Kruppel-like Factor 4 Promotes Differentiation by Transforming Growth Factor-β Receptor-mediated Smad and p38 MAPK Signaling in Vascular Smooth Muscle Cells

被引：78

作者：

Li, Hui-xuan ^{[1
,2
]}

Han, Mei ^{[1
]}

Bernier, Michel ^{[3
]}

Zheng, Bin ^{[1
]}

Sun, Shao-guang ^{[1
]}

Su, Ming ^{[1
]}

Zhang, Rui ^{[1
]}

Fu, Jian-ran ^{[1
]}

Wen, Jin-kun ^{[1
]}

机构：

[1] Hebei Med Univ, China Minist Educ, Key Lab Neural & Vasc Biol, Dept Biochem & Mol Biol, Shijiazhuang 050017, Peoples R China

[2] Hebei Univ Econ & Business, Coll Biol Sci & Engn, Shijiazhuang 050061, Peoples R China

[3] NIA, Clin Invest Lab, NIH, Baltimore, MD 21224 USA

来源：

JOURNAL OF BIOLOGICAL CHEMISTRY | 2010年 / 285卷 / 23期

基金：

美国国家卫生研究院; 中国国家自然科学基金;

关键词：

TGF-BETA; DOWN-REGULATION; MARKER GENES; ACTIVATION; INHIBITION; EXPRESSION; PROLIFERATION; PROTEIN; KRUPPEL-LIKE-FACTOR-4; MECHANISM;

D O I：

10.1074/jbc.M109.076992

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

KLF4 (Kruppel-like factor 4) has been implicated in vascular smooth muscle cell (VSMC) differentiation induced by transforming growth factor beta (TGF-beta). However, the role of KLF4 and mechanism of KLF4 actions in regulating TGF-beta signaling in VSMCs remain unclear. In this study, we showed that TGF-beta 1 inhibited cell cycle progression and induced differentiation in cultured rat VSMCs. This activity of TGF-beta 1 was accompanied by up-regulation of KLF4, with concomitant increase in T beta RI (TGF-beta type I receptor) expression. KLF4 was found to transduce TGF-beta 1 signals via phosphorylation-mediated activation of Smad2, Smad3, and p38 MAPK. The activation of both pathways, in turn, increased the phosphorylation of KLF4, which enabled the formation of KLF4-Smad2 complex in response to TGF-beta 1. Chromatin immunoprecipitation studies and oligonucleotide pull-down assays showed the direct binding of KLF4 to the KLF4-binding sites 2 and 3 of the T beta RI promoter and the recruitment of Smad2 to the Smad-responsive region. Formation of a stable KLF4-Smad2 complex in the promoter's Smad-responsive region mediated cooperative T beta RI promoter transcription in response to TGF-beta 1. These results suggest that KLF4-dependent regulation of Smad and p38 MAPK signaling via T beta RI requires prior phosphorylation of KLF4 through Smad and p38 MAPK pathways. This study demonstrates a novel mechanism by which TGF-beta 1 regulates VSMC differentiation.

引用

页码：17846 / 17856

页数：11

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