Bone morphogenetic protein-induced Msx1 and Msx2 inhibit myocardin-dependent smooth muscle gene transcription
Bone morphogenetic protein-induced Msx1 and Msx2 inhibit myocardin-dependent smooth muscle gene transcription
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DOI：
10.1128/mcb.00759-06
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发表时间：
2006-12-01
影响因子：
5.3
通讯作者：
Sobue, Kenji
中科院分区：
文献类型：
--
作者：
Hayashi, Ken'ichiro;Nakamura, Seiji;Sobue, Kenji
在动脉粥样硬化的发生和发展过程中，血管平滑肌细胞（VSMC）表型由分化向去分化转变，在某些情况下，这种变化伴随着成骨转变，导致血管钙化。去分化的VSMC的一个特征是平滑肌细胞（SMC）标记基因表达的下调。骨形态发生蛋白（BMP），这是参与诱导成骨基因的表达，检测钙化血管。在这项研究中，我们发现，BMP 2-，BMP 4-，和BMP 6-诱导Msx转录因子（Msx 1和Msx 2）的表达之前，在培养的分化VSMCs的SMC标记物表达下调。Msx 1或Msx 2均显著降低SMC标记基因（SM 22 α和caldesmon）的心肌蛋白依赖性启动子活性。我们使用免疫共沉淀、凝胶迁移和染色质免疫沉淀测定进一步研究了Msx 1与心肌蛋白/血清反应因子（SRF）/CArG盒基序（SRF的顺式元件）之间的相互作用。我们的研究结果表明，Msx 1或Msx 2与SRF和myocardin形成三元复合物，并抑制SRF或SRF/myocardin与CArG-box基序的结合，从而抑制它们的转录。
During the onset and progression of atherosclerosis, the vascular smooth muscle cell (VSMC) phenotype changes from differentiated to dedifferentiated, and in some cases, this change is accompanied by osteogenic transition, resulting in vascular calcification. One characteristic of dedifferentiated VSMCs is the down-regulation of smooth muscle cell (SMC) marker gene expression. Bone morphogenetic proteins (BMPs), which are involved in the induction of osteogenic gene expression, are detected in calcified vasculature. In this study, we found that the BMP2-, BMP4-, and BMP6-induced expression of Msx transcription factors (Msx1 and Msx2) preceded the down-regulation of SMC marker expression in cultured differentiated VSMCs. Either Msx1 or Msx2 markedly reduced the myocardin-dependent promoter activities of SMC marker genes (SM22 alpha and caldesmon). We further investigated interactions between Msx1 and myocardin/serum response factor (SRF)/CArG-box motif (cis element for SRF) using coimmunoprecipitation, gel-shift, and chromatin immunoprecipitation assays. Our results showed that Msx1 or Msx2 formed a ternary complex with SRF and myocardin and inhibited the binding of SRF or SRF/myocardin to the CArG-box motif, resulting in inhibition of their transcription.