172H/R172H  . Salivary tumors from these mice were characterized with regard to age of tumor onset, tumor growth rates, cell cycle distribution, apoptotic levels, tumor histopathology, as well as response to doxorubicin treatment. Microarray analysis was also performed to profile gene expression. The MMTV- Hras/p53 -/-   and MMTV- Hras / p53 R172H/R172H   mice displayed similar properties with regard to age of tumor onset, tumor growth rates, tumor histopathology, and response to doxorubicin, while both groups were clearly distinct from the MMTV- Hras/p53 +/+   mice by these measurements. In addition, the gene expression profiles of the MMTV- Hras/p53 -/-   and MMTV- Hras / p53 R172H/R172H   tumors were tightly clustered, and clearly distinct from the profiles of the MMTV- Hras/p53 +/+   tumors. Only a small group of genes showing differential expression between the MMTV- Hras / p53 -/-   and MMTV- Hras / p53 R172H/R172H   tumors, that did not appear to be regulated by wild-type p53, were identified. Taken together, these results indicate that in this MMTV- Hras -driven salivary tumor model, the major effect of the p53 R172H mutant is due to the loss of wild-type p53 function, with little or no gain-of-function effect on tumorigenesis, which may be explained by the tissue- and tumor type-specific properties of this gain-of-function mutant of p53.

Comparison of Effects of p53 Null and Gain-of-Function Mutations on Salivary Tumors in MMTV-Hras Transgenic Mice