title: Glutathione protects cells against arsenite-induced toxicity.
abstract: To understand the role of glutathione (GSH) in the protection of cells from arsenite toxicity, we studied the mechanism of apoptotic cell death in cells genetically unable to synthesize GSH (GCS-2 cells). Arsenite stimulated an increase in protein ubiquitination in GCS-2 cells while the wild-type cells were unaffected. Arsenite treatment increased lipid peroxidation and induced ubiquitination of molecular chaperone Hsp90 and impaired its ability to bind cochaperone p50(Cdc-37) and client proteins Plk-1 and Cdk-4 in GCS-2 cells. Treatment with arsenite also partially inhibited proteasome activity in GCS-2 cells. In these cells stably transfected with GFP(u) (a reporter consisting of a short degron fused to the COOH-terminus of GFP), intracellular fluorescence increased, suggesting the accumulation of GFP aggregates. GCS-2 cells underwent apoptosis accompanied by release of cytochrome c into the cytoplasm. Taken together, these data suggest that a possible mechanism of arsenite-induced apoptosis is the accumulation of ubiquitinated proteins and impairment of the protein degradative pathway. Further, protection from arsenite-induced ubiquitination is mediated by GSH and to a lesser extent by available reducing equivalents in the cells.
authors.affiliation: Department of Pathology, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA. ghabib@bcm.tmc.edu
authors.forename: Geetha M
authors.initials: GM
authors.lastname: Habib
authors.forename: Zheng-Zheng
authors.initials: ZZ
authors.lastname: Shi
authors.forename: Michael W
authors.initials: MW
authors.lastname: Lieberman
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology; D018053:Arsenites / Q000633:toxicity*; D015152:Blotting, Northern; D015153:Blotting, Western; D015870:Gene Expression / Q000187:drug effects; D005978:Glutathione / Q000378:metabolism*; D049452:Green Fluorescent Proteins; D018841:HSP90 Heat-Shock Proteins / Q000187:drug effects; D047468:Immunoprecipitation; D015227:Lipid Peroxidation / Q000187:drug effects; D051379:Mice; D046988:Proteasome Endopeptidase Complex / Q000187:drug effects*; D013723:Teratogens / Q000633:toxicity*; D014162:Transfection; D025801:Ubiquitin / Q000378:metabolism
chemical_list: D018053:Arsenites; D018841:HSP90 Heat-Shock Proteins; D013723:Teratogens; D025801:Ubiquitin; D049452:Green Fluorescent Proteins; D046988:Proteasome Endopeptidase Complex; D005978:Glutathione; C015001:arsenite