Transcriptional regulation of small HSP-HSF1 and beyond
Transcriptional regulation of small HSP-HSF1 and beyond
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DOI：
10.1016/j.biocel.2012.06.012
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发表时间：
2012-10-01
影响因子：
4
通讯作者：
Mezger, Valerie
中科院分区：
文献类型：
--
作者：
de Thonel, Aurelie;Le Mouel, Anne;Mezger, Valerie
小分子热休克蛋白（small heat shock protein，sHSP）家族成员是一类在发育、应激反应和疾病中起重要作用的分子伴侣，被认为是治疗的靶点，尤其是在癌症中。在正常、应激或病理条件下，调节其转录的分子机制具有极其复杂和微妙的特征。虽然历史上与热休克转录因子（HSFs）相关，但包括HSPB1/Hsp27/Hsp25、α A-晶状体蛋白/HSPB4和α B-晶状体蛋白/HSPB5的不同成员的应激诱导或发育表达依赖于许多转录因子的组合作用。再加上显着不同的顺式元件结构的sHsp调节区，他们赋予每个成员的发育表达或应力诱导。例如，在透镜发育过程中，多种调节途径通过主基因的作用协调小鼠α A-、α B-晶状体蛋白和Hsp 25基因的时空表达，所述主基因如大Maf家族蛋白和Pax6，还有HSF 4。通过各种应激诱导Hsp27和α B-晶状体蛋白转录是通过HSF依赖性机制实现的，通过该机制观察到Hsp27和α B-晶状体蛋白表达的伴随诱导。相反，HSF非依赖性途径可导致α B-晶状体蛋白表达，但不诱导Hsp27。不足为奇的是，sHSP表达的失调与各种病理学相关，包括癌症、神经退行性疾病或心脏病。然而，仍有许多问题有待解决，进一步阐明sHsp基因转录的发育机制可能有助于解开这类迷人的蛋白质的组织和阶段特异性功能，这可能被证明是未来治疗策略的关键。这篇文章是一个定向问题的一部分，题为：小HSP在生理学和病理学。(C)2012爱思唯尔有限公司保留所有权利。
The members of the small heat shock protein (sHSP) family are molecular chaperones that play major roles in development, stress responses, and diseases, and have been envisioned as targets for therapy, particularly in cancer. The molecular mechanisms that regulate their transcription, in normal, stress, or pathological conditions, are characterized by extreme complexity and subtlety. Although historically linked to the heat shock transcription factors (HSFs), the stress-induced or developmental expression of the diverse members, including HSPB1/Hsp27/Hsp25, alpha A-crystallin/HSPB4, and alpha B-crystallin/HSPB5, relies on the combinatory effects of many transcription factors. Coupled with remarkably different cis-element architectures in the sHsp regulatory regions, they confer to each member its developmental expression or stress-inducibility. For example, multiple regulatory pathways coordinate the spatio-temporal expression of mouse alpha A-, alpha B-crystallin, and Hsp25 genes during lens development, through the action of master genes, like the large Maf family proteins and Pax6, but also HSF4. The inducibility of Hsp27 and alpha B-crystallin transcription by various stresses is exerted by HSF-dependent mechanisms, by which concomitant induction of Hsp27 and alpha B-crystallin expression is observed. In contrast, HSF-independent pathways can lead to alpha B-crystallin expression, but not to Hsp27 induction. Not surprisingly, deregulation of the expression of sHSP is associated with various pathologies, including cancer, neurodegenerative, or cardiac diseases. However, many questions remain to be addressed, and further elucidation of the developmental mechanisms of sHsp gene transcription might help to unravel the tissue- and stage-specific functions of this fascinating class of proteins, which might prove to be crucial for future therapeutic strategies. This article is part of a Directed Issue entitled: Small HSPs in physiology and pathology. (C) 2012 Elsevier Ltd. All rights reserved.