Extracellular superoxide dismutase (EC-SOD) is a single gene, yet its gene product can be post-translationally modified to form two distinct proteins. They differ by proteolytic cleavage of 18 amino acids at the C-terminus and are termed native EC-SOD and cleaved EC-SOD. Although cleaved EC-SOD was previously thought to be an unimportant intermediate in the degradation pathway, preliminary results show that the cleaved form of EC-SOD is formed before secretion and can be specifically induced. It is proposed that EC-SOD has two distinct functions that are influenced by the proteolytic cleavage event: a) the native or uncleaved EC-SOD regulates smooth muscle tone by controlling the bioavailability of nitric oxide and b) the cleaved EC-SOD protects the extracellular milieu from free radical injury induced under proinflammatory conditions. This project proposes to test the hypothesis that the distribution and function of EC-SOD are controlled by proteolysis of the C-terminal heparin binding domain.
The Specific Aims are to: 1) Characterize the proteolytic processing pathway of EC-SOD; 2) Examine the role native EC-SOD plays in modulating vascular tone and inflammation in mammalian vessels; 3) Characterize the secretion of cleaved EC-SOD during inflammation; 4) Immunolocalize EC-SOD to determine the impact of cleavage on EC-SOD tissue distribution; and 5) Purify and characterize the EC-SOD proteolytic processing enzyme(s).
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