The enzyme prostaglandin G/H synthase catalyzes the rate-limiting steps in the synthesis of prostaglandins, which are potent bioactive molecules involved with inflammation, pain, clotting, vasodilation and other important processes in the body. Nonsteroidal anti-inflammatory drugs exert many of their pharmacological effects by inhibiting this enzyme. Heretofore, only one prostaglandin G/H synthase has been known, but our laboratory has recently discovered a new form which is induced in chicken embryo fibroblasts by v-src, the oncogene of Rous sarcoma virus. The synthesis of this form is tightly linked to mitogenesis in fibroblasts in culture, suggesting that it plays a role in cell division. The goal of the proposed studies is to characterize this new form of prostaglandin synthesis, with particular attention being given to its function in v-src-induced neoplasia. Immunological and enzymatic studies will compare the mitogen-inducible synthase with the non- mitogen-inducible form with regard to enzyme activities, subcellular localization, posttranslational modification, developmental- and tissue- specific expression, structure of cellular membranes, interaction with non-steroidal anti-inflammatory drugs, and expression during normal cell division and during tumorigenesis. The molecular mechanism(s) by which the mitogen-induced form of prostaglandin synthase is regulated during cell division will also be placed on a unique posttranscriptional mechanism which appears to decrease translation of the protein in non- dividing cells by inhibiting the splicing of a 5' intron that interrupts the coding sequence of the MRNA.
