title: Methylmercury, an environmental electrophile capable of activation and disruption of the Akt/CREB/Bcl-2 signal transduction pathway in SH-SY5Y cells.
abstract: Methylmercury (MeHg) modifies cellular proteins via their thiol groups in a process referred to as "S-mercuration", potentially resulting in modulation of the cellular signal transduction pathway. We examined whether low-dose MeHg could affect Akt signaling involved in cell survival. Exposure of human neuroblastoma SH-SY5Y cells of up to 2 μM MeHg phosphorylated Akt and its downstream signal molecule CREB, presumably due to inactivation of PTEN through S-mercuration. As a result, the anti-apoptotic protein Bcl-2 was up-regulated by MeHg. The activation of Akt/CREB/Bcl-2 signaling mediated by MeHg was, at least in part, linked to cellular defence because either pretreatment with wortmannin to block PI3K/Akt signaling or knockdown of Bcl-2 enhanced MeHg-mediated cytotoxicity. In contrast, increasing concentrations of MeHg disrupted Akt/CREB/Bcl-2 signaling. This phenomenon was attributed to S-mercuration of CREB through Cys286 rather than Akt. These results suggest that although MeHg is an apoptosis-inducing toxicant, this environmental electrophile is able to activate the cell survival signal transduction pathway at lower concentrations prior to apoptotic cell death.
authors.affiliation: Faculty of Medicine, University of Tsukuba, Tsukuba, Ibaraki 305-8575, Japan.
authors.forename: Takamitsu
authors.initials: T
authors.lastname: Unoki
authors.affiliation: Faculty of Medicine, University of Tsukuba, Tsukuba, Ibaraki 305-8575, Japan.
authors.forename: Yumi
authors.initials: Y
authors.lastname: Abiko
authors.affiliation: Faculty of Medicine, University of Tsukuba, Tsukuba, Ibaraki 305-8575, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Toyama
authors.affiliation: Department of Medicinal Pharmacology, Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama University, Okayama 700-8530, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Uehara
authors.affiliation: Faculty of Medicine, University of Tsukuba, Tsukuba, Ibaraki 305-8575, Japan.
authors.forename: Koji
authors.initials: K
authors.lastname: Tsuboi
authors.affiliation: Division of Cardiocirculatory Signaling, Okazaki Institute for Integrative Bioscience (National Institute for Physiological Sciences), National Institutes of Natural Sciences, Okazaki, Aichi 444-8787, Japan.|Department of Translational Pharmaceutical Sciences, Graduate School of Pharmaceutical Sciences, Kyushu University, Fukuoka 812-8582, Japan.
authors.forename: Motohiro
authors.initials: M
authors.lastname: Nishida
authors.affiliation: Faculty of Pharmaceutical Sciences, Tokyo University of Science, Noda, Chiba 275-8510, Japan.
authors.forename: Toshiyuki
authors.initials: T
authors.lastname: Kaji
authors.affiliation: Faculty of Medicine, University of Tsukuba, Tsukuba, Ibaraki 305-8575, Japan.
authors.forename: Yoshito
authors.initials: Y
authors.lastname: Kumagai
mesh_terms: D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects*; D006801:Humans; D008767:Methylmercury Compounds / Q000378:metabolism*; D009474:Neurons / Q000187:drug effects* / Q000502:physiology*; D051058:Oncogene Protein v-akt / Q000378:metabolism; D010766:Phosphorylation; D011499:Protein Processing, Post-Translational; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000096:biosynthesis; D015398:Signal Transduction / Q000187:drug effects*; D015854:Up-Regulation
chemical_list: C115163:CREB1 protein, human; D017362:Cyclic AMP Response Element-Binding Protein; D008767:Methylmercury Compounds; D019253:Proto-Oncogene Proteins c-bcl-2; D051058:Oncogene Protein v-akt