title: Promotion of Hras-induced squamous carcinomas by a polymorphic variant of the Patched gene in FVB mice.
abstract: 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.
authors.affiliation: Cancer Research Institute, University of California at San Francisco, 2340 Sutter Street, San Francisco, California 94143, USA.
authors.forename: Yuichi
authors.initials: Y
authors.lastname: Wakabayashi
authors.forename: Jian-Hua
authors.initials: JH
authors.lastname: Mao
authors.forename: Ken
authors.initials: K
authors.lastname: Brown
authors.forename: Michael
authors.initials: M
authors.lastname: Girardi
authors.forename: Allan
authors.initials: A
authors.lastname: Balmain
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D017209:Apoptosis; D002294:Carcinoma, Squamous Cell / Q000235:genetics* / Q000473:pathology*; D002460:Cell Line; D002471:Cell Transformation, Neoplastic; D003433:Crosses, Genetic; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D011905:Genes, ras; D050956:HSP40 Heat-Shock Proteins / Q000378:metabolism; D006801:Humans; D051741:Kruppel-Like Transcription Factors / Q000235:genetics; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D000072079:Patched Receptors; D000072081:Patched-1 Receptor; D011110:Polymorphism, Genetic / Q000235:genetics*; D011956:Receptors, Cell Surface / Q000235:genetics* / Q000378:metabolism; D000075746:Zinc Finger Protein Gli2; D018631:ras Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: C485636:Dnaja3 protein, mouse; C000618551:Gli2 protein, mouse; D050956:HSP40 Heat-Shock Proteins; D051741:Kruppel-Like Transcription Factors; C000606236:PTCH1 protein, human; D000072079:Patched Receptors; D000072081:Patched-1 Receptor; C000606240:Ptch1 protein, mouse; D011956:Receptors, Cell Surface; D000075746:Zinc Finger Protein Gli2; D018631:ras Proteins