Potentiation of Rho-A-mediated lysophosphatidic acid activity by hyperinsulinemia.
We have shown previously that insulin promotes phosphorylation and activation of farnesyltransferase and geranylgeranyltransferase (GGTase) II. We have now examined the effect of insulin on geranylgeranyltransferase I in MCF-7 breast cancer cells. Insulin increased GGTase I activity 3-fold and augmented the amounts of geranylgeranylated Rho-A by 18%. Both effects of the insulin were blocked by an inhibitor of GGTase I, GGTI-286. The insulin-induced increases in the amounts of geranylgeranylated Rho-A resulted in potentiation of the Rho-A-mediated effects of lysophosphatidic acid (LPA) on a serum response element-luciferase construct. Preincubation of cells with insulin augmented the LPA-stimulated serum response element-luciferase activation to 12-fold, compared with just 6-fold for LPA alone (p < 0.05). The potentiating effect of insulin was dose-dependent, inhibited by GGTI-286 and not mimicked by insulin-like growth factor-1. We conclude that insulin activates GGTase I, increases the amounts of geranylgeranylated Rho-A protein, and potentiates the Rho-A-dependent nuclear effects of LPA in MCF-7 breast cancer cells.
Research Service of the Department of Veterans Affairs and the Department of Medicine, University of Colorado Health Sciences Center, Denver, Colorado 80220, USA.
J
J
Chappell
I
I
Golovchenko
K
K
Wall
R
R
Stjernholm
J W
JW
Leitner
M
M
Goalstone
B
B
Draznin
D019883:Alkyl and Aryl Transferases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D001943:Breast Neoplasms; D004268:DNA-Binding Proteins / Q000502:physiology; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D017930:Genes, Reporter / Q000235:genetics; D006160:Guanosine Triphosphate / Q000378:metabolism; D006801:Humans; D006946:Hyperinsulinism / Q000201:enzymology / Q000378:metabolism; D007328:Insulin / Q000494:pharmacology*; D007334:Insulin-Like Growth Factor I / Q000494:pharmacology; D008156:Luciferases / Q000235:genetics; D008246:Lysophospholipids / Q000494:pharmacology*; D009687:Nuclear Proteins / Q000502:physiology; D010766:Phosphorylation / Q000187:drug effects; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D020218:Response Elements / Q000235:genetics; D026362:Serum Response Factor; D015533:Transcriptional Activation / Q000187:drug effects; D014407:Tumor Cells, Cultured; D020742:rhoA GTP-Binding Protein / Q000378:metabolism*
D004268:DNA-Binding Proteins; D004791:Enzyme Inhibitors; D007328:Insulin; D008246:Lysophospholipids; D009687:Nuclear Proteins; D026362:Serum Response Factor; D007334:Insulin-Like Growth Factor I; D006160:Guanosine Triphosphate; D008156:Luciferases; D019883:Alkyl and Aryl Transferases; C083291:geranylgeranyltransferase type-I; D020742:rhoA GTP-Binding Protein