Faculty of Medicine, University of Tsukuba, Tsukuba, Ibaraki 305-8575, Japan.
Department of Medicinal Pharmacology, Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama University, Okayama 700-8530, Japan.
Sci Rep. 2016 Jun 30;6:28944. doi: 10.1038/srep28944.
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.
甲基汞（MeHg）通过其巯基修饰细胞蛋白，这一过程被称为“S-汞化”，可能导致细胞信号转导途径的调节。我们研究了低剂量 MeHg 是否会影响参与细胞存活的 Akt 信号。高达 2μM 的 MeHg 暴露于人神经母细胞瘤 SH-SY5Y 细胞中，磷酸化 Akt 及其下游信号分子 CREB，推测是通过 S-汞化使 PTEN 失活。结果，MeHg 上调了抗凋亡蛋白 Bcl-2。MeHg 介导的 Akt/CREB/Bcl-2 信号的激活至少部分与细胞防御有关，因为用 wortmannin 预处理以阻断 PI3K/Akt 信号或敲低 Bcl-2 均可增强 MeHg 介导的细胞毒性。相比之下，增加浓度的 MeHg 破坏了 Akt/CREB/Bcl-2 信号。这种现象归因于 Cys286 处的 CREB 通过 S-汞化，而不是 Akt。这些结果表明，尽管 MeHg 是一种诱导细胞凋亡的有毒物质，但这种环境中的亲电试剂能够在细胞凋亡之前的较低浓度下激活细胞存活信号转导途径。
