Regulation of the PA-plasmin cascade

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Plasminogen activators (PAs) are serine proteases that convert the zymogen plasminogen to the active protease, plasmin. The PA-plasmin cascade plays a central role in processes involving limited protein breakdown, including dissolving blood clots, tissue remodeling, and tumor cell invasion. Type-1 PA-inhibitor (PAI-1) is the major physiologic regulator of plasminogen activation and its expression is tightly regulated. In this project, we have studied the regulation of PA-plasmin system in terms of the molecular mechanisms by which hormones and growth factors regulate expression of the PAI-1 gene. The major results obtained by this project are as follows ; 1) IL-1β is a critical inducer of hepatic PAI-1 gene expression during the acute phase response. Hepatocytes are responsible for the hepatic expression of the PAI-1 gene. 2) Urokinase (uPA) is one of the markers for the differentiation of preadipocytes. Insulin, and dexamethasone are potent regulators of the fibrinolytic activity in differentiated adipocytes, reciprocally affecting PA and PAI-1 levels in them. 3) A novel TGFβ-responsive element was identified in the human PAI-1 gene that is required for mediating transcriptional activation by TGFβ, and that directly binds Smad3 and Smad4, the downstream transducers of TGFβ signaling. 4) A region of the PAI-1 mRNA that confers cyclic nucleotide regulation of mRNA stability was defined. PAI-1 mRNA-binding protein (PAI-RBP1) that identifies a highly conserved family of putative RNA-binding proteins was also isolated and cloned.These studies will increase our understanding of the molecular mechanisms of gene regulation in the PA-plasmin cascade.