Methylmercury Induces Cytotoxicity through Inhibition of PTEN Activity by a Decrease in Its Solubility-猫眼课题宝

DOI：

10.1248/bpbreports.1.1_1

发表时间：

2018

期刊：

影响因子：

通讯作者：

中科院分区：

其他

文献类型：

作者：

Takumi Kobayashi;T. Toyama;Jin-Yong Lee;N. Miura;S. Kuge;A. Naganuma;Gi-Wook Hwang

甲基汞是一种代表性的环境污染物，会导致中枢神经系统（CNS）损伤。1,2）自然界中的汞通过细菌作用转化为甲基汞，并沿着食物链积累，因此在大型鱼类中含量相对较高。近年来，它已成为一个全球性问题，食用大量鱼类的母亲所生婴儿的中枢神经系统缺陷证实了这一点。3,4) 然而，甲基汞毒性的机制及其防护措施大多仍不清楚。我们发现泛素-蛋白酶体系统（UPS，一种蛋白水解系统）和自噬与甲基汞毒性有关。5-7）我们还报道过过度诱导的自噬可能与增强甲基汞毒性有关。7）Chang 等人。据报道，甲基汞降低了哺乳动物雷帕霉素靶标（mTOR，一种自噬抑制剂）的水平，从而诱导自噬。8）这导致神经干细胞分化为神经元的抑制。此外，有人提出，在星形胶质细胞和鼠胚胎成纤维细胞中，自噬可能是响应甲基汞毒性的防御机制。9,10) 自噬是细胞内降解蛋白质的系统，用于防止过度合成的蛋白质和各种应激产生的异常蛋白质的积累。11) 自噬还有助于生物稳态，包括饥饿状态下蛋白质循环的表现。12) 众所周知，当细胞经历低血糖或缺氧饥饿状态时，AMP 激活的蛋白激酶的激活会诱导自噬。13) 进一步知道，当恢复到正常的细胞内营养状态时，mTOR 被激活，自噬诱导受到抑制。 14) mTOR 是一种由蛋白激酶 B (Akt) 激活的丝氨酸-苏氨酸激酶。15) 此外，已知 Akt 通过磷脂酰肌醇-3,4,5-三磷酸 (PIP3) 激活，而磷脂酰肌醇-4,5-二磷酸 (PIP2) 被磷酸肌醇 3-激酶磷酸化 (PI3K);该信号转导系统被称为 PI3K/Akt/mTOR 途径。16) 已知该途径受到称为 PTEN 的磷酸酶（10 号染色体上删除的磷酸酶和张力蛋白同源物）的负控制。16) PTEN 主要存在于细胞质中。当 PTEN 移动到细胞膜时，通过将 PIP3 去磷酸化为 PIP2，抑制 Akt 激活。17) 近年来，许多报道表明 PTEN 功能异常导致 Akt 过度激活并导致癌症进展。18-20) 这表明 Akt 过度激活介导的自噬抑制参与其中。21) 细胞内 PTEN 受 UPS 监管。参与这个过程的，作为泛素连接酶的是神经前体细胞表达的发育下调蛋白4-1（NEDD4-1）。22）据报道，NEDD4-1水平因氧化应激而增加，然后PTEN泛素化是proRegular Article

Methylmercury is a representative environmental pollutant that causes central nervous system (CNS) damage.1,2) Mercury in the natural world is transformed by bacterial action to methylmercury and accumulates along the food chain so that it is found at relatively high levels in large fish. In recent years, it has become a global problem, confirmed by CNS defects in babies born to mothers who consume large amounts of fish.3,4) Nevertheless, the mechanisms involved in methylmercury toxicity and the protection against it are mostly still unknown. We have found that the ubiquitin–proteasome system (UPS, a proteolytic system) and autophagy are involved in methylmercury toxicity.5-7) We have also reported that excessively induced autophagy may be involved in enhancing methylmercury toxicity.7) Chang et al. reported that methylmercury reduces the levels of mammalian target of rapamycin (mTOR, an autophagy inhibitor), thereby inducing autophagy.8) This results in the inhibition of differentiation of neural stem cells into neurons. In addition, it has been suggested that in astrocytes and murine embryonic fibroblasts, autophagy may be a defense mechanism in response to methylmercury toxicity.9,10) Autophagy is a system for degrading proteins in cells, serving to prevent the accumulation of hypersynthesized proteins and abnormal proteins generated by a variety of stresses.11) Autophagy also contributes to biological homeostasis, including in the performance of protein cycles during starvation states.12) It is known that autophagy is induced by the activation of AMP-activated protein kinase when cells experience hypoglycemic or hypoxic starvation states.13) It is further known that when there is recovery to a normal intracellular nutrition state, mTOR is activated, and autophagy induction is inhibited.14) mTOR is a serine–threonine kinase activated by protein kinase B (Akt).15) Moreover, it is known that Akt is activated via phosphatidylinositol-3,4,5-trisphosphate (PIP3), phosphorylated from phosphatidylinositol-4,5-bisphosphate (PIP2) by phosphoinositide 3-kinase (PI3K); this signaltransduction system is known as the PI3K/Akt/mTOR pathway.16) This pathway is known to be negatively controlled by a phosphatase called PTEN (phosphatase and tensin homolog deleted on chromosome 10).16) PTEN exists mainly in the cytoplasm. When PTEN moves to the cell membrane, by dephosphorylating PIP3 to PIP2, it inhibits Akt activation.17) In recent years, many reports have emerged that PTEN functional abnormalities resulting in hyperactivation of Akt and causing progression of cancer.18-20) This suggests the involvement of autophagy inhibition mediated by Akt hyperactivation.21) Intracellular levels of PTEN are regulated by the UPS. Involved in this process, as a ubiquitin ligase, is a neural precursor cell-expressed developmentally down-regulated protein 4-1 (NEDD4-1).22) It is reported that NEDD4-1 levels increase by oxidative stress, and then ubiquitination of PTEN is proRegular Article

Methylmercury Induces Cytotoxicity through Inhibition of PTEN Activity by a Decrease in Its Solubility

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