c-Jun NH2-terminal kinase targeting and phosphorylation of heat shock factor-1 suppress its transcriptional activity
c-Jun NH2-terminal kinase targeting and phosphorylation of heat shock factor-1 suppress its transcriptional activity
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DOI：
10.1074/jbc.m000958200
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发表时间：
2000-06-16
影响因子：
4.8
通讯作者：
Mivechi, NF
中科院分区：
文献类型：
--
作者：
Dai, RJ;Frejtag, W;Mivechi, NF
哺乳动物热休克转录因子HSF-1调节热休克蛋白的表达，热休克蛋白是参与从高级组装到蛋白质降解的细胞过程的分子伴侣。HSF-1是生理生长条件下的磷酸化单体，主要定位于细胞质。当被各种环境胁迫激活时，HSF-I被移位到细胞核内，形成三聚体，获得DNA结合活性，被过度磷酸化，以点状颗粒的形式出现，并增加靶基因的转录活性。随着细胞从应激中恢复，点状颗粒逐渐消失，HSF-I在细胞质和细胞核中以弥漫染色的方式出现。我们先前已经证明，丝裂原激活的蛋白激酶ERK能磷酸化并抑制热休克蛋白L驱动的转录。在这里，Re表明c-Jun氨基末端激酶(JNK)也可以磷酸化和失活HSF-I。JNK的过表达促进了热休克后HSF-1点状颗粒的迅速消失，类似于ERE，JNK在保守的丝裂原活化蛋白激酶结合基序中与HSF-1结合，并在调节域中磷酸化HSF-1。缺乏JNK磷酸化位点的hsf-L-绿色荧光蛋白融合结构的过表达导致该hsf-1突变体形成核颗粒，并在热休克后在核中停留更长时间。综上所述，这些发现表明JNK通过快速清除转录位点上的HSF-1来磷酸化HSF-1并抑制其转录活性。
The mammalian heat shock transcription factor HSF-1 regulates the expression of the heat shock proteins, molecular chaperones that are involved in cellular processes from higher order assembly to protein degradation. HSF-1 is a phosphorylated monomer under physiological growth conditions and is located mainly in the cytoplasm. Upon activation by a variety of environmental stresses, HSF-I is translocated into the nucleus, forms trimers, acquires DNA binding activity, is hyperphosphorylated, appears as punctate granules, and increases transcriptional activity of target genes. As cells recover from stress, the punctate granules gradually disappear, and HSF-I appears in a diffused staining pattern in the cytoplasm and nucleus. We have previously shown that the mitogen-activated protein kinase ERK phosphorylates and suppresses HSF-l-driven transcription. Here, Re show that c-Jun NH2-terminal kinase (JNK) also phosphorylates and inactivates HSF-I. Overexpression of JNK facilitates the rapid disappearance of HSF-1 punctate granules after heat shock Similar to ERE, JNK binds to HSF-1 in the conserved mitogen-activated protein kinases binding motifs and phosphorylates HSF-1 in the regulatory domain. The overexpression of an HSF-l-green fluorescent protein fusion construct lacking JNK phosphorylation sites causes this HSF-1 mutant to form nuclear granules that remain longer in the nucleus after heat shock. Taken together, these findings indicate that JNK phosphorylates HSF-1 and suppresses its transcriptional activity by rapidly clearing HSF-1 hom the sites of transcription.