Abstract
TGFbeta-related growth factors have been implicated in a variety of developmental and physiological processes in organisms ranging from nematodes to mammals. TGFbeta transduces its signal to the interior of the cell via Smad2, Smad3, and Smad4. We report the cloning and targeted disruption of the mouse Smad3 gene. Smad3 mutant mice are viable and fertile. Between 4 and 6 months of age, the Smad3 mutant mice become moribund with colorectal adenocarcinomas. The neoplasms penetrate through the intestinal wall and metastasize to lymph nodes. These results directly implicate TGFbeta signaling in the pathogenesis of colorectal cancer and provide a compelling animal model for the study of human colorectal cancer.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Adenocarcinoma / genetics*
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Adenocarcinoma / mortality
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Adenocarcinoma / secondary*
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Adenomatous Polyposis Coli Protein
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Alleles
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Animals
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Cell Division / genetics
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Cloning, Molecular
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Colorectal Neoplasms / genetics*
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Colorectal Neoplasms / mortality
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Colorectal Neoplasms / secondary*
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Cytoskeletal Proteins / genetics
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DNA-Binding Proteins / genetics*
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Female
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Gene Expression Regulation, Developmental
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Gene Expression Regulation, Neoplastic
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Genes, Recessive
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Genes, Reporter
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Heterozygote
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Hybridization, Genetic
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Lac Operon
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Lymph Nodes / pathology
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Male
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Mice
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Mice, Inbred C57BL
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Mice, Mutant Strains
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Signal Transduction / genetics
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Smad3 Protein
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Survival Analysis
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Trans-Activators / genetics*
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Xenopus
Substances
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Adenomatous Polyposis Coli Protein
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Cytoskeletal Proteins
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DNA-Binding Proteins
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Smad3 Protein
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Smad3 protein, mouse
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Trans-Activators