Induction of hepatic metallothionein synthesis by endoplasmic reticulum stress in mice
Induction of hepatic metallothionein synthesis by endoplasmic reticulum stress in mice
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DOI：
10.1016/j.toxlet.2003.12.066
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发表时间：
2004-03-14
影响因子：
3.5
通讯作者：
Sato, M
中科院分区：
文献类型：
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作者：
Kondoh, M;Tsukada, A;Sato, M
金属硫蛋白（MT）是一种富含巯基的小蛋白质，其水平会因细胞器应激的各种诱导剂而升高，如核应激（顺铂）、线粒体应激（抗霉素A、2，4-二硝基苯酚）和溶酶体应激（百草枯）。虽然内质网（ER）中蛋白质的异常折叠导致ER应激，但ER应激诱导NIT合成的研究从未进行过。在这项研究中，我们研究了MT的诱导ER应激诱导剂，衣霉素（Tun），诱导ER应激，通过抑制N-连接的糖基化的蛋白质在ER。Tun（0.5-1.5 mg/kg，sc）给药可增加C57 BL/6 J小鼠肝脏MT水平（3.1倍）。Tun（1.0 mg/kg）给药后48-96 h观察到肝脏NIT的最大增加。Tun处理后检测MT-Ⅰ、Ⅱ和内质网应激诱导的分子伴侣葡萄糖调节蛋白78（Bip/GRP 78）mRNA的表达。Thapsigargin（Thap）通过抑制ER Ca ~（2+）-ATP酶而产生ER应激，也增加肝MT水平和MT-I和-II mRNA的表达。Tun诱导MT基因敲除小鼠Bip/GRP 78 mRNA表达水平高于野生型小鼠。总之，这些发现表明ER抑制剂是MT的有效诱导剂。(C)2004爱思唯尔爱尔兰有限公司保留所有权利。
Metallothionein (MT) is a small sulfhydryl-rich protein whose levels are elevated by various inducers of organelle stresses, such as nuclear stress (cisplatin), mitochondrial stress (antimycin A, 2,4-dinitrophenol) and lysosomal stress (paraquat). Although abnormal folding of protein in the endoplasmic reticulum (ER) causes ER stress, induction of NIT synthesis by ER stress has never been investigated. In this study, we examined the induction of MT by an inducer of ER stress, tunicamycin (Tun), which induces ER stress by inhibiting N-linked glycosylation of protein in the ER. Administration of Tun (0.5-1.5 mg/kg, sc) increased hepatic MT levels in C57BL/6J mice (3.1-fold). The maximal increase in hepatic NIT was observed 48-96 h after the administration of Tun (1.0 mg/kg). Expressions of MT-I, II and glucose-regulated protein 78 (Bip/GRP78), which is a molecular chaperone induced by ER stress, mRNA were also detected by administration of Tun. Thapsigargin (Thap), a generator of ER stress by inhibiting ER Ca2+-ATPase, also increased both hepatic MT levels and expression of MT-I and -II mRNA. The level of expression of Bip/GRP78 mRNA induced by Tun administration in MT-null mice was greater than that in wild-type mice. Taken together, these findings suggest that inhibitors of ER are potent inducers of MT. (C) 2004 Elsevier Ireland Ltd. All rights reserved.