Cadmium-Mediated Activation of the HSP90/HSF1 Pathway Regulated by Reactive Persulfides/Polysulfides

Yasuhiro Shinkai; Akira Masuda; Masahiro Akiyama; Ming Xian; Yoshito Kumagai

doi:10.1093/toxsci/kfw268

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Cadmium-Mediated Activation of the HSP90/HSF1 Pathway Regulated by Reactive Persulfides/Polysulfides

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Cadmium-Mediated Activation of the HSP90/HSF1 Pathway Regulated by Reactive Persulfides/Polysulfides

Yasuhiro Shinkai, Akira Masuda, Masahiro Akiyama, Ming Xian and Yoshito Kumagai

Toxicological sciences, Vol.156(2), pp.412-421

04/01/2017

DOI: https://doi.org/10.1093/toxsci/kfw268

Handle:

https://hdl.handle.net/2376/100331

PMCID: PMC5412070

PMID: 28115653

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Abstract

Cell Survival - drug effects

Heat Shock Transcription Factors - metabolism

Cadmium - toxicity

Endothelial Cells - metabolism

Cells, Cultured

Cystathionine gamma-Lyase - metabolism

Cystathionine beta-Synthase - metabolism

Animals

Signal Transduction - drug effects

Cattle

HSP90 Heat-Shock Proteins - metabolism

Sulfides - metabolism

Cell Culture Techniques

Endothelial Cells - drug effects

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.

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Title: Cadmium-Mediated Activation of the HSP90/HSF1 Pathway Regulated by Reactive Persulfides/Polysulfides
Creators: Yasuhiro Shinkai - Graduate School of Life and Environmental Sciences, University of Tsukuba, Tsukuba, Ibaraki 305-8575, Japan
Akira Masuda - Graduate School of Life and Environmental Sciences, University of Tsukuba, Tsukuba, Ibaraki 305-8575, Japan
Masahiro Akiyama - Environmental Biology Laboratory, Faculty of Medicine
Ming Xian - Department of Chemistry, Washington State University, Pullman, Washington 99164
Yoshito Kumagai - Graduate School of Life and Environmental Sciences, University of Tsukuba, Tsukuba, Ibaraki 305-8575, Japan
Publication Details: Toxicological sciences, Vol.156(2), pp.412-421
Academic Unit: Chemistry, Department of
Publisher: United States
Identifiers: 99900546568601842
Language: English
Resource Type: Journal article