Mechanisms of Regulatory Pathways for Stromelysin-1 Matrix metalloproteinases (MMPs) are a family of enzymes involved in the degradation of multiple extracellular matrix (ECM) components such as gelatin, collagens, elastin, fibronectin, and laminin. Increased levels of MMP-3 (stromelysin-1) have been observed in disease processes such as arthritis and metastatic cancers. Recently investigators has demonstrated that the expression of stromelysin can be regulated by ligand-receptor interactions of the fibronectin receptor, alpha5Beta1 integrin. The phosphorylation of a focal-contact associated tyrosine kinase (p125fak) has been shown to be involved with integrin signaling of the fibronectin receptor. The conditions of integrin-ligand interaction which are associated with a decrease in phosphorylation of P125fak are conditions that are associated with an increase in the expression of mRNA for stromelysin-1. These observations suggested that the mechanism for regulation of stromelysin mRNA mediated by the fibronectin receptor may involve a decrease in the phosphorylation of p125fak.
Specific Aim #1. Deletion and mutation CAT constructs of the stromelysin promoter, already development by other investigators, will be used to determine the region of the promoter involved in the integrin mediated regulation of stromelysin.
Specific Aim #2. Correlation between the activation of the promoter region defined in specific aim #1 and the decrease in phosphorylation of p125fak will be investigated using immunoprecipitation techniques.
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