RNA-mediated response to heat shock in mammalian cells
RNA-mediated response to heat shock in mammalian cells
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DOI：
10.1038/nature04518
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发表时间：
2006-03-23
期刊：
影响因子：
64.8
通讯作者：
Nudler, E
中科院分区：
文献类型：
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作者：
Shamovsky, I;Ivannikov, M;Nudler, E
热休克转录因子1 （HSF1）通过诱导热休克蛋白（HSPs）和其他细胞保护蛋白的表达，在脊椎动物热休克反应中发挥重要作用(1)。HSF1以无活性单体形式存在于非应激细胞中，并在热和其他应激刺激下被激活。HSF1的激活涉及三聚化和获得位点特异性dna结合活性（2,3），这是通过与某些热休克蛋白相互作用负调控的（4-6）。在这里，我们发现HSF1被热休克激活是一个活跃的过程，它是由含有翻译延伸因子eEF1A的核糖核蛋白复合物和一种以前未知的非编码RNA介导的，我们称之为HSR1（热休克RNA-1）。HSR1在人和啮齿动物细胞中组成性表达，其同源物在功能上是可互换的。体外激活HSF1需要HSR1和eEF1A；抗HSR1的反义寡核苷酸或短干扰（si）RNA在体内损害热休克反应，使细胞具有热敏性。HSR1在热休克过程中的核心作用表明，靶向这种RNA可以作为一种新的治疗模式，用于治疗与HSF1失调相关的癌症、炎症和其他疾病。
The heat-shock transcription factor 1 (HSF1) has an important role in the heat-shock response in vertebrates by inducing the expression of heat-shock proteins (HSPs) and other cytoprotective proteins(1). HSF1 is present in unstressed cells in an inactive monomeric form and becomes activated by heat and other stress stimuli. HSF1 activation involves trimerization and acquisition of a site-specific DNA-binding activity(2,3), which is negatively regulated by interaction with certain HSPs(4-6). Here we show that HSF1 activation by heat shock is an active process that is mediated by a ribonucleoprotein complex containing translation elongation factor eEF1A and a previously unknown non-coding RNA that we term HSR1 (heat shock RNA-1). HSR1 is constitutively expressed in human and rodent cells and its homologues are functionally interchangeable. Both HSR1 and eEF1A are required for HSF1 activation in vitro; antisense oligonucleotides or short interfering (si)RNA against HSR1 impair the heat-shock response in vivo, rendering cells thermosensitive. The central role of HSR1 during heat shock implies that targeting this RNA could serve as a new therapeutic model for cancer, inflammation and other conditions associated with HSF1 deregulation.