Regulation of molecular chaperone gene transcription involves the serine phosphorylation, 14-3-3ε binding, and cytoplasmic sequestration of heat shock factor 1
Regulation of molecular chaperone gene transcription involves the serine phosphorylation, 14-3-3ε binding, and cytoplasmic sequestration of heat shock factor 1
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DOI：
10.1128/mcb.23.17.6013-6026.2003
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发表时间：
2003-09-01
影响因子：
5.3
通讯作者：
Calderwood, SK
中科院分区：
文献类型：
--
作者：
Wang, XZ;Grammatikakis, N;Calderwood, SK
热休克因子1(HSF1)调节分子伴侣热休克蛋白基因的转录。然而，调控HSF1活性的细胞控制机制还不是很清楚。在这项研究中，我们首次证明了人HSF1与基本细胞信号蛋白14-3-3 epsilon结合。HSF1与14-3-3 epsilon的结合发生在细胞外信号调节激酶(ERK)被激活的细胞中，体内特异性ERK途径抑制剂PD98059阻断ERK途径可强烈抑制这种结合。我们以前发现ERK1在丝氨酸307上磷酸化HSF1，并导致调节结构域内丝氨酸303上的糖原合成酶激酶3(GSK3)的二次磷酸化，这些磷酸化事件抑制HSF1。我们在这里表明，HSF1与14-3-3 epsilon的结合需要丝氨酸303和307上的HSF1磷酸化。此外，依赖丝氨酸磷酸化的HSF1与14-3-3 epsilon的结合导致HSF1的转录抑制和细胞质中的隔离。核出口受体CRM1的特异性抑制剂列普霉素B逆转了14-3-3 epsilon介导的HSF1的胞浆滞留，提示CRM1/14-3-3 epsilon介导的核输出在ERK/GSK3/14-3-3 epsilon途径抑制HSF1中起主要作用。我们的实验表明了一条新的HSF1调节途径，并提出了一种在细胞增殖过程中抑制其活性的机制。
Heat shock factor 1 (HSF1) regulates the transcription of molecular chaperone hsp genes. However, the cellular control mechanisms that regulate HSF1 activity are not well understood. In this study, we have demonstrated for the first time that human HSF1 binds to the essential cell signaling protein 14-3-3epsilon. Binding of HSF1 to 14-3-3epsilon occurs in cells in which extracellular signal regulated kinase (ERK) is activated and blockade of the ERK pathway by treatment with the specific ERK pathway inhibitor PD98059 in vivo strongly suppresses the binding. We previously showed that ERK1 phosphorylates HSF1 on serine 307 and leads to secondary phosphorylation by glycogen synthase kinase 3 (GSK3) on serine 303 within the regulatory domain and that these phosphorylation events repress HSF1. We show here that HSF1 binding to 14-3-3epsilon requires HSF1 phosphorylation on serines 303 and 307. Furthermore, the serine phosphorylation-dependent binding of HSF1 to 14-3-3epsilon results in the transcriptional repression of HSF1 and its sequestration in the cytoplasm. Leptomycin B, a specific inhibitor of nuclear export receptor CRM1, was found to reverse the cytoplasmic sequestration of HSF1 mediated by 14-3-3epsilon, suggesting that CRM1/14-3-3epsilon directed nuclear export plays a major role in repression of HSF1 by the ERK/GSK3/14-3-3epsilon pathway. Our experiments indicate a novel pathway for HSF1 regulation and suggest a mechanism for suppression of its activity during cellular proliferation.