Abstract
Mutations in the human adenomatous polyposis coli (APC) gene are thought to initiate colorectal tumorigenesis. The tumor suppressor function of APC is attributed primarily to its ability to regulate the WNT pathway by targeting the destruction of beta-catenin. We report here a novel role for APC in regulating degradation of the transcriptional co-repressor C-terminal-binding protein-1 (CtBP1) through a proteasome-dependent process. Further, CtBP1 suppresses the expression of intestinal retinol dehydrogenases, which are required for retinoic acid production and intestinal differentiation. In support of a role for CtBP1 in initiation of colorectal cancer, adenomas taken from individuals with familial adenomatous polyposis contain high levels of CtBP1 protein in comparison with matched, uninvolved tissue. The relationship between APC and CtBP1 is conserved between humans and zebrafish and provides a mechanistic model explaining APC control of intestinal retinoic acid biosynthesis.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Adenoma / genetics
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Adenoma / metabolism
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Adenomatous Polyposis Coli / genetics
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Adenomatous Polyposis Coli / metabolism
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Alcohol Oxidoreductases / antagonists & inhibitors
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Alcohol Oxidoreductases / genetics
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Alcohol Oxidoreductases / metabolism*
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Animals
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Base Sequence
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Cell Line, Tumor
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Colonic Neoplasms / genetics
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Colonic Neoplasms / metabolism
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DNA-Binding Proteins / antagonists & inhibitors
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DNA-Binding Proteins / genetics
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DNA-Binding Proteins / metabolism*
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Genes, APC*
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Humans
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In Vitro Techniques
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Intestinal Mucosa / metabolism*
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Models, Biological
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Mutation
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Proteasome Endopeptidase Complex / metabolism
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RNA, Small Interfering / genetics
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Species Specificity
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Tretinoin / metabolism
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Zebrafish / embryology
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Zebrafish / genetics
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Zebrafish / metabolism
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beta Catenin / antagonists & inhibitors
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beta Catenin / genetics
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beta Catenin / metabolism
Substances
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CTNNB1 protein, human
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DNA-Binding Proteins
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RNA, Small Interfering
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beta Catenin
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Tretinoin
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Alcohol Oxidoreductases
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C-terminal binding protein
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retinol dehydrogenase
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Proteasome Endopeptidase Complex