Novel nuclear target for thrombin: activation of the Elk1 transcription factor leads to chemokine gene expression

Thrombin is primarily known for its role in homeostasis and thrombosis. How ever, this enzyme also plays important roles in wound healing and pathologi c situations such as inflammation and tumorigenesis, Among the molecules st imulated by thrombin in these latter processes are the stress response prot eins, chemokines. Chemokines are also known for their roles in inflammatory responses and tumor development. These correlative observations strongly s uggest 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 expressi on can be modulated. Up-regulation of the chemokine 9E3/cCAF by thrombin oc curs via its proteolytically activated receptor with subsequent transactiva tion of the epidermal growth factor receptor tyrosine kinase, This study sh ows that stimulation by thrombin very rapidly activates this chemokine at t he transcriptional level, that 2 Elk1 binding elements located between -534 and -483 bp of the promoter are major thrombin response elements, that act ivation occurs via the Elk1 transcription factor, and that the latter is di rectly activated by MEK1/ERK2, The common occurrence of Elk1 binding domain s in the promoters of immediate early response genes suggests that it may b e characteristically involved in gene activation by stress-inducing agents. (C) 2000 by The American Society of Hematology.