title: Heat shock protein coinducers with no effect on protein denaturation specifically modulate the membrane lipid phase.
abstract: The hydroxylamine derivative bimoclomol (BM) has been shown to activate natural cytoprotective homeostatic responses by enhancing the capability of cells to cope with various pathophysiological conditions. It exerts its effect in synergy with low levels of stress to induce the synthesis of members of major stress protein families. We show here that the presence of BM does not influence protein denaturation in the cells. BM and its derivatives selectively interact with acidic lipids and modulate their thermal and dynamic properties. BM acts as a membrane fluidizer at normal temperature, but it is a highly efficient membrane stabilizer, inhibiting the bilayer-nonbilayer phase transitions during severe heat shock. We suggest that BM and the related compounds modify those domains of membrane lipids where the thermally or chemically induced perturbation of lipid phase is sensed and transduced into a cellular signal, leading to enhanced activation of heat shock genes. BM may be a prototype for clinically safe membrane-interacting drug candidates that rebalance the level and composition of heat shock proteins.
authors.affiliation: Institute of Biochemistry, Biological Research Centre, Hungarian Academy of Sciences, P.O. Box 521, H-6701 Szeged, Hungary.
authors.forename: Zsolt
authors.initials: Z
authors.lastname: Török
authors.forename: Nelly M
authors.initials: NM
authors.lastname: Tsvetkova
authors.forename: Gábor
authors.initials: G
authors.lastname: Balogh
authors.forename: Ibolya
authors.initials: I
authors.lastname: Horváth
authors.forename: Enikö
authors.initials: E
authors.lastname: Nagy
authors.forename: Zoltán
authors.initials: Z
authors.lastname: Pénzes
authors.forename: Judit
authors.initials: J
authors.lastname: Hargitai
authors.forename: Olivier
authors.initials: O
authors.lastname: Bensaude
authors.forename: Péter
authors.initials: P
authors.lastname: Csermely
authors.forename: John H
authors.initials: JH
authors.lastname: Crowe
authors.forename: Bruno
authors.initials: B
authors.lastname: Maresca
authors.forename: László
authors.initials: L
authors.lastname: Vigh
mesh_terms: D016475:3T3 Cells; D000818:Animals; D018840:HSP70 Heat-Shock Proteins / Q000096:biosynthesis; D006367:HeLa Cells; D006360:Heat-Shock Proteins / Q000096:biosynthesis* / Q000235:genetics; D006801:Humans; D007094:Imides / Q000494:pharmacology*; D007425:Intracellular Membranes / Q000187:drug effects / Q000378:metabolism; D008560:Membrane Fluidity / Q000187:drug effects; D008563:Membrane Lipids / Q000737:chemistry / Q000378:metabolism*; D051379:Mice; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D008954:Models, Biological; D011489:Protein Denaturation / Q000187:drug effects; D011725:Pyridines / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D018840:HSP70 Heat-Shock Proteins; D006360:Heat-Shock Proteins; D007094:Imides; D008563:Membrane Lipids; D011725:Pyridines; C108730:bimoclomol