Regulation of proliferation and apoptosis by epidermal growth factor and protein kinase C in human ovarian surface epithelial cells

Epidermal growth factor (EGF) is produced in the ovary and influences proli feration of the malignant ovarian surface epithelium (OSE); yet its role in malignancy or in regulating the normal surface epithelium is unclear. In h uman OSE cells derived from primary cultures of normal tissue transfected w ith SV40 large T antigen (IOSE cells), EGF promoted survival but not prolif eration. This survival effect was reversed by acute treatment with the phor bol ester, 12-0-tetradecanoyl-13-phorbol acetate (TPA) which alone markedly inhibited IOSE proliferation. We tested whether the activities of the mito gen-activated protein kinases (ERK1/2 and JNK1) varied in response to EGF, TPA, or combinations of these agonists and if the same treatments altered p atterns of immediate early gene expression. Alone, EGF activated ERK1/2, in creased and sustained levels of c-jun mRNA, but had almost no effect on JNK 1 activation. Conversely, PKC activation resulted in a rapid, but transient induction of c-fos RNA and of both kinases, JNK1 and ERK2, When combined, EGF and TPA further enhanced the phosphorylation of both enzymes despite in hibiting survival. Though JNKs and ERKs are thought to transduce opposing c ellular responses, in IOSE cells, robust costimulation of the JNK and ERK p athways may redirect the survival message. (C) 1999 Academic Press.