title: Endoplasmic reticulum stress preconditioning attenuates methylmercury-induced cellular damage by inducing favorable stress responses.
abstract: We demonstrate that methylmercury (MeHg)-susceptible cells preconditioned with an inhibitor of endoplasmic reticulum (ER) Ca(2+)-ATPase, thapsigargin, showed resistance to MeHg cytotoxicity through favorable stress responses, which included phosphorylation of eukaryotic initiation factor 2 alpha (Eif2α), accumulation of activating transcription factor 4 (Atf4), upregulation of stress-related proteins, and activation of extracellular signal regulated kinase pathway. In addition, ER stress preconditioning induced suppression of nonsense-mediated mRNA decay (NMD) mainly through the phospho-Eif2α-mediated general suppression of translation initiation and possible combined effects of decreased several NMD components expression. Atf4 accumulation was not mediated by NMD inhibition but translation inhibition of its upstream open reading frame (uORF) and translation facilitation of its protein-coding ORF by the phospho-Eif2α. These results suggested that ER stress plays an important role in MeHg cytotoxicity and that the modulation of ER stress has therapeutic potential to attenuate MeHg cytotoxicity, the underlying mechanism being the induction of integrated stress responses.
authors.affiliation: Department of Clinical Medicine, National Institute for Minamata Disease, 4058-18 Hama, Minamata 867-0008, Japan. usuki@nimd.go.jp
authors.forename: Fusako
authors.initials: F
authors.lastname: Usuki
authors.forename: Masatake
authors.initials: M
authors.lastname: Fujimura
authors.forename: Akio
authors.initials: A
authors.lastname: Yamashita
mesh_terms: D000251:Adenosine Triphosphatases / Q000037:antagonists & inhibitors; D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D002460:Cell Line; D004721:Endoplasmic Reticulum / Q000187:drug effects / Q000502:physiology*; D015852:Eukaryotic Initiation Factor-2 / Q000378:metabolism*; D008767:Methylmercury Compounds / Q000494:pharmacology*; D051379:Mice; D032446:Myoblasts / Q000187:drug effects / Q000502:physiology*; D013312:Stress, Physiological / Q000187:drug effects / Q000502:physiology*; D019284:Thapsigargin / Q000494:pharmacology*
chemical_list: D015852:Eukaryotic Initiation Factor-2; D008767:Methylmercury Compounds; D019284:Thapsigargin; D000251:Adenosine Triphosphatases
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