Darragh Joanne, Soloaga Ana, Beardmore Victoria A, Wingate Andrew D, Wiggin Giselle R, Peggie Mark, Arthur J Simon C
MRC Protein Phosphorylation Unit, Faculty of Life Sciences, University of Dundee, Dundee DD1 5EH, Scotland, UK.
Biochem J. 2005 Sep 15;390(Pt 3):749-59. doi: 10.1042/BJ20050196.
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)-1-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.
丝裂原和应激激活蛋白激酶（MSK）1和MSK2是体内细胞外信号调节激酶（ERK）1/2或p38丝裂原活化蛋白激酶（MAPK）途径下游激活的激酶，是cAMP反应元件结合蛋白（CREB）和组蛋白H3磷酸化所必需的。在此我们表明，MSK参与调控即早基因Nur77的转录。用佛波酯（PMA）、表皮生长因子（EGF）、肿瘤坏死因子（TNF）或茴香霉素刺激小鼠胚胎成纤维细胞可诱导Nur77 mRNA的表达。TNF和茴香霉素诱导的Nur77在MSK1/2双敲除细胞中被消除，而对PMA或EGF的诱导反应则显著降低。MSK反应元件定位于Nur77启动子中的两个激活蛋白（AP）-1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水平的降低一致，还发现MSK是PMA和TNF诱导Nur77蛋白所必需的。还发现MSK是与Nur77相关的两个基因Nurr1和Nor1转录所必需的，这两个基因也以CREB或激活转录因子-1（ATF1）依赖的方式转录。在茴香霉素信号传导下游，Nurr1和Nor1的转录还需要第二条独立于MSK和CREB的ERK依赖途径。
