Hyperinsulinemia potentiates activation of p21Ras by growth factors.
Incubation of 3T3-L1 fibroblasts with insulin (10 nM or 100 nM) for 24 or 48 hours resulted in a significant increase in the amount of farnesylated p21Ras with a concomitant increase in the amount of GTP-loaded p21Ras. Cells preincubated with 100 nM insulin for 24 or 48 hours exhibited further 5-8 fold increases in p21Ras.GTP loading in response to an acute (10 minute) challenge with either insulin, EGF, or IGF-1. Effects of hyperinsulinemia were completely abolished by the presence of 1 microM alpha-hydroxyfarnesylphosphonic acid, a potent inhibitor of farnesyltransferase. These novel observations indicate that hyperinsulinemia increases the cellular pool of farnesylated p21Ras and thereby potentiates activation of p21Ras by growth factors.
Leitner
J W
JW
Department of Medicine, Veterans Affairs Medical Center and the University of Colorado Health Sciences Center, Denver 80220, USA.
Kline
T
T
Carel
K
K
Goalstone
M
M
Draznin
B
B
D016475:3T3 Cells; D019883:Alkyl and Aryl Transferases; D000818:Animals; D004357:Drug Synergism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004815:Epidermal Growth Factor / Q000494:pharmacology; D005204:Farnesol / Q000031:analogs & derivatives / Q000494:pharmacology; D051231:Farnesyltranstransferase; D006133:Growth Substances / Q000494:pharmacology*; D006160:Guanosine Triphosphate / Q000378:metabolism; D007328:Insulin / Q000494:pharmacology*; D007334:Insulin-Like Growth Factor I / Q000494:pharmacology; D051379:Mice; D063065:Organophosphonates; D009943:Organophosphorus Compounds / Q000494:pharmacology; D017368:Protein Prenylation; D016283:Proto-Oncogene Proteins p21(ras) / Q000378:metabolism*; D014166:Transferases / Q000037:antagonists & inhibitors
C080570:(alpha-hydroxyfarnesyl)phosphonic acid; D004791:Enzyme Inhibitors; D006133:Growth Substances; D007328:Insulin; D063065:Organophosphonates; D009943:Organophosphorus Compounds; D005204:Farnesol; D004815:Epidermal Growth Factor; D007334:Insulin-Like Growth Factor I; D006160:Guanosine Triphosphate; D014166:Transferases; D019883:Alkyl and Aryl Transferases; D051231:Farnesyltranstransferase; D016283:Proto-Oncogene Proteins p21(ras)