IRE-1α regulates expression of ubiquitin specific peptidases during hypoxic response in U87 glioma cells

IF 0.7
O. Minchenko, D. O. Tsymbal, D. Minchenko, O. O. Riabovol, O. V. Halkin, O. Ratushna
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引用次数: 9

Abstract

Abstract IRE-1α (inositol requiring enzyme-1α), the most evolutionarily conserved of the endoplasmic reticulum stress signaling pathways, is highly implicated in sustaining the proliferation of glioma cells and subsequent tumor growth, which is decreased by the inhibition of IRE-1α. To explore the IRE-1α mediated regulation of ubiquitin system in glioma cells, the expression of a subset of ubiquitin specific peptidases (USP) and of ubiquitin activating enzyme E1-like protein/autophagy related 7 (GSA7/ATG7) genes was studied, during hypoxic stress in wild type and U87 glioma cells with inhibited IRE-1α. Hypoxic treatment of wild type glioma cells leads to the up-regulation of USP25 and the concomitant downregulation of USP1, USP10, USP14, and GSA7 genes. USP4 and USP22 genes expression did not significantly change with hypoxic treatment. Inhibition of IRE-1α activity led to up-regulation of USP1, USP4, USP10, USP22, and USP25, while USP14 and GSA7 genes were down-regulated. Therefore, IRE-1α activity modifies substrate-targeting specificity to proteasome during hypoxic stress, which in turn can affect cell survival. Inhibition of IRE-1α correlates directly with deregulation of ubiquitin specific peptidases and GSA7 in a fashion that ultimately slows tumor growth.
IRE-1α调控U87胶质瘤细胞缺氧反应中泛素特异性肽酶的表达
IRE-1α(肌醇要求酶-1α)是内质网应激信号通路中进化上最保守的信号通路,与维持胶质瘤细胞的增殖和随后的肿瘤生长密切相关,而抑制IRE-1α可降低胶质瘤细胞的增殖。为了探讨IRE-1α对胶质瘤细胞中泛素系统的调控作用,我们研究了野生型和U87型受IRE-1α抑制的胶质瘤细胞在缺氧应激下泛素特异性肽酶(USP)和泛素激活酶e1样蛋白/自噬相关基因7 (GSA7/ATG7)的表达。缺氧处理野生型胶质瘤细胞导致USP25表达上调,同时USP1、USP10、USP14和GSA7基因下调。USP4和USP22基因表达随缺氧处理无显著变化。IRE-1α活性抑制导致USP1、USP4、USP10、USP22和USP25基因上调,而USP14和GSA7基因下调。因此,IRE-1α活性在缺氧胁迫下改变底物靶向蛋白酶体的特异性,从而影响细胞存活。IRE-1α的抑制与泛素特异性肽酶和GSA7的解除直接相关,最终减缓肿瘤生长。
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