Busche Stephan, Descot Arnaud, Julien Sylvia, Genth Harald, Posern Guido
Department of Molecular Biology, AG Regulation of Gene Expression, Max-Planck-Institute of Biochemistry, 82152 Martinsried, Germany.
J Cell Sci. 2008 Apr 1;121(Pt 7):1025-35. doi: 10.1242/jcs.014456. Epub 2008 Mar 11.
Epithelial cell-cell junctions are specialised structures connecting individual cells in epithelial tissues. They are dynamically and functionally linked to the actin cytoskeleton. Disassembly of these junctions is a key event during physiological and pathological processes, but how this influences gene expression is largely uncharacterised. Here, we investigate whether junction disassembly regulates transcription by serum response factor (SRF) and its coactivator MAL/MRTF. Ca2+-dependent dissociation of epithelial integrity was found to correlate strictly with SRF-mediated transcription. In cells lacking E-cadherin expression, no SRF activation was observed. Direct evidence is provided that signalling occurs via monomeric actin and MAL. Dissociation of epithelial junctions is accompanied by induction of RhoA and Rac1. However, using clostridial cytotoxins, we demonstrate that Rac, but not RhoA, is required for SRF and target gene induction in epithelial cells, in contrast to serum-stimulated fibroblasts. Actomyosin contractility is a prerequisite for signalling but failed to induce SRF activation, excluding a sufficient role of the Rho-ROCK-actomyosin pathway. We conclude that E-cadherin-dependent cell-cell junctions facilitate transcriptional activation via Rac, G-actin, MAL and SRF upon epithelial disintegration.
上皮细胞间连接是连接上皮组织中单个细胞的特殊结构。它们在动态和功能上与肌动蛋白细胞骨架相连。这些连接的解体是生理和病理过程中的关键事件，但这如何影响基因表达在很大程度上尚不清楚。在这里，我们研究连接解体是否通过血清反应因子（SRF）及其共激活因子MAL/MRTF调节转录。发现上皮完整性的Ca2+依赖性解离与SRF介导的转录密切相关。在缺乏E-钙黏蛋白表达的细胞中，未观察到SRF激活。提供了直接证据表明信号通过单体肌动蛋白和MAL发生。上皮连接的解离伴随着RhoA和Rac1的诱导。然而，使用梭菌细胞毒素，我们证明与血清刺激的成纤维细胞不同，Rac而非RhoA是上皮细胞中SRF和靶基因诱导所必需的。肌动球蛋白收缩性是信号传导的先决条件，但未能诱导SRF激活，排除了Rho-ROCK-肌动球蛋白途径的充分作用。我们得出结论，E-钙黏蛋白依赖性细胞间连接在上皮解体时通过Rac、G-肌动蛋白、MAL和SRF促进转录激活。
