Cyclic AMP inhibition of thrombin-induced growth in vascular smooth muscle cells correlates with decreased JNK1 activity and c-Jun expression

被引:60
作者
Rao, GN
Runge, MS
机构
[1] Division of Cardiology, University of Texas, Medical Branch, Galveston
[2] Division of Cardiology, University of Texas, Medical Branch, Galveston, TX 77555-1064
关键词
D O I
10.1074/jbc.271.34.20805
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
Thrombin is a potent modulator of vascular tone and vascular smooth muscle cell (VSMC) mitogenesis. Early studies from other laboratories demonstrated that cyclic AMP (cAMP) antagonizes the mitogenic effects of platelet-derived growth factor and epidermal growth factor by inhibiting the extracellular signal-regulated protein kinases (ERKs; p42, p44) group of mitogen-activated protein kinases (MAPKs) in several cell types. This report examines the role of ERKs and Jun N-terminal kinase 1 (JNK1) groups of mitogen-activated protein kinases in thrombin-induced DNA synthesis in VSMCs using agents such as forskolin and dibutyrylcyclic AMP that increase intracellular cAMP levels, Both agents significantly inhibited thrombin-stimulated DNA synthesis in VSMCs, These agents, however, had no effect on thrombin induction of ERKs activation and c-Fos expression, suggesting divergence of the latter two events from the growth-signaling events of thrombin that are sensitive to inhibition by cAMP. Thrombin activated JNK1 and induced c-Jun expression in VSMCs in a time-dependent manner, In contrast to ERKs and c-Fos, thrombin-induced JNK1 activation and c-Jun expression were sensitive to inhibition by forskolin, suggesting an association of these events with thrombin-stimulated growth in these cells, Thrombin also increased AP-1 activity, and this response was significantly blunted by forskolin, Together, these results demonstrate a correlation between JNK1 activation and c-Jun expression by thrombin and their association with the mitogenic signaling events of thrombin in VSMCs.
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收藏
页码:20805 / 20810
页数:6
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