title: A20 restricts wnt signaling in intestinal epithelial cells and suppresses colon carcinogenesis.
abstract: Colon carcinogenesis consists of a multistep process during which a series of genetic and epigenetic adaptations occur that lead to malignant transformation. Here, we have studied the role of A20 (also known as TNFAIP3), a ubiquitin-editing enzyme that restricts NFκB and cell death signaling, in intestinal homeostasis and tumorigenesis. We have found that A20 expression is consistently reduced in human colonic adenomas than in normal colonic tissues. To further investigate A20's potential roles in regulating colon carcinogenesis, we have generated mice lacking A20 specifically in intestinal epithelial cells and interbred these with mice harboring a mutation in the adenomatous polyposis coli gene (APC(min)). While A20(FL/FL) villin-Cre mice exhibit uninflamed intestines without polyps, A20(FL/FL) villin-Cre APC(min/+) mice contain far greater numbers and larger colonic polyps than control APC(min) mice. We find that A20 binds to the β-catenin destruction complex and restricts canonical wnt signaling by supporting ubiquitination and degradation of β-catenin in intestinal epithelial cells. Moreover, acute deletion of A20 from intestinal epithelial cells in vivo leads to enhanced expression of the β-catenin dependent genes cyclinD1 and c-myc, known promoters of colon cancer. Taken together, these findings demonstrate new roles for A20 in restricting β-catenin signaling and preventing colon tumorigenesis.
authors.affiliation: Department of Medicine, University of California San Francisco, San Francisco, California, United States of America.
authors.forename: Ling
authors.initials: L
authors.lastname: Shao
authors.forename: Shigeru
authors.initials: S
authors.lastname: Oshima
authors.forename: Bao
authors.initials: B
authors.lastname: Duong
authors.forename: Rommel
authors.initials: R
authors.lastname: Advincula
authors.forename: Julio
authors.initials: J
authors.lastname: Barrera
authors.forename: Barbara A
authors.initials: BA
authors.lastname: Malynn
authors.forename: Averil
authors.initials: A
authors.lastname: Ma
mesh_terms: D000236:Adenoma / Q000378:metabolism*; D000818:Animals; D063646:Carcinogenesis / Q000378:metabolism; D002478:Cells, Cultured; D003110:Colonic Neoplasms / Q000378:metabolism*; D019938:Cyclin D1 / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D004847:Epithelial Cells / Q000378:metabolism*; D015870:Gene Expression; D006801:Humans; D007413:Intestinal Mucosa / Q000378:metabolism / Q000473:pathology; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D059748:Proteolysis; D016271:Proto-Oncogene Proteins c-myc / Q000378:metabolism; D000072598:Tumor Necrosis Factor alpha-Induced Protein 3; D054875:Ubiquitination; D060449:Wnt Signaling Pathway; D051176:beta Catenin / Q000378:metabolism
chemical_list: C530104:CCND1 protein, human; D004268:DNA-Binding Proteins; D047908:Intracellular Signaling Peptides and Proteins; C489427:MYC protein, human; D009687:Nuclear Proteins; D016271:Proto-Oncogene Proteins c-myc; D051176:beta Catenin; D019938:Cyclin D1; C076529:TNFAIP3 protein, human; D000072598:Tumor Necrosis Factor alpha-Induced Protein 3