The cyclooxygenase (COX) enzymes are differentially regulated and expressed in various developmental and pathological situations. The applicant's laboratory has had a long standing interest in the biology of these isoenzymes and the principal investigator is one of the first to clone the cDNA for cyclooxygenase. This competitive renewal attempts to critically examine the hypothesis that post-transcriptional mechanisms contribute to the dysregulated expression of cyclooxygenase gene and that the activation of the cyclooxygenase pathway regulates distinct signaling pathways, viz., the well characterized extracellular prostanoid dependent and the novel, intracellular, non-prostanoid dependent pathways.
Two specific aims are delineated. The applicant wishes to further examine at the molecular level the regulation of COX-2 expression at the post transcriptional level. Mechanisms that involve the basal and induced COX-2 messenger RNA stabilization/ destabilization will be defined at the level of messenger RNA structure and the associate polypeptide complexes. Furthermore, the ability of signaling pathways to influence COX-2 mRNA metabolism will be characterized. In addition, unique post-transcriptional regulatory mechanisms of COX-2 regulation in mammary carcinoma cells will be defined. The second specific aim is set out to define the molecular basis of COX isoenzyme signaling via the prostanoid independent pathway. The ability of COX 1 and 2 isoenzyme and the active site mutants which are deficient in prostanoid synthesis will be assessed that are involved with the regulation of endothelial cell growth apoptosis and tumorigenic transformation. Constitutively expressed COX-1 and inducibly expressed COX-2 in the endothelial cell system will be used to isolate specific COX induced genes, thus, molecularly defining the down stream targets of specific COX signaling pathways.
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