%0 Journal Article %J Nature %D 2007 %T Promotion of Hras-induced squamous carcinomas by a polymorphic variant of the Patched gene in FVB mice. %A Wakabayashi, Yuichi %A Jiang-Hua Mao %A Brown, Ken %A Girardi, Michael %A Balmain, Allan %K Amino Acid Sequence %K Animals %K Apoptosis %K Carcinoma, Squamous Cell %K Cell Line %K Cell Transformation, Neoplastic %K Crosses, Genetic %K Female %K Gene Expression Regulation, Neoplastic %K Genes, ras %K HSP40 Heat-Shock Proteins %K Humans %K Kruppel-Like Transcription Factors %K Male %K Mice %K Mice, Inbred C57BL %K Mice, Transgenic %K Molecular Sequence Data %K Polymorphism, Genetic %K ras Proteins %K Receptors, Cell Surface %X

Mice of the C57BL/6 strain are resistant to the development of skin squamous carcinomas (SCCs) induced by an activated Ras oncogene, whereas FVB/N mice are highly susceptible. The genetic basis of this difference in phenotype is unknown. Here we show that susceptibility to SCC is under the control of a carboxy-terminal polymorphism in the mouse Ptch gene. F1 hybrids between C57BL/6 and FVB/N strains ((B6FVB)F1) are resistant to Ras-induced SCCs, but resistance can be overcome either by elimination of the C57BL/6 Ptch allele (Ptch(B6)) or by overexpression of the FVB/N Ptch allele (Ptch(FVB)) in the epidermis of K5Hras-transgenic (B6FVB)F1 hybrid mice. The human Patched (PTCH) gene is a classical tumour suppressor gene for basal cell carcinomas and medulloblastomas, the loss of which causes increased signalling through the Sonic Hedgehog (SHH) pathway. SCCs that develop in PtchB6+/- mice do not lose the wild-type Ptch gene or show evidence of increased SHH signalling. Although Ptch(FVB) overexpression can promote SCC formation, continued expression is not required for tumour maintenance, suggesting a role at an early stage of tumour cell lineage commitment. The Ptch polymorphism affects Hras-induced apoptosis, and binding to Tid1, the mouse homologue of the Drosophila l(2)tid tumour suppressor gene. We propose that Ptch occupies a critical niche in determining basal or squamous cell lineage, and that both tumour types can arise from the same target cell depending on carcinogen exposure and host genetic background.

%B Nature %V 445 %P 761-5 %8 2007 Feb 15 %G eng %N 7129 %1 http://www.ncbi.nlm.nih.gov/pubmed/17230190?dopt=Abstract %R 10.1038/nature05489