MSKs are required for the transcription of the nuclear orphan receptors Nur77, Nurr1 and Nor1 downstream of MAPK signalling
MSKs are required for the transcription of the nuclear orphan receptors Nur77, Nurr1 and Nor1 downstream of MAPK signalling
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DOI：
10.1042/bj20050196
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发表时间：
2005-09-15
影响因子：
4.1
通讯作者：
Arthur, JSC
中科院分区：
文献类型：
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作者：
Darragh, J;Soloaga, A;Arthur, JSC
MSK（丝裂原和应激活化蛋白激酶）1和MSK2是在体内ERK（细胞外信号调节激酶）1/2或p38 MAPK（丝裂原活化蛋白激酶）途径下游活化的激酶，是cAMP反应元件结合蛋白CREB和组蛋白H3磷酸化所必需的。在这里，我们表明msk参与调节直接早期基因Nur77的转录。PMA、表皮生长因子（EGF）、肿瘤坏死因子（TNF）或大霉素刺激小鼠胚胎成纤维细胞可诱导Nur77 mRNA表达。在MSK1/2双敲除细胞中，TNF和大霉素对Nur77的诱导作用被消除，而PMA或EGF对Nur77的诱导作用则显著降低。MSK应答元件被定位到Nur77启动子中的两个AP（激活蛋白）-l样元件。A-CREB也阻断了Nur77的诱导，这表明msk通过磷酸化与两个ap -1样元件结合的CREB来控制Nur77的转录。与msk1 /2敲除细胞中Nur77 mRNA水平的下降一致，我们还发现msk是PMA和TNF诱导Nur77蛋白所必需的。msk也被发现是两个与Nur77相关的基因，Nurr1和Nor1的转录所必需的，这两个基因也以CREB-或ATF1（激活转录因子-1）依赖的方式转录。在大霉素信号传导的下游，另一条erk依赖通路独立于MSK和CREB，也是Nurr1和Nor1转录所必需的。
MSK (mitogen- and stress-activated protein kinase) 1 and MSK2 are kinases activated downstream of either the ERK (extracellular-signal-regulated kinase) 1/2 or p38 MAPK (mitogen-activated protein kinase) pathways in vivo and are required for the phosphorylation of CREB (cAMP response element-binding protein) and histone H3. Here we show that the MSKs are involved in regulating the transcription of the immediate early gene Nur77. Stimulation of mouse embryonic fibroblasts with PMA, EGF (epidermal growth factor), TNF (tumour necrosis factor) or anisomycin resulted in induction of the Nur77 mRNA. The induction of Nur77 by TNF and anisomycin was abolished in MSK1/2 double-knockout cells, whereas induction was significantly reduced in response to PMA or EGF. The MSK responsive elements were mapped to two AP (activator protein)-l-like elements in the Nur77 promoter. The induction of Nur77 was also blocked by A-CREB, suggesting that MSKs control Nur77 transcription by phosphorylating CREB bound to the two AP-1-like elements. Consistent with the decrease in Nur77 mRNA levels in the MSK1/2-knockout cells, it was also found that MSKs were required for the induction of Nur77 protein by PMA and TNF. MSKs were also found to be required for the transcription of two genes related to Nur77, Nurr1 and Nor1, which were also transcribed in a CREB- or ATF1 (activating transcription factor-1)-dependent manner. Downstream of anisomycin signalling, a second ERK-dependent pathway, independent of MSK and CREB, was also required for the transcription of Nurr1 and Nor1.