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

Exp Cell Res. 1999 Feb 1;246(2):471-9. doi: 10.1006/excr.1998.4328.

Abstract

Epidermal growth factor (EGF) is produced in the ovary and influences proliferation of the malignant ovarian surface epithelium (OSE); yet its role in malignancy or in regulating the normal surface epithelium is unclear. In human OSE cells derived from primary cultures of normal tissue transfected with SV40 large T antigen (IOSE cells), EGF promoted survival but not proliferation. This survival effect was reversed by acute treatment with the phorbol ester, 12-0-tetradecanoyl-13-phorbol acetate (TPA) which alone markedly inhibited IOSE proliferation. We tested whether the activities of the mitogen-activated protein kinases (ERK1/2 and JNK1) varied in response to EGF, TPA, or combinations of these agonists and if the same treatments altered patterns of immediate early gene expression. Alone, EGF activated ERK1/2, increased and sustained levels of c-jun mRNA, but had almost no effect on JNK1 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 inhibiting survival. Though JNKs and ERKs are thought to transduce opposing cellular responses, in IOSE cells, robust costimulation of the JNK and ERK pathways may redirect the survival message.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Apoptosis*
  • Calcium-Calmodulin-Dependent Protein Kinases / metabolism
  • Cell Division / drug effects
  • Cells, Cultured
  • Enzyme Activation
  • Epidermal Growth Factor / metabolism*
  • Epidermal Growth Factor / pharmacology
  • Epithelial Cells / drug effects
  • Female
  • Gene Expression Regulation / drug effects
  • Genes, Immediate-Early
  • Humans
  • Insulin-Like Growth Factor I / pharmacology
  • Ovary / cytology*
  • Protein Kinase C / metabolism*
  • Proto-Oncogene Proteins c-fos / genetics
  • Proto-Oncogene Proteins c-jun / genetics
  • Tetradecanoylphorbol Acetate / pharmacology
  • Transforming Growth Factor alpha / pharmacology

Substances

  • Proto-Oncogene Proteins c-fos
  • Proto-Oncogene Proteins c-jun
  • Transforming Growth Factor alpha
  • Epidermal Growth Factor
  • Insulin-Like Growth Factor I
  • Protein Kinase C
  • Calcium-Calmodulin-Dependent Protein Kinases
  • Tetradecanoylphorbol Acetate