SOX9 and myocardin counteract each other in regulating vascular smooth muscle cell differentiation.
SOX9 and myocardin counteract each other in regulating vascular smooth muscle cell differentiation.
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DOI：
10.1016/j.bbrc.2012.04.149
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发表时间：
2012-06-01
影响因子：
3.1
通讯作者：
Li L
中科院分区：
文献类型：
--
作者：
Xu Z;Ji G;Shen J;Wang X;Zhou J;Li L
在动脉粥样硬化的发病过程中，血管平滑肌细胞(VSMC)向软骨细胞的转分化是导致血管钙化的重要因素。然而，控制这种表型转换的转录机制仍不清楚。这个过程的特点是Sox9和Col2a1基因的诱导，并伴随着肌钙蛋白(myocardin，MYOCD)和平滑肌细胞分化标志物SM22、SMα-Actin和SM-MHC的抑制。在这里，我们探索了SOX9，软骨形成的主要调节因子，在调节SMC标记基因表达中的调节作用。QRT-PCR和荧光素酶分析表明，SOX9的过表达抑制了肌钙蛋白诱导的SMC基因转录和启动子活性，肌钙蛋白是平滑肌分化的主要调节因子。这种抑制不依赖于SMC启动子中的Carg盒，但依赖于myocardin。EMSA分析进一步表明，SOX9既不参与与Carg盒结合的SRF(血清反应因子)，也不与SRF相互作用，而免疫共沉淀显示SOX9与Myocardin相关。相反，myocardin抑制SOX9介导的软骨形成基因Col2a1的表达。这些发现首次提供了对SOX9和myocardin在SMC转分化为软骨细胞过程中控制转录程序的重要调节作用的第一个机械性见解。
Transdifferentiation of vascular smooth muscle cells (VSMC) into chondrogenic cells contributes significantly to vascular calcification during the pathogenesis of atherosclerosis. However, the transcriptional mechanisms that control such phenotypic switch remain unclear. This process is characterized by the induction of Sox9 and Col2a1 genes accompanied by the repression of myocardin (Myocd) and SMC differentiation markers such as SM22, SM α-actin and SM-MHC. Here we explore the regulatory role of SOX9, the master regulator for chondrogenesis, in modulating SMC marker gene expression. qRT-PCR and luciferase assays show that over-expression of SOX9 inhibits SMC gene transcription and promoter activities induced by myocardin, the master regulator of smooth muscle differentiation. Such suppression is independent of the CArG box in the SMC promoters but dependent on myocardin. EMSA assay further shows that SOX9 neither participates in SRF (serum response factor) binding to the CArG box nor interacts with SRF, while co-immunoprecipitation demonstrates an association of SOX9 with myocardin. Conversely, myocardin suppresses SOX9-mediated chondrogenic gene Col2a1 expression. These findings provide the first mechanistic insights into the important regulatory role of SOX9 and myocardin in controlling the transcription program during SMC transdifferentiation into chondrocytes.
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影响因子：
10.5
作者：
Akiyama, H;Chaboissier, MC;de Crombrugghe, B
通讯作者：
de Crombrugghe, B
影响因子：
5.3
作者：
Lefebvre, V;Huang, WD;deCrombrugghe, B
通讯作者：
deCrombrugghe, B
影响因子：
11.8
作者：
Liu, ZP;Wang, ZG;Olson, EN
通讯作者：
Olson, EN
影响因子：
4
作者：
Speer, Mei Y.;Li, Xianwu;Hiremath, Pranoti G.;Giachelli, Cecilia M.
通讯作者：
Giachelli, Cecilia M.
影响因子：
20.1
作者：
Speer MY;Yang HY;Brabb T;Leaf E;Look A;Lin WL;Frutkin A;Dichek D;Giachelli CM
通讯作者：
Giachelli CM