Abstract
Mutations in Apc underlie the intestinal lesions in familial adenomatous polyposis and are found in >85% of sporadic colon cancers. They are frequently associated with overexpression of prostaglandin endoperoxide H synthase-2 (PGHS-2) in colonic adenomas. It has been suggested that Apc mutations are linked mechanistically to increased PGHS-2 expression by elevated nuclear accumulation of beta-catenin-Tcf-LEF transcription complex. In the present study, we show that PGHS-2 is differentially expressed in mouse colonic epithelial cells with distinct Apc status. Cells with a mutated Apc expressed markedly higher levels of PGHS-2 mRNA and protein and produced significantly more prostaglandin E2 than cells with normal Apc. Using electrophoretic mobility shift assays, we demonstrate that DNA-beta-catenin-LEF-1 complex formation is differentially induced in these two cell lines in an Apc-dependent manner. Our data indicate that the differential induction of beta-catenin-LEF-1 complex correlates closely with differential expression of PGHS-2. These findings support the hypothesis that the differential expression of PGHS-2 is mediated through the proposed beta-catenin/Tcf-LEF signaling pathway.
MeSH terms
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Alleles
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Animals
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Antigens, Polyomavirus Transforming / genetics
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Antigens, Polyomavirus Transforming / physiology
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Binding, Competitive
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Cell Line
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Cell Line, Transformed
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Cell Nucleus / metabolism
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Cell Transformation, Viral
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Colon / cytology*
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Colon / metabolism
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Crosses, Genetic
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Cyclooxygenase 2
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Cytoskeletal Proteins / metabolism*
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DNA / genetics
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DNA / metabolism
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DNA-Binding Proteins / metabolism*
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Dinoprostone / biosynthesis
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Enzyme Induction
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Epithelial Cells / metabolism
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Genes, APC*
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Isoenzymes / biosynthesis*
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Isoenzymes / genetics
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Lymphoid Enhancer-Binding Factor 1
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Macromolecular Substances
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Mice
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Mice, Mutant Strains
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Oligonucleotides / metabolism
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Prostaglandin-Endoperoxide Synthases / biosynthesis*
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Prostaglandin-Endoperoxide Synthases / genetics
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RNA, Messenger / biosynthesis
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RNA, Messenger / genetics
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Simian virus 40 / genetics
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Temperature
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Trans-Activators*
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Transcription Factors / metabolism*
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beta Catenin
Substances
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Antigens, Polyomavirus Transforming
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CTNNB1 protein, mouse
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Cytoskeletal Proteins
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DNA-Binding Proteins
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Isoenzymes
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Lymphoid Enhancer-Binding Factor 1
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Macromolecular Substances
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Oligonucleotides
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RNA, Messenger
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Trans-Activators
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Transcription Factors
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beta Catenin
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DNA
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Cyclooxygenase 2
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Prostaglandin-Endoperoxide Synthases
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Dinoprostone