title: Adenomatous polyposis coli (APC)-independent regulation of beta-catenin degradation via a retinoid X receptor-mediated pathway.
abstract: Beta-catenin is a component of stable cell adherent complexes whereas its free form functions as a transcription factor that regulate genes involved in oncogenesis and metastasis. Free beta-catenin is eliminated by two adenomatous polyposis coli (APC)-dependent proteasomal degradation pathways regulated by glycogen synthase kinase 3beta (GSK3 beta) or p53-inducible Siah-1. Dysregulation of beta-catenin turnover consequent to mutations in critical genes of the APC-dependent pathways is implicated in cancers such as colorectal cancer. We have identified a novel retinoid X receptor (RXR)-mediated APC-independent pathway in the regulation of beta-catenin. In this proteasomal pathway, RXR agonists induce degradation of beta-catenin and RXR alpha and repress beta-catenin-mediated transcription. In vivo, beta-catenin interacts with RXR alpha in the absence of ligand, but RXR agonists enhanced the interaction. RXR agonist action was not impaired by GSK3 beta inhibitors or deletion of the GSK3 beta-targeted sequence from beta-catenin. In APC- and p53-mutated colorectal cancer cells, RXR agonists still inactivated endogenous beta-catenin via RXR alpha. Interestingly, deletion of the RXR alpha A/B region abolished ligand-induced beta-catenin degradation but not RXR alpha-mediated transactivation. RXR alpha-mediated inactivation of oncogenic beta-catenin paralleled a reduction in cell proliferation. These results suggest a potential role for RXR and its agonists in the regulation of beta-catenin turnover and related biological events.
authors.affiliation: Retinoid Research, the Department of Biology, Allergan, Inc., Irvine, California 92623, USA. xiao_jia-hao@allergan.com
authors.forename: Jia-Hao
authors.initials: JH
authors.lastname: Xiao
authors.forename: Corine
authors.initials: C
authors.lastname: Ghosn
authors.forename: Cory
authors.initials: C
authors.lastname: Hinchman
authors.forename: Chad
authors.initials: C
authors.lastname: Forbes
authors.forename: Jenny
authors.initials: J
authors.lastname: Wang
authors.forename: Nonna
authors.initials: N
authors.lastname: Snider
authors.forename: Allison
authors.initials: A
authors.lastname: Cordrey
authors.forename: Yi
authors.initials: Y
authors.lastname: Zhao
authors.forename: Roshantha A S
authors.initials: RA
authors.lastname: Chandraratna
mesh_terms: D011125:Adenomatous Polyposis Coli / Q000378:metabolism*; D015153:Blotting, Western; D002455:Cell Division; D002460:Cell Line; D003432:Cross-Linking Reagents / Q000494:pharmacology; D003598:Cytoskeletal Proteins / Q000378:metabolism*; D003600:Cytosol / Q000378:metabolism; D018076:DNA, Complementary / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D017353:Gene Deletion; D005786:Gene Expression Regulation; D015723:Gene Library; D017930:Genes, Reporter; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D006367:HeLa Cells; D006801:Humans; D008024:Ligands; D008156:Luciferases / Q000378:metabolism; D008954:Models, Biological; D009154:Mutation; D010957:Plasmids / Q000378:metabolism; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D018168:Receptors, Retinoic Acid / Q000378:metabolism*; D047488:Retinoid X Receptors; D013997:Time Factors; D015534:Trans-Activators / Q000378:metabolism*; D014157:Transcription Factors / Q000378:metabolism*; D014158:Transcription, Genetic; D015533:Transcriptional Activation; D014162:Transfection; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D020798:Two-Hybrid System Techniques; D051176:beta Catenin
chemical_list: C495270:CTNNB1 protein, human; D003432:Cross-Linking Reagents; D003598:Cytoskeletal Proteins; D018076:DNA, Complementary; D008024:Ligands; D018168:Receptors, Retinoic Acid; D047488:Retinoid X Receptors; D015534:Trans-Activators; D014157:Transcription Factors; D016159:Tumor Suppressor Protein p53; D051176:beta Catenin; D008156:Luciferases; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; D038362:Glycogen Synthase Kinase 3