title: Nuclear beta-catenin displays GSK-3beta- and APC-independent proteasome sensitivity in melanoma cells.
abstract: Colon carcinoma and melanoma cells containing either a deletion of the adenomatous polyposis coli tumor suppressor protein (APC) or mutation of the site in beta-catenin phosphorylated by glycogen synthase kinase-3beta (GSK-3beta) display elevated levels of detergent-soluble beta-catenin due to insensitivity of the cytosolic protein to proteasome-dependent degradation. In this study, we have examined the effect of beta-catenin mutation (S37F) or APC loss on the proteasome sensitivity of additional subcellular beta-catenin pools in melanoma cells. In contrast to detergent-soluble beta-catenin, the detergent-insoluble protein remains proteasome-sensitive irrespective of S37F mutation or APC status. This insoluble component appears associated primarily with nuclear cytoskeletal elements. In addition, DNase I treatment solubilized a portion of detergent-insoluble beta-catenin, suggesting that this fraction also contains chromatin-associated protein, and correlating with a proteasome-sensitive elevation in beta-catenin-stimulated reporter activity. Since the detergent-insoluble nuclear component of beta-catenin displays GSK-3beta- and APC-independent proteasome sensitivity, distinct from the soluble nuclear and cytosolic pools of this protein, regulation of beta-catenin proteasome sensitivity and the contribution of this process to beta-catenin function may be more complex than previously appreciated.
authors.affiliation: Department of Cell and Cancer Biology, Medicine Branch, NCI, NIH, 9610 Medical Center Drive, Suite 300, Rockville, MD 20850, USA.
authors.forename: P
authors.initials: P
authors.lastname: Bonvini
authors.forename: S G
authors.initials: SG
authors.lastname: Hwang
authors.forename: M
authors.initials: M
authors.lastname: El-Gamil
authors.forename: P
authors.initials: P
authors.lastname: Robbins
authors.forename: J S
authors.initials: JS
authors.lastname: Kim
authors.forename: J
authors.initials: J
authors.lastname: Trepel
authors.forename: L
authors.initials: L
authors.lastname: Neckers
mesh_terms: D025601:Adenomatous Polyposis Coli Protein; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism*; D002467:Cell Nucleus / Q000378:metabolism; D002843:Chromatin / Q000378:metabolism; D003546:Cysteine Endopeptidases / Q000378:metabolism*; D003598:Cytoskeletal Proteins / Q000378:metabolism*; D003902:Detergents / Q000737:chemistry; D038362:Glycogen Synthase Kinase 3; D038341:Glycogen Synthase Kinases; D006801:Humans; D008545:Melanoma; D009097:Multienzyme Complexes / Q000037:antagonists & inhibitors / Q000378:metabolism*; D046988:Proteasome Endopeptidase Complex; D012995:Solubility; D013347:Subcellular Fractions / Q000378:metabolism; D015534:Trans-Activators; D014407:Tumor Cells, Cultured; D051176:beta Catenin
chemical_list: D025601:Adenomatous Polyposis Coli Protein; C495270:CTNNB1 protein, human; D002843:Chromatin; D003598:Cytoskeletal Proteins; D003902:Detergents; D009097:Multienzyme Complexes; D015534:Trans-Activators; D051176:beta Catenin; D038341:Glycogen Synthase Kinases; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D038362:Glycogen Synthase Kinase 3; D003546:Cysteine Endopeptidases; D046988:Proteasome Endopeptidase Complex