Characterization of stanniocalcin 2, a novel target of the mammalian unfolded protein response with cytoprotective properties
Characterization of stanniocalcin 2, a novel target of the mammalian unfolded protein response with cytoprotective properties
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DOI：
10.1128/mcb.24.21.9456-9469.2004
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发表时间：
2004-11-01
影响因子：
5.3
通讯作者：
Thinakaran, G
中科院分区：
文献类型：
--
作者：
Ito, D;Walker, JR;Thinakaran, G
错误折叠蛋白在内质网（ER）中的积累在所有真核细胞中诱导高度保守的稳态反应，称为未折叠蛋白反应（UPR）。在这里，我们描述了斯钙素2（STC 2），哺乳动物同源的钙和磷酸盐调节激素首先在鱼中发现，作为一种新的目标的UPR的表征。STC 2基因的表达在暴露于衣霉素和毒胡萝卜素后的培养细胞中快速上调，在ER驻留激酶PERK活化后由ATF 4上调。此外，STC 2的表达也被激活的神经元细胞的氧化应激和缺氧，但不是由几个细胞应激无关的UPR。相比之下，另一个同源物STC 1的表达仅通过缺氧上调，而不依赖于PERK或ATF 4的表达。在体内研究表明，大鼠皮层神经元迅速上调STC 2短暂大脑中动脉闭塞后。最后，STC2表达的siRNA介导的抑制使得N2a神经母细胞瘤细胞和HeLa细胞在用毒胡萝卜素处理后明显更容易发生凋亡性细胞死亡，并且STC2的过表达减弱毒胡萝卜素诱导的细胞死亡。因此，诱导的STC 2表达是UPR的存活组分的基本特征。
Accumulation of misfolded proteins in the endoplasmic reticulum (ER) induces a highly conserved homeostatic response in all eukaryotic cells, termed the unfolded-protein response (UPR). Here we describe the characterization of stanniocalcin 2 (STC2), a mammalian homologue of a calcium- and phosphate-regulating hormone first identified in fish, as a novel target of the UPR. Expression of STC2 gene is rapidly upregulated in cultured cells after exposure to tunicamycin and thapsigargin, by ATF4 after activation of the ER-resident kinase PERK. In addition, STC2 expression is also activated in neuronal cells by oxidative stress and hypoxia but not by several cellular stresses unrelated to the UPR. In contrast, expression of another homologue, STC1, is only upregulated by hypoxia independent of PERK or ATF4 expression. In vivo studies revealed that rat cortical neurons rapidly upregulate STC2 after transient middle cerebral artery occlusion. Finally, siRNAmediated inhibition of STC2 expression renders N2a neuroblastoma cells and HeLa cells significantly more vulnerable to apoptotic cell death after treatment with thapsigargin, and overexpression of STC2 attenuated thapsigargin-induced cell death. Consequently, induced STC2 expression is an essential feature of survival component of the UPR.