title: Gamma-secretase activity is not involved in presenilin-mediated regulation of beta-catenin.
abstract: Presenilins (PS) are involved in gamma-secretase-mediated processing of beta-amyloid precursor protein (APP) and the Notch family of proteins. In addition, presenilin 1 (PS-1) binds to members of the armadillo family of proteins. In this study the relationship between PS-1-mediated proteolytic activity and PS-1-mediated regulation of beta-catenin function was investigated. Incubation of cells with a potent, small molecule gamma-secretase inhibitor did not affect PS-1/beta-catenin interaction as determined by co-immunoprecipitation, or affect the regulation of beta-catenin turnover, as determined by pulse-chase analysis, even at inhibitor concentrations that completely blocked PS-mediated APP processing. Moreover, inhibition of PS-1-mediated proteolytic activity did not affect beta-catenin trafficking, as determined by immunolocalization and immunoblotting, or beta-catenin-mediated transcription. These results indicate that PS-1-mediated regulation of gamma-secretase activity and PS-1-mediated regulation of beta-catenin function can be pharmacologically separated and support the idea that these are distinct functions.
authors.affiliation: Bristol-Myers Squibb Company, The Pharmaceutical Research Institute, Experimental Station, Route 141 and Henry Clay Rd., Wilmington, DE 19880, USA. jere.meredith@bms.com
authors.forename: Jere E
authors.initials: JE
authors.lastname: Meredith
authors.forename: Qian
authors.initials: Q
authors.lastname: Wang
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Mitchell
authors.forename: Richard E
authors.initials: RE
authors.lastname: Olson
authors.forename: Robert
authors.initials: R
authors.lastname: Zaczek
authors.forename: Andrew M
authors.initials: AM
authors.lastname: Stern
authors.forename: Dietmar
authors.initials: D
authors.lastname: Seiffert
mesh_terms: D021581:Active Transport, Cell Nucleus; D053829:Amyloid Precursor Protein Secretases; D016282:Aspartic Acid Endopeptidases; D002460:Cell Line; D002467:Cell Nucleus / Q000378:metabolism; D003598:Cytoskeletal Proteins / Q000378:metabolism* / Q000502:physiology; D004305:Dose-Response Relationship, Drug; D010450:Endopeptidases / Q000378:metabolism* / Q000502:physiology; D006801:Humans; D007700:Kinetics; D018021:Lithium Chloride / Q000494:pharmacology; D008565:Membrane Proteins / Q000502:physiology*; D053764:Presenilin-1; D011480:Protease Inhibitors / Q000737:chemistry / Q000494:pharmacology; D015534:Trans-Activators / Q000378:metabolism* / Q000502:physiology; D014158:Transcription, Genetic; D051176:beta Catenin
chemical_list: C495270:CTNNB1 protein, human; D003598:Cytoskeletal Proteins; D008565:Membrane Proteins; C508853:PSEN1 protein, human; D053764:Presenilin-1; D011480:Protease Inhibitors; D015534:Trans-Activators; D051176:beta Catenin; D053829:Amyloid Precursor Protein Secretases; D010450:Endopeptidases; D016282:Aspartic Acid Endopeptidases; C509280:BACE1 protein, human; D018021:Lithium Chloride