Abstract
The DPC4 (SMAD4) gene plays a key role in the TGFbeta signaling pathway. We inactivated its mouse homolog Dpc4 (Smad4). The homozygous mutants were embryonic lethal, whereas the heterozygotes showed no abnormality. We then introduced the Dpc4 mutation into the Apc(delta716) knockout mice, a model for human familial adenomatous polyposis. Because both Apc and Dpc4 are located on chromosome 18, we constructed compound heterozygotes carrying both mutations on the same chromosome by meiotic recombination. In such mice, intestinal polyps developed into more malignant tumors than those in the simple Apc(delta716) heterozygotes, showing an extensive stromal cell proliferation, submucosal invasion, cell type heterogeneity, and in vivo transplantability. These results indicate that mutations in DPC4 (SMAD4) play a significant role in the malignant progression of colorectal tumors.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Adenocarcinoma / chemistry
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Adenocarcinoma / genetics*
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Adenocarcinoma / pathology
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Adenomatous Polyposis Coli / genetics*
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Adenomatous Polyposis Coli / pathology
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Animals
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Chromosome Deletion
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Colonic Neoplasms / chemistry
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Colonic Neoplasms / genetics*
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Colonic Neoplasms / pathology
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Crosses, Genetic
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DNA-Binding Proteins*
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Disease Progression
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Duodenal Neoplasms / chemistry
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Duodenal Neoplasms / pathology
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Genes, APC / physiology*
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Genes, Tumor Suppressor / physiology*
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Heterozygote
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Homozygote
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Humans
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Intestinal Polyps / chemistry
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Intestinal Polyps / genetics
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Intestinal Polyps / pathology
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Intestine, Small
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Loss of Heterozygosity
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Mice
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Mice, Knockout
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Neoplasm Invasiveness
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Smad4 Protein
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Trans-Activators / analysis
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Trans-Activators / genetics*
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Tumor Cells, Cultured
Substances
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DNA-Binding Proteins
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SMAD4 protein, human
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Smad4 Protein
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Smad4 protein, mouse
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Trans-Activators