Investigations are concerned with the oxidation of arachidonic and linoleic acids to prostaglandin (PG), leukotrienes and hydroxy-fatty acids and the relationship of this metabolism to the regulation or modulation of biological processes. We have studied the role of arachidonic and linoleic acids metabolism in the response of cells to growth factors. Epidermal growth factor(EGF) activates a unique 15-lipoxygenase that converts linoleic acid to 13-(S)-HODE. The activation of this lipoxygenase is dependent on the tyrosine kinase activity of the EGF receptor which activates the lipoxygenase and appears to enhance its de novo synthesis. Inhibition of 13-HODE formation inhibits EGF mitogenesis and the addition to cells greatly enhances the response to EGF. The importance of this 15- lipoxygenase in EGF dependent mitogenesis is established in Syrian hamster embryo cells (SHE) cells and more recently in Balb MK keratinocytes. Studies are currently underway to further investigate the mechanism for the activation of the 15-lipoxygenase by EGF using both biochemical and molecular biology techniques. We have also studied the regulation of PHS expression in cells. 12-0- tetradecanoylphorbol-13-acetate (TPA) and other growth factors induce the synthesis of a new PHS by enhancing the expression of PHS mRNA. Mitogen induces the formation of a new form of PHS that has a unique substrate specificity. Other data indicate that steroids inhibit the expression of PHS. These findings suggest a possible important role for arachidonic and linoleic acid metabolism in regulation cell growth.
