Abstract
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.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, Non-P.H.S.
MeSH terms
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Alkyl and Aryl Transferases / antagonists & inhibitors
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Alkyl and Aryl Transferases / metabolism*
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Breast Neoplasms
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DNA-Binding Proteins / physiology
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Dose-Response Relationship, Drug
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Drug Synergism
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Enzyme Activation / drug effects
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Enzyme Inhibitors / pharmacology
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Genes, Reporter / genetics
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Guanosine Triphosphate / metabolism
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Humans
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Hyperinsulinism / enzymology
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Hyperinsulinism / metabolism
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Insulin / pharmacology*
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Insulin-Like Growth Factor I / pharmacology
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Luciferases / genetics
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Lysophospholipids / pharmacology*
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Nuclear Proteins / physiology
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Phosphorylation / drug effects
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Protein Processing, Post-Translational / drug effects
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Response Elements / genetics
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Serum Response Factor
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Transcriptional Activation / drug effects
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Tumor Cells, Cultured
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rhoA GTP-Binding Protein / metabolism*
Substances
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DNA-Binding Proteins
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Enzyme Inhibitors
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Insulin
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Lysophospholipids
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Nuclear Proteins
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Serum Response Factor
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Insulin-Like Growth Factor I
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Guanosine Triphosphate
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Luciferases
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Alkyl and Aryl Transferases
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geranylgeranyltransferase type-I
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rhoA GTP-Binding Protein