title: Cadmium-Mediated Activation of the HSP90/HSF1 Pathway Regulated by Reactive Persulfides/Polysulfides.
abstract: Cadmium is an environmental electrophile that modifies reactive thiols in proteins, indicating that this heavy metal may modulate redox-signal transduction pathways. The current consensus is that reactive persulfides and polysulfides produced by cystathionine γ-lyase (CSE) and cystathionine β-synthase are highly nucleophilic and thus cadmium may be captured by these reactive sulfur species. It has previously been found that electrophile-mediated covalent modifications of the heat shock protein (HSP) are involved in the activation of heat shock factor 1 (HSF1) pathway. The effects of cadmium on the activation of HSP/HSF1 pathway were investigated in this study. Exposure of bovine aortic endothelial cells to cadmium resulted in modification of HSP90 and HSF1 activation, thereby up-regulating the downstream protein HSP70. The siRNA-mediated knockdown of HSF1 enhanced the cytotoxicity induced by cadmium, suggesting that the HSP90/HSF1 pathway contributes to protection against cadmium toxicity. The knockdown of CSE and/or cystathionine β-synthase decreased the levels of reactive sulfur species in the cells and increased the degree of HSP70 induction and cytotoxicity caused by exposure to cadmium. Overexpression of CSE diminished cadmium-mediated up-regulation of HSP70 and cytotoxicity. These results suggest that cadmium activates HSF1 by modifying HSP90 and that reactive sulfur species regulate the redox signal transduction pathway presumably via capture of cadmium, resulting in protection against cadmium toxicity under toxic conditions.
authors.affiliation: Environmental Biology Laboratory, Faculty of Medicine.|Graduate School of Life and Environmental Sciences, University of Tsukuba, Tsukuba, Ibaraki 305-8575, Japan.
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Shinkai
authors.affiliation: Graduate School of Life and Environmental Sciences, University of Tsukuba, Tsukuba, Ibaraki 305-8575, Japan.
authors.forename: Akira
authors.initials: A
authors.lastname: Masuda
authors.affiliation: Environmental Biology Laboratory, Faculty of Medicine.
authors.forename: Masahiro
authors.initials: M
authors.lastname: Akiyama
authors.affiliation: Department of Chemistry, Washington State University, Pullman, Washington 99164.
authors.forename: Ming
authors.initials: M
authors.lastname: Xian
authors.affiliation: Environmental Biology Laboratory, Faculty of Medicine.|Graduate School of Life and Environmental Sciences, University of Tsukuba, Tsukuba, Ibaraki 305-8575, Japan.
authors.forename: Yoshito
authors.initials: Y
authors.lastname: Kumagai
mesh_terms: D000818:Animals; D002104:Cadmium / Q000633:toxicity*; D002417:Cattle; D018929:Cell Culture Techniques; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D003541:Cystathionine beta-Synthase / Q000378:metabolism; D003542:Cystathionine gamma-Lyase / Q000378:metabolism; D042783:Endothelial Cells / Q000187:drug effects* / Q000378:metabolism; D018841:HSP90 Heat-Shock Proteins / Q000378:metabolism*; D000076249:Heat Shock Transcription Factors / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects*; D013440:Sulfides / Q000378:metabolism*
chemical_list: D018841:HSP90 Heat-Shock Proteins; D000076249:Heat Shock Transcription Factors; D013440:Sulfides; C051552:persulfides; D002104:Cadmium; C032915:polysulfide; D003541:Cystathionine beta-Synthase; D003542:Cystathionine gamma-Lyase
keywords: cadmium; cystathionine γ-lyase; heat shock factor 1; heat shock protein; persulfides/polysulfides.