Department of Immunology, University of Manitoba, Manitoba Institute of Cell Biology, Winnipeg, Manitoba R3E 0V9, Canada.
Nucleic Acids Res. 2010 Jun;38(10):3196-208. doi: 10.1093/nar/gkq030. Epub 2010 Feb 3.
Upon activation of the ERK and p38 MAPK pathways, the MSK1/2-mediated nucleosomal response, including H3 phosphorylation at serine 28 or 10, is coupled with the induction of immediate-early (IE) gene transcription. The outcome of this response, varying with the stimuli and cellular contexts, ranges from neoplastic transformation to neuronal synaptic plasticity. Here, we used sequential co-immunoprecipitation assays and sequential chromatin immunoprecipitation (ChIP) assays on mouse fibroblast 10T1/2 and MSK1 knockdown 10T1/2 cells to show that H3 serine 28 and 10 phosphorylation leads to promoter remodeling. MSK1, in complexes with phospho-serine adaptor 14-3-3 proteins and BRG1 the ATPase subunit of the SWI/SNF remodeler, is recruited to the promoter of target genes by transcription factors such as Elk-1 or NF-kappaB. Following MSK1-mediated H3 phosphorylation, BRG1 associates with the promoter of target genes via 14-3-3 proteins, which act as scaffolds. The recruited SWI/SNF remodels nucleosomes at the promoter of IE genes enabling the binding of transcription factors like JUN and the onset of transcription.
当 ERK 和 p38 MAPK 途径被激活时，MSK1/2 介导的核小体反应，包括组蛋白 H3 丝氨酸 28 或 10 的磷酸化，与即刻早期（IE）基因转录的诱导偶联。这种反应的结果，因刺激物和细胞环境的不同而不同，从肿瘤转化到神经元突触可塑性。在这里，我们使用小鼠成纤维细胞 10T1/2 和 MSK1 敲低 10T1/2 细胞的顺序共免疫沉淀测定和顺序染色质免疫沉淀（ChIP）测定，表明 H3 丝氨酸 28 和 10 的磷酸化导致启动子重塑。MSK1 与磷酸丝氨酸接头蛋白 14-3-3 和 SWI/SNF 重塑子的 ATP 酶亚基 BRG1 形成复合物，通过 Elk-1 或 NF-κB 等转录因子被招募到靶基因的启动子。在 MSK1 介导的 H3 磷酸化之后，BRG1 通过 14-3-3 蛋白与靶基因的启动子结合，14-3-3 蛋白作为支架。募集的 SWI/SNF 在 IE 基因的启动子处重塑核小体，允许转录因子如 JUN 的结合和转录的开始。
