title: Inhibition of Daxx-mediated apoptosis by heat shock protein 27.
abstract: Heat shock protein 27 (HSP27) confers cellular protection against a variety of cytotoxic stresses and also against physiological stresses associated with growth arrest or receptor-mediated apoptosis. Phosphorylation modulates the activity of HSP27 by causing a major change in the supramolecular organization of the protein, which shifts from oligomers to dimers. Here we show that phosphorylated dimers of HSP27 interact with Daxx, a mediator of Fas-induced apoptosis, preventing the interaction of Daxx with both Ask1 and Fas and blocking Daxx-mediated apoptosis. No such inhibition was observed with an HSP27 phosphorylation mutant that is only expressed as oligomers or when apoptosis was induced by transfection of a Daxx mutant lacking its HSP27 binding domain. HSP27 expression had no effect on Fas-induced FADD- and caspase-dependent apoptosis. However, HSP27 blocked Fas-induced translocation of Daxx from the nucleus to the cytoplasm and Fas-induced Daxx- and Ask1-dependent apoptosis. The observations revealed a new level of regulation of the Fas pathway and suggest a mechanism for the phosphorylation-dependent protective function of HSP27 during stress and differentiation.
authors.affiliation: Centre de Recherche en Cancérologie de l'Université Laval, L'Hôtel-Dieu de Québec, Québec, Canada G1R 2J6.
authors.forename: S J
authors.initials: SJ
authors.lastname: Charette
authors.forename: J N
authors.initials: JN
authors.lastname: Lavoie
authors.forename: H
authors.initials: H
authors.lastname: Lambert
authors.forename: J
authors.initials: J
authors.lastname: Landry
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000590:Amino Acid Chloromethyl Ketones / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D029681:Arabidopsis Proteins; D001665:Binding Sites; D002352:Carrier Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism*; D061945:Caspase Inhibitors; D020169:Caspases / Q000378:metabolism; D002454:Cell Differentiation; D002460:Cell Line; D002467:Cell Nucleus / Q000378:metabolism; D056970:Co-Repressor Proteins; D003593:Cytoplasm / Q000378:metabolism; D019281:Dimerization; D053200:Fas-Associated Death Domain Protein; D006360:Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D007700:Kinetics; D008856:Microscopy, Fluorescence; D018832:Molecular Chaperones; D009154:Mutation; D009687:Nuclear Proteins; D010766:Phosphorylation; D010940:Plant Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D011485:Protein Binding; D021381:Protein Transport; D015398:Signal Transduction / Q000187:drug effects; D014162:Transfection; D020798:Two-Hybrid System Techniques; D019014:fas Receptor / Q000235:genetics / Q000378:metabolism
chemical_list: C120363:ASK1 protein, Arabidopsis; D048868:Adaptor Proteins, Signal Transducing; D000590:Amino Acid Chloromethyl Ketones; D029681:Arabidopsis Proteins; D002352:Carrier Proteins; D061945:Caspase Inhibitors; D056970:Co-Repressor Proteins; C106985:DAXX protein, human; C505533:FADD protein, human; D053200:Fas-Associated Death Domain Protein; D006360:Heat-Shock Proteins; D047908:Intracellular Signaling Peptides and Proteins; D018832:Molecular Chaperones; D009687:Nuclear Proteins; D010940:Plant Proteins; C096713:benzyloxycarbonylvalyl-alanyl-aspartyl fluoromethyl ketone; D019014:fas Receptor; D020169:Caspases