Human Molecular Genetics Advance Access originally published online on October 5, 2005
Human Molecular Genetics 2005 14(22):3449-3461; doi:10.1093/hmg/ddi373
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Cancer development induced by graded expression of Snail in mice
1Laboratorio 13, Instituto de Biología Molecular y Celular del Cáncer (IBMCC), CSIC/Universidad de Salamanca, Campus Unamuno, 37007 Salamanca, Spain, 2Servicio de Anatomía Patológica and 3Servicio de Citometría, University of Salamanca, Salamanca, Spain, 4Unitat de Biologia Cellular i Molecular, Institut Municipal d'Investigacio Medica, Universitat Pompeu Fabra, Barcelona, Spain, 5Area de Reproducción Animal, Centro de Investigación y Tecnología, Ctra de la Coruña km 5.9, 28040 Madrid, Spain and 6Departamento de Medicina, Universidad de Salamanca, Salamanca, Spain
* To whom correspondence should be addressed. Tel: +34 923238403; Fax: +34 923294813; Email: isg{at}usal.es
Received August 18, 2005; Accepted September 29, 2005
The zinc-finger transcription factor Snail is believed to trigger epithelial–mesenchymal transitions (EMTs) during cancer progression. This idea is supported by analysis of Snail knockout mice, which uncovered crucial role of Snail in gastrulation, and of individuals with cancer, in whom Snail expression is frequently upregulated. However, these results have not shown a direct link between Snail and the pathogenesis of cancer. Here we show that mice carrying hypomorphic tetracycline-repressible Snail transgenes, that increase Snail expression to 20% above normal levels, exhibit no morphological alterations and develop both epithelial and mesenchymal tumours (leukaemias). Suppression of the Snail transgene did not rescue the malignant phenotype, indicating that alterations induced by Snail are irreversible. CombitTA-Snail murine embryonic fibroblasts show similar migratory ability to that of control mouse embryonic fibroblasts (MEFs). However, CombitTA-Snail-MEFs induce tumour formation in nude mice. CombitTA-Snail expression results in increased radioprotection in vivo, although it does not affect p53 regulation in response to DNA damage. In concert with these results, Snail expression is repressed following DNA damage. This regulation of Snail by DNA damage is p53-independent. Our results connect DNA damage with the requirement of a critical level of an EMT regulator and provide genetic evidence that Snail plays essential roles in cancer development in mammals and thereby influences cell fate in the genotoxic stress response.
The authors wish it to be known that, in their opinion, the first two authors should be regarded as joint First Authors.
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