Interaction of p38 and Sp1 in a mechanical force-induced, β1, integrin-mediated transcriptional circuit that regulates the actin-binding protein filamin-A
Interaction of p38 and Sp1 in a mechanical force-induced, β1, integrin-mediated transcriptional circuit that regulates the actin-binding protein filamin-A
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DOI：
10.1074/jbc.m207681200
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发表时间：
2002-12-06
影响因子：
4.8
通讯作者：
McCulloch, CAG
中科院分区：
文献类型：
--
作者：
D'Addario, M;Arora, PD;McCulloch, CAG
结缔组织细胞在机械活跃的环境中通过修改稳定细胞膜的肌动蛋白细胞骨架结构而在施加的物理力下存活。在成纤维细胞中，张力诱导细丝蛋白-A，一种机械保护肌动蛋白结合蛋白的表达，但力激活细丝蛋白-A转录的机制和蛋白质相互作用尚未确定。我们发现，在成纤维细胞中，通过胶原包被的磁铁矿珠对细胞表面β（1）整合素施加张力诱导细丝蛋白A表达。这种诱导需要肌动蛋白丝和p38丝裂原活化蛋白激酶的选择性激活。力促进p38的整合素/珠位点和细胞核的重新分配，以及增强的转录因子Sp1的近端，细丝蛋白-A启动子的调节结构域的结合。施力增加了Sp1与p38的结合和Sp1的磷酸化。转录激活的细丝蛋白-A在力处理的成纤维细胞随后介导的Sp1-结合位点的细丝蛋白-A启动子。这些结果提供了证据的机械耦合转录电路，起源于磁铁矿珠/整联蛋白基因座，激活p38，拴p38肌动蛋白丝，促进结合的p38到Sp1在细胞核中，并诱导细丝蛋白-A的表达。
Connective tissue cells in mechanically active environments survive applied physical forces by modifying actin cytoskeletal structures that stabilize cell membranes. In fibroblasts, tensile forces induce the expression of filamin-A, a mechanoprotective actin-binding protein, but the mechanisms and protein interactions by which force activates filamin-A transcription are not defined. We found that in fibroblasts, application of tensile forces through collagen-coated magnetite beads to cell surface beta(1) integrins induced filamin-A expression. This induction required actin filaments and selective activation of the p38 mitogen-activated protein kinase. Force promoted the redistribution of p38 to the integrin/bead locus and the nucleus as well as enhanced binding of the transcription factor Sp1 to proximal, regulatory domains of the filamin-A promoter. Force application increased association of Sp1 with p38 and phosphorylation of Sp1. Transcriptional activation of filamin-A in force-treated fibroblasts was subsequently mediated by Sp1-binding sites on the filamin-A promoter. These results provide evidence for a mechanically coupled transcriptional circuit that originates at the magnetite bead/integrin locus, activates p38, tethers p38 to actin filaments, promotes binding of p38 to Sp1 in the nucleus, and induces filamin-A expression.