Differential usage of signal transduction pathways defines two types of serum response factor target gene
Differential usage of signal transduction pathways defines two types of serum response factor target gene
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DOI：
10.1074/jbc.m102678200
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发表时间：
2001-07-06
影响因子：
4.8
通讯作者：
Treisman, R
中科院分区：
文献类型：
--
作者：
Gineitis, D;Treisman, R
转录因子血清反应因子（SRF）的激活依赖于rho控制的肌动蛋白动力学变化。我们使用途径特异性抑制剂来比较肌动蛋白动力学、细胞外信号调节激酶（ERK）信号传导和磷脂酰肌醇i激酶在SRF本身或四个细胞SRF靶基因信号传导中的作用。血清、溶血磷脂酸、血小板衍生生长因子和phorbol 12-肉豆蔻酸13-乙酸酯（PMA）分别激活了一个稳定整合的SRF报告基因的转录，该基因依赖于功能性RhoA GTPase。抑制丝裂原活化蛋白激酶- erk激酶（MEK）信号传导使SRF报告基因在所有刺激下的激活减少了约50%，但PMA被有效阻断。抑制磷脂酰肌醇3-激酶可轻微降低血清和溶血磷脂酸对报告细胞的激活，但可显著抑制血小板源性生长因子和PMA对报告细胞的激活。所有刺激对报告细胞的诱导都完全依赖于肌动蛋白动力学。SRF （SRF）和vinculin （ucl）基因的调控与SRF报告基因相似；所有刺激的激活都依赖于rho，并且需要肌动蛋白动力学，但在很大程度上独立于MEK活性。相比之下，fos和egr1的激活独立于RhoA和肌动蛋白聚合，但几乎完全依赖于MEK的激活。这些结果表明，根据对RhoA-actin和MEK-ERK信号通路的相对敏感性，至少可以区分出两类SRF靶基因。
Activation of the transcription factor serum response factor (SRF) is dependent on Rho-controled changes in actin dynamics. We used pathway-specific inhibitors to compare the roles of actin dynamics, extracellular signal-regulated kinase (ERK) signaling, and phosphatidylinositol I-kinase in signaling either to SRF itself or to four cellular SRF target genes. Serum, lysophosphatidic acid, platelet-derived growth factor, and phorbol 12-myristate 13-acetate (PMA) each activated transcription of a stably integrated SRF reporter gene dependent on functional RhoA GTPase, Inhibition of mitogen-activated protein kinase-ERK kinase (MEK) signalling reduced activation of the SRF reporter by all stimuli by about 50%, except for PMA, which was effectively blocked. inhibition of phosphatidylinositol 3-kinase slightly reduced reporter activation by serum and lysophosphatidic acid but substantially inhibited activation by platelet-derived growth factor and PMA. Reporter induction by all stimuli was absolutely dependent on actin dynamics. Regulation of the SRF (srf) and vinculin (ucl) genes was similar to that of the SRF reporter gene; activation by all stimuli was Rho-dependent and required actin dynamics but was largely independent of MEK activity. In contrast, activation of fos and egr1 occurred independently of RhoA and actin polymerization but was almost completely dependent on MEK activation. These results show that at least two classes of SRF target genes can be distinguished on the basis of their relative sensitivity to RhoA-actin and MEK-ERK signaling pathways.