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Promotion of Hras-induced squamous carcinomas by a polymorphic variant of the Patched gene in FVB mice
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Promotion of Hras-induced squamous carcinomas by a polymorphic variant of the Patched gene in FVB mice
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Journal Article
Promotion of Hras-induced squamous carcinomas by a polymorphic variant of the Patched gene in FVB mice
2007
Overview
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
1
. 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. F
1
hybrids between C57BL/6 and FVB/N strains ((B6FVB)F
1
) 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)F
1
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
2
,
3
,
4
,
5
. SCCs that develop in
Ptch
B6
+/-
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.
Publisher
Nature Publishing Group UK,Nature Publishing,Nature Publishing Group
Subject
/ Animals
/ Biological and medical sciences
/ Carcinoma, Squamous Cell - genetics
/ Carcinoma, Squamous Cell - pathology
/ Cell transformation and carcinogenesis. Action of oncogenes and antioncogenes
/ Cell Transformation, Neoplastic
/ Female
/ Fundamental and applied biological sciences. Psychology
/ Gene Expression Regulation, Neoplastic
/ HSP40 Heat-Shock Proteins - metabolism
/ Humanities and Social Sciences
/ Humans
/ Hybrids
/ Kruppel-Like Transcription Factors - genetics
/ letter
/ Male
/ Mice
/ Molecular and cellular biology
/ Polymorphism, Genetic - genetics
/ Receptors, Cell Surface - genetics
/ Receptors, Cell Surface - metabolism
/ Rodents
/ Science
/ Tumors
