Mitogen- and stress-activated protein kinase 1 activity and histone H3 phosphorylation in oncogene-transformed mouse fibroblasts
Mitogen- and stress-activated protein kinase 1 activity and histone H3 phosphorylation in oncogene-transformed mouse fibroblasts
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DOI：
10.1158/0008-5472.can-04-2369
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发表时间：
2004-12-15
期刊：
影响因子：
11.2
通讯作者：
Davie, JR
中科院分区：
文献类型：
--
作者：
Drobic, B;Espino, PS;Davie, JR
Ras-Raf-丝裂原活化蛋白/细胞外信号调节激酶（ERK）激酶-ERK信号转导通路或SAPK 2/p38通路的激活导致丝裂原和应激活化蛋白激酶1（MSK 1）的激活。MSK 1的这种激活导致组蛋白H3在Ser处的快速磷酸化（10）。以前，我们已经证明，Ser（10）磷酸化的H3在Ciras-3（c-Ha-ras转化的10 T1/2）小鼠成纤维细胞中升高，H3磷酸酶活性在Ciras-3和10 T1/2细胞中相似。在这里，我们证明，ERK和MSK 1的活动，但不是p38，在Ciras-3细胞中相对于这些活动在亲本10 T1/2细胞中升高。对MSK 1亚细胞分布的分析表明，H3激酶在Ciras-3和10 T1/2细胞中的分布相似，大多数MSK 1存在于细胞核中。与许多其他染色质修饰酶相反，MSK 1松散地结合在细胞核中，并且不是核基质的组分。我们的研究结果提供的证据表明，癌基因介导的Ras-有丝分裂原活化蛋白激酶信号转导通路的激活提高了MSK 1的活性，导致磷酸化H3的稳态水平增加，这可能有助于在这些细胞中观察到的染色质去凝聚和异常基因表达。
Activation of the Ras-Raf-mitogen-activated protein/extracellular signal-regulated kinase (ERK) kinase-ERK signal transductionpathway or the SAPK2/p38 pathway results in the activation of mitogen- and stress-activated protein kinase 1 (MSK1). This activation of MSK1 leads to a rapid phosphorylation of histone H3 at Ser(10). Previously, we had demonstrated that Ser(10) phosphorylated H3 was elevated in Ciras-3 (c-Ha-ras-transformed 10T1/2) mouse fbroblasts and that H3 phosphatase activity was similar in Ciras-3 and 10T1/2 cells. Here, we demonstrate that the activities of ERK and MSK1, but not p38, are elevated in Ciras-3 cells relative to these activities in the parental 10T1/2 cells. Analyses of the subcellular distribution of MSK1 showed that the H3 kinase was similarly distributed in Ciras-3 and 10T1/2 cells, with most MSK1 being present in the nucleus. In contrast to many other chromatin modifying enzymes, MSK1 was loosely bound in the nucleus and was not a component of the nuclear matrix. Our results provide evidence that oncogene-mediated activation of the Ras-mitogen-activated protein kinase signal transduction pathway elevates the activity of MSK1, resulting in the increased steady-state levels of phosphorylated H3, which may contribute to the chromatin decondensation and aberrant gene expression observed in these cells.