Investigations are concerned with the oxidation of arachidonic and linoleic acid acids to prostaglandins (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) treatment of SHE cells stimulates the metabolism of linoleic acid to 13-(S)-HODE. The """"""""activation"""""""" of this apparently unique lipoxygenase is dependent on the tyrosine kinase activity of the EGF receptor but the mechanism is poorly understood. In response to EGF a very rapid formation of 13-HODE was observed followed by a more extensive but slower increase in formation. 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. Balb MK keratinocytes which are dependent on EGF for growth metabolize arachidonic acid to PGE2 and linoleic acid to 9- and 13- HODE. However, formation of the HODE metabolites was catalyzed by PHS-2 rather than a 15-lipoxygenase as determined by inhibitor and chiral analysis of the metabolites. 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 cloned the PHS whose expression in rat tracheal epithelial cells is regulated by 12-O-tetra-decanoylphorbol-13-acetate(TPA). Analysis of the partial sequence of several clones suggest that a possible third form of PHS is present in these cells. Further studies are in progress to fully characterize this form of PHS.
