Role of protein kinase C in diacylglycerol-mediated induction of ornithine decarboxylase and reduction of epidermal growth factor binding.
Tumor-promoting phorbol esters induce ornithine decarboxylase (ODCase) activity and reduce epidermal growth factor (EGF) binding in rat tracheal epithelial 2C5 cells. Phorbol esters activate protein kinase C by interacting at the same site as sn-1,2-diacylglycerols, the presumed physiological regulators. The effects of added sn-1,2-diacylglycerols and those generated by phospholipase C treatment of 2C5 cells on ODCase induction and EGF binding were investigated to establish a role for protein kinase C in these cellular responses. Treatment of 2C5 cells with phospholipase C induced ODCase activity and reduced EGF binding, whereas phospholipases A2 and D were inactive. When sn-1,2-diacylglycerols containing fatty acids 3-10 carbons in length were added to 2C5 cells, those diacylglycerols containing fatty acids 5-10 carbons in length caused ODCase induction and reduction in EGF binding. sn-1,2-Dioctanoylglycerol was one of the most active compounds tested. It induced ODCase in a dose- (50-500 microM) and time-dependent manner. The reduction of binding of 125I-labeled EGF by sn-1,2-dioctanoylglycerol was also time and dose dependent and appeared to result from a change in EGF affinity and not the number of receptor sites. This series of sn-1,2-diacylglycerols showed similar structure-function relationships in their ability to induce ODCase activity, to decrease EGF binding, to stimulate protein kinase C, and to inhibit [3H]phorbol dibutyrate binding to the phorbol ester receptor. These data demonstrate biological activities for a number of diacylglycerols and indicate that protein kinase C activation is implicated in ODCase induction and decreased EGF binding.
Jetten
A M
AM
Ganong
B R
BR
Vandenbark
G R
GR
Shirley
J E
JE
Bell
R M
RM
D000818:Animals; D002478:Cells, Cultured; D004075:Diglycerides / Q000494:pharmacology*; D004790:Enzyme Induction; D004815:Epidermal Growth Factor / Q000378:metabolism*; D005989:Glycerides / Q000494:pharmacology*; D009955:Ornithine Decarboxylase / Q000096:biosynthesis*; D015240:Phorbol 12,13-Dibutyrate; D010703:Phorbol Esters / Q000378:metabolism; D011493:Protein Kinase C; D011494:Protein Kinases / Q000378:metabolism*; D051381:Rats; D013329:Structure-Activity Relationship; D014132:Trachea / Q000378:metabolism; D010738:Type C Phospholipases / Q000494:pharmacology
D004075:Diglycerides; D005989:Glycerides; D010703:Phorbol Esters; D015240:Phorbol 12,13-Dibutyrate; D004815:Epidermal Growth Factor; D011494:Protein Kinases; D011493:Protein Kinase C; D010738:Type C Phospholipases; D009955:Ornithine Decarboxylase