Tumor necrosis factor-α inhibits growth factor-mediated cell proliferation through SHP-1 activation in endothelial cells
Tumor necrosis factor-α inhibits growth factor-mediated cell proliferation through SHP-1 activation in endothelial cells
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DOI：
10.1161/hq0202.104001
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发表时间：
2002-02-01
影响因子：
8.7
通讯作者：
Horiuchi, M
中科院分区：
文献类型：
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作者：
Nakagami, H;Cui, TX;Horiuchi, M
含Src同源2蛋白酪氨酸磷酸酶I（SHP-1）通过酪氨酸激酶的去磷酸化来调节信号转导。在这项研究中，我们解决了SHP-1的作用下，肿瘤坏死因子-α（TNF-α）刺激内皮细胞。添加重组血管内皮生长因子（50 ng/mL）或表皮生长因子（50 ng/mL）显着增加胸苷掺入和c-fos启动子活性，而TNF-α（5 ng/mL）减弱这些作用在人或牛主动脉内皮细胞。在牛主动脉内皮细胞中，我们证实了内源性SHP-1表达和TNF-α激活SHP-1。重要的是，显性负性SHP-1的过表达减弱了TNF-α对胸苷掺入和c-fos启动子活性的影响。此外，TNF-α减弱了血管内皮生长因子和表皮生长因子诱导的细胞外信号调节激酶磷酸化，而显性负性SHP-1的过度表达阻止了TNF-α的这种抑制作用。总之，我们的结果表明，TNF-α抑制生长因子介导的细胞增殖通过SHP-1激活。
Src homology 2-containing protein-tyrosine phosphatase I (SHP-1) is known to regulate signal transduction through the dephosphorylation of tyrosine kinases. In this study, we addressed the role of SHP-1 under tumor necrosis factor-a (TNF-alpha) stimulation in endothelial cells. The addition of recombinant vascular endothelial growth factor (50 ng/mL) or epidermal growth factor (50 ng/mL) significantly increased thymidine incorporation and c-fos promoter activity, whereas TNF-alpha (5 ng/mL) attenuated these effects in human or bovine aortic endothelial cells. In bovine aortic endothelial cells, we confirmed endogenous SHP-1 expression and that TNF-alpha activated SHP-1. Importantly, overexpression of dominant-negative SHP-1 attenuated the effect of TNF-alpha on thymidine incorporation and c-fos promoter activity. In addition, TNF-alpha attenuated vascular endothelial growth factor- and epidermal growth factor-induced extracellular signal-regulated kinase phosphorylation, whereas overexpression of dominant-negative SHP-1 prevented this inhibitory effect of TNF-alpha. Taken together, our results suggested that TNF-alpha inhibited growth factor-mediated cell proliferation through SHP-1 activation.