Novel nuclear target for thrombin: activation of the Elk1 transcription factor leads to chemokine gene expression
Novel nuclear target for thrombin: activation of the Elk1 transcription factor leads to chemokine gene expression
复制标题
DOI：
10.1182/blood.v96.12.3696.h8003696_3696_3706
复制
发表时间：
2000-12-01
期刊：
影响因子：
20.3
通讯作者：
Martins-Green, M
中科院分区：
文献类型：
--
作者：
Li, QJ;Vaingankar, S;Martins-Green, M
凝血酶主要因其在体内平衡和血栓形成中的作用而为人所知。然而，这种酶在伤口愈合和炎症和肿瘤发生等病理情况中也发挥着重要作用，在这些过程中凝血酶刺激的分子包括应激反应蛋白、趋化因子。趋化因子也因其在炎症反应和肿瘤发展中的作用而闻名。这些相关的观察结果有力地表明，趋化因子可能是凝血酶在这些过程中的某些功能的介体。阐明凝血酶刺激趋化因子的分子机制可能有助于解开其表达调控的途径。凝血酶通过其蛋白水解性受体上调趋化因子9E3/CCAF，继而反式激活表皮生长因子受体酪氨酸激酶，本研究表明，凝血酶刺激在转录水平上非常迅速地激活这种趋化因子，位于启动子-534到-483bp之间的2个ELK1结合元件是主要的凝血酶反应元件，这种激活通过ELK1转录因子发生，后者直接被MEK1/ERK2激活，在早期反应基因的启动子中常见的ELK1结合域表明它可能参与了应激诱导的基因激活。(C)2000年，由美国血液病学会提供。
Thrombin is primarily known for its role in homeostasis and thrombosis. However, this enzyme also plays important roles in wound healing and pathologic situations such as inflammation and tumorigenesis, Among the molecules stimulated by thrombin in these latter processes are the stress response proteins, chemokines. Chemokines are also known for their roles in inflammatory responses and tumor development. These correlative observations strongly suggest that chemokines may be mediators of some of thrombin's functions in these processes. Elucidation of the molecular mechanisms of stimulation of chemokines by thrombin may help to unravel the ways in which their expression can be modulated. Up-regulation of the chemokine 9E3/cCAF by thrombin occurs via its proteolytically activated receptor with subsequent transactivation of the epidermal growth factor receptor tyrosine kinase, This study shows that stimulation by thrombin very rapidly activates this chemokine at the transcriptional level, that 2 Elk1 binding elements located between -534 and -483 bp of the promoter are major thrombin response elements, that activation occurs via the Elk1 transcription factor, and that the latter is directly activated by MEK1/ERK2, The common occurrence of Elk1 binding domains in the promoters of immediate early response genes suggests that it may be characteristically involved in gene activation by stress-inducing agents. (C) 2000 by The American Society of Hematology.