Our laboratory has characterized linoleic acid metabolism as playing a central role in transducing the epidermal growth factor (EGF) mitogenic signal in several fibroblast cell lines. Lipoxygenase-derived linoleate products were found to be quite potent in augmenting DNA synthesis in EGF-stimulated cells. Inhibition of EGF receptor tyrosine kinase activity blocks the formation of linoleic acid metabolites, while inhibition of tyrosine phosphatase activity potentiates EGF-dependent biosynthesis of linoleate derivatives. These results link activation of lipoxygenase metabolism of linoleic acid to the tyrosine kinase activity of the EGF receptor. The erbB oncogene family encodes a truncated EGF receptor that retains homologous tyrosine kinase catalytic activity. Overexpression and amplification of the erbB oncogene has been observed in several types of human carcinoma. We have transfected normal fibroblasts with the retroviral v-erbB oncogene or its cellular homolog c-erbB2. Western analyses have revealed the expression of erbB oncogene protein and increased tyrosine phosphorylation of proteins involved in the EGF mitogenic signal cascade. Inhibitors of linoleic acid metabolism attenuate the EGF-stimulated proliferative response of transfected cells. Future investigations will determine the effects of erbB transformation on the metabolic fate of linoleic acid and will test specific metabolites for thei ability to modulate oncogenic signal transduction.

National Institute of Health (NIH)
National Institute of Environmental Health Sciences (NIEHS)
Intramural Research (Z01)
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