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Heat Shock Response and Protein Degradation: Regulation of HSF2 by the Ubiquitin-Proteasome Pathway

机译:热休克反应和蛋白质降解:泛素-蛋白酶体途径对HSF2的调节。

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Mammalian cells coexpress a family of heat shock factors (HSFs) whose activities are regulated by diverse stress conditions to coordinate the inducible expression of heat shock genes. Distinct from HSF1, which is expressed ubiquitously and activated by heat shock and other stresses that result in the appearance of nonnative proteins, the stress signal for HSF2 has not been identified. HSF2 activity has been associated with development and differentiation, and the activation properties of HSF2 have been characterized in hemin-treated human K562 erythroleukemia cells. Here, we demonstrate that a stress signal for HSF2 activation occurs when the ubiquitin-proteasome pathway is inhibited. HSF2 DNA-binding activity is induced upon exposure of mammalian cells to the proteasome inhibitors hemin, MG132, and lactacystin, and in the mouse ts85 cell line, which carries a temperature sensitivity mutation in the ubiquitin-activating enzyme (E1) upon shift to the nonpermissive temperature. HSF2 is labile, and its activation requires both continued protein synthesis and reduced degradation. The downstream effect of HSF2 activation by proteasome inhibitors is the induction of the same set of heat shock genes that are induced during heat shock by HSF1, thus revealing that HSF2 affords the cell with a novel heat shock gene-regulatory mechanism to respond to changes in the protein-degradative machinery.
机译:哺乳动物细胞共表达热休克因子(HSF)家族,其活性受多种应激条件调节,以协调热激基因的诱导表达。与HSF1不同,HSF1普遍表达并被热激和其他导致非天然蛋白出现的压力激活,尚未鉴定出HSF2的压力信号。 HSF2活性与发育和分化有关,并且在血红素处理的人K562红白血病细胞中已表征了HSF2的激活特性。在这里,我们证明了当遍在蛋白-蛋白酶体途径被抑制时,HSF2激活就会产生应激信号。当哺乳动物细胞暴露于蛋白酶体抑制剂hemin,MG132和lacacycystin时,以及在小鼠ts85细胞系中诱导HSF2 DNA结合活性,该小鼠ts85细胞系在转移至细胞表面后会在泛素激活酶(E1)中引起温度敏感性突变。不允许的温度。 HSF2不稳定,其激活需要持续的蛋白质合成和减少的降解。蛋白酶体抑制剂激活HSF2的下游效应是诱导与HSF1热激过程中诱导的同一组热激基因,因此表明HSF2为细胞提供了一种新颖的热激基因调节机制,以响应HSF1的变化。蛋白质降解机制。

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