APC-mediated downregulation of beta-catenin activity involves nuclear sequestration and nuclear export.
Mutational inactivation of adenomatous polyposis coli (APC) initiates most colon carcinomas. APC functions include targeting cytoplasmic beta-catenin, a Wnt pathway mediator, for proteolysis. Although APC shuttles between cytoplasm and nucleus, the role of nuclear APC protein, particularly with respect to nuclear beta-catenin levels and activity, remains unclear. Here, we demonstrate that APC lacking functional nuclear localization signals (NLSs) or nuclear export signals (NESs) does not effectively downregulate nuclear beta-catenin levels; neither does wild-type APC when nuclear export is blocked. While APC bearing mutated NLSs could not downregulate beta-catenin-mediated transcriptional activation, APC lacking NESs remained active. Consistent with the hypothesis that nuclear APC lacking NESs can inhibit beta-catenin function by sequestration, we show that endogenous APC and beta-catenin proteins interact within the nucleus. These data demonstrate that nuclear APC binding to beta-catenin, and then inducing its nuclear export, plays a critical role in the control of nuclear beta-catenin levels and activity.
Department of Oncological Sciences, Huntsman Cancer Institute, University of Utah, Salt Lake City 84112, USA. kristi.neufeld@genetics.utah.edu
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Zhang
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White
D011125:Adenomatous Polyposis Coli / Q000235:genetics* / Q000378:metabolism*; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology; D015153:Blotting, Western; D002460:Cell Line; D002467:Cell Nucleus / Q000378:metabolism*; D003001:Cloning, Molecular; D003110:Colonic Neoplasms / Q000235:genetics; D003593:Cytoplasm / Q000378:metabolism; D003598:Cytoskeletal Proteins / Q000096:biosynthesis* / Q000235:genetics; D004268:DNA-Binding Proteins / Q000378:metabolism; D015536:Down-Regulation; D005231:Fatty Acids, Unsaturated / Q000494:pharmacology; D006801:Humans; D051821:Lymphoid Enhancer-Binding Factor 1; D008856:Microscopy, Fluorescence; D008957:Models, Genetic; D009154:Mutation; D011233:Precipitin Tests; D011485:Protein Binding; D021381:Protein Transport; D015534:Trans-Activators; D014157:Transcription Factors / Q000378:metabolism; D015533:Transcriptional Activation; D014162:Transfection; D051176:beta Catenin
D000903:Antibiotics, Antineoplastic; C495270:CTNNB1 protein, human; D003598:Cytoskeletal Proteins; D004268:DNA-Binding Proteins; D005231:Fatty Acids, Unsaturated; D051821:Lymphoid Enhancer-Binding Factor 1; D015534:Trans-Activators; D014157:Transcription Factors; D051176:beta Catenin; C038753:leptomycin B