An inducible mouse model for skin cancer reveals distinct roles for gain- and loss-of-function p53 mutations

Carlos Caulin, Thao Nguyen, Gene A. Lang, Thea M. Goepfert, Bill R. Brinkley, Wei Wen Cai, Guillermina Lozano, Dennis R. Roop

Research output: Contribution to journalArticlepeer-review

114 Scopus citations


Mutations in ras and p53 are the most prevalent mutations found in human nonmelanoma skin cancers. Although some p53 mutations cause a loss of function, most result in expression of altered forms of p53, which may exhibit gain-of-function properties. Therefore, understanding the consequences of acquiring p53 gain-of-function versus loss-of-function mutations is critical for the generation of effective therapies for tumors harboring p53 mutations. Here we describe an inducible mouse model in which skin tumor formation is initiated by activation of an endogenous K-rasG12D allele. Using this model we compared the consequences of activating the p53 gain-of-function mutation p53R172H and of deleting the p53 gene. Activation of the p53 R172H allele resulted in increased skin tumor formation, accelerated tumor progression, and induction of metastasis compared with deletion of p53. Consistent with these observations, the p53R172H tumors exhibited aneuploidy associated with centrosome amplification, which may underlie the mechanism by which p53R172H exerts its oncogenic properties. These results clearly demonstrate that p53 gain-of-function mutations confer poorer prognosis than loss of p53 during skin carcinogenesis and have important implications for the future design of therapies for tumors that exhibit p53 gain-of-function mutations.

Original languageEnglish (US)
Pages (from-to)1893-1901
Number of pages9
JournalJournal of Clinical Investigation
Issue number7
StatePublished - Jul 2 2007
Externally publishedYes

ASJC Scopus subject areas

  • General Medicine


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