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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/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/p53R172H/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/p53R172H/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.
Jiang, D., Dumur, C. I., & Massey, H. D., et al. Comparison of Effects of p53 Null and Gain-of-Function Mutations on Salivary Tumors in MMTV-Hras Transgenic Mice. PLoS ONE, 10, e0118029. Copyright © 2015 Jiang et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
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VCU Human and Molecular Genetics Publications
Tumor growth rates.
S1_Methods.docx (22 kB)
Supplementary Materials and Methods
S1_Table.docx (12 kB)
Summary of the mice used for the age of tumor onset analysis
S2_Fig.tif (742 kB)
S2_Table.docx (12 kB)
Overall expression levels and functional meaning of genes in different clusters
S3_Fig.tif (6386 kB)
S3_Table.docx (28 kB)
List of genes in different clusters
S4_Fig.tif (349 kB)
Tumor growth responses to doxorubicin.
S4_Table.docx (25 kB)
Genes previously reported as regulated by p53
S5_Fig.tif (928 kB)
The top two networks identified through Ingenuity Pathway Analysis (IPA) on the significantly differentially expressed genes.
S5_Table.docx (12 kB)
Top enriched biological functions from WT-p53 vs. p53-null comparison
S6_Table.docx (12 kB)
Number of significant genes from different probe-level data summarization algorithms and statistical approaches
S7_Table.docx (12 kB)
Primers used in the quantitative PCR assays