title: Comparison of effects of p53 null and gain-of-function mutations on salivary tumors in MMTV-Hras transgenic mice.
abstract: 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/p53R172H/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/p53R172H/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.
authors.affiliation: Department of Human and Molecular Genetics, Virginia Commonwealth University, Richmond, Virginia, United States of America.
authors.forename: Dadi
authors.initials: D
authors.lastname: Jiang
authors.affiliation: Department of Pathology, Virginia Commonwealth University, Richmond, Virginia, United States of America; Massey Cancer Center, Virginia Commonwealth University, Richmond, Virginia, United States of America.
authors.forename: Catherine I
authors.initials: CI
authors.lastname: Dumur
authors.affiliation: Department of Pathology, Virginia Commonwealth University, Richmond, Virginia, United States of America; Massey Cancer Center, Virginia Commonwealth University, Richmond, Virginia, United States of America.
authors.forename: H Davis
authors.initials: HD
authors.lastname: Massey
authors.affiliation: Department of Public Health Sciences, Medical University of South Carolina, Charleston, South Carolina, United States of America.
authors.forename: Viswanathan
authors.initials: V
authors.lastname: Ramakrishnan
authors.affiliation: Department of Human and Molecular Genetics, Virginia Commonwealth University, Richmond, Virginia, United States of America.
authors.forename: Mark A
authors.initials: MA
authors.lastname: Subler
authors.affiliation: Department of Human and Molecular Genetics, Virginia Commonwealth University, Richmond, Virginia, United States of America; Massey Cancer Center, Virginia Commonwealth University, Richmond, Virginia, United States of America.
authors.forename: Jolene J
authors.initials: JJ
authors.lastname: Windle
mesh_terms: D000818:Animals; D017209:Apoptosis; D004317:Doxorubicin / Q000627:therapeutic use; D015972:Gene Expression Regulation, Neoplastic; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D009154:Mutation; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics* / Q000378:metabolism; D012468:Salivary Gland Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D016159:Tumor Suppressor Protein p53 / Q000235:genetics* / Q000378:metabolism
chemical_list: D016159:Tumor Suppressor Protein p53; D004317:Doxorubicin; D016283:Proto-Oncogene Proteins p21(ras)