Yin Feng, Herring B Paul
Department of Cellular and Integrative Physiology, Indiana University School of Medicine, Indianapolis, Indiana 46202-5120, USA.
J Biol Chem. 2005 Feb 11;280(6):4745-52. doi: 10.1074/jbc.M411585200. Epub 2004 Nov 18.
The GATA-4/5/6 family of transcription factors is important for the development of the cardiovascular system and the visceral endoderm. GATA-6 is the only family member expressed in vascular smooth muscle cells and has been shown to be important for controlling the phenotype of these cells following vascular injury. To clarify further the role of GATA-6 in regulating vascular smooth muscle differentiation, we directly examined its ability to regulate the promoters of smooth muscle-specific genes. This analysis revealed that GATA-6 strongly repressed telokin promoter activity. In contrast, GATA-6 activated the smooth muscle myosin heavy chain and smooth muscle alpha-actin promoters and had no significant effect on the SM22alpha promoter. Gel mobility shift assays demonstrate that GATA-6 binds to a consensus site adjacent to the CArG box in the telokin promoter. GATA-6 did not interfere with the serum-response factor-stimulated promoter activity but blocked myocardin-induced activation of the telokin promoter. In contrast, GATA-6 and myocardin resulted in synergistic activation of the smooth muscle myosin heavy chain promoter. Consistent with these findings, overexpression of GATA-6 in smooth muscle cells selectively inhibited expression of endogenous telokin, while simultaneously increasing expression of other smooth muscle proteins. These data suggest that GATA-6 selectively inhibits telokin expression by triggering the displacement of myocardin from the serum-response factor. As GATA-6 is expressed at high levels in vascular smooth muscle, this finding may explain the relatively low levels of telokin expression in the vascular system. These data also reveal a novel transcription regulatory mechanism by which GATA-6 can modulate the activity of the myocardin-serum-response factor complexes.
转录因子GATA-4/5/6家族对心血管系统和内脏内胚层的发育至关重要。GATA-6是在血管平滑肌细胞中表达的唯一家族成员，并且已被证明在控制血管损伤后这些细胞的表型方面很重要。为了进一步阐明GATA-6在调节血管平滑肌分化中的作用，我们直接检测了其调节平滑肌特异性基因启动子的能力。该分析表明，GATA-6强烈抑制端激酶启动子活性。相反，GATA-6激活平滑肌肌球蛋白重链和平滑肌α-肌动蛋白启动子，而对SM22α启动子没有显著影响。凝胶迁移率变动分析表明，GATA-6与端激酶启动子中CArG框相邻的共有位点结合。GATA-6不干扰血清反应因子刺激的启动子活性，但阻断心肌素诱导的端激酶启动子激活。相反，GATA-6和心肌素导致平滑肌肌球蛋白重链启动子的协同激活。与这些发现一致，平滑肌细胞中GATA-6的过表达选择性抑制内源性端激酶的表达，同时增加其他平滑肌蛋白的表达。这些数据表明，GATA-6通过触发心肌素从血清反应因子上的位移来选择性抑制端激酶表达。由于GATA-6在血管平滑肌中高水平表达，这一发现可能解释了血管系统中端激酶表达水平相对较低的原因。这些数据还揭示了一种新的转录调控机制，通过该机制GATA-6可以调节心肌素-血清反应因子复合物的活性。
