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Abrogation of insulin-like growth factor-I (IGF-I) and insulin action by mevalonic acid depletion: synergy between protein prenylation and receptor glycosylation pathways

Siddals, Kirk W ; Marshman, Emma ; Westwood, Melissa ; Gibson, J Martin

The Journal of biological chemistry, 2004-09, Vol.279 (37), p.38353 [Periódico revisado por pares]

United States

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Título:
Abrogation of insulin-like growth factor-I (IGF-I) and insulin action by mevalonic acid depletion: synergy between protein prenylation and receptor glycosylation pathways
Autor: Siddals, Kirk W ; Marshman, Emma ; Westwood, Melissa ; Gibson, J Martin
Assuntos: 3T3-L1 Cells ; Animals ; Apoptosis ; Biotinylation ; Blotting, Western ; Cell Differentiation ; Cell Division ; Cell Membrane - metabolism ; Deoxyglucose - metabolism ; Dose-Response Relationship, Drug ; Glucose - metabolism ; Glycosylation ; Hydroxymethylglutaryl-CoA Reductase Inhibitors - pharmacology ; Indolizines - pharmacology ; Insulin - metabolism ; Insulin-Like Growth Factor I - metabolism ; Mevalonic Acid - metabolism ; Mice ; Precipitin Tests ; Protein Prenylation ; Pyridines - pharmacology ; ras Proteins - metabolism ; Receptor, Insulin - metabolism ; Signal Transduction ; Thymidine - chemistry ; Tunicamycin - pharmacology
É parte de: The Journal of biological chemistry, 2004-09, Vol.279 (37), p.38353
Descrição: The vasculoprotective effects of hydroxy-3-methylglutaryl (HMG)-CoA reductase inhibitors (statins) correlate with cholesterol lowering. HMG-CoA reductase inhibitors also disrupt cellular processes by the depletion of isoprenoids and dolichol. Insulin and insulin-like growth factor (IGF) signaling appear particularly prone to such disruption as intracellular receptor processing requires dolichol for correct N-glycosylation, whereas downstream signaling through Ras requires the appropriate prenylation (farnesol). We determined how HMG-CoA reductase inhibition affected the mitogenic effects of IGF-I and metabolic actions of insulin in 3T3-L1 cells and examined the respective roles of receptor glycosylation and Ras prenylation. IGF-I- and insulin-induced proliferation was significantly reduced by all statins tested, although cerivastatin (10 nm) had the greatest effect (p < 0.005). Although inhibitors of Ras prenylation induced similar results (10 microm FTI-277 89% +/- 7.4%, p < 0.01), the effect of HMG-CoA reductase inhibition could only be partially reversed by farnesyl pyrophosphate refeeding. Treatment with statins resulted in decreased membrane expression of receptors and accumulation of proreceptors, suggesting disruption of glycosylation-dependent cleavage. Glycosylation inhibitors inhibited IGF-I-induced proliferation (tunicamycin p < 0.005, castanospermine p < 0.01, deoxymannojirimycin p < 0.01). High concentrations of statin were necessary to impair insulin-mediated glucose uptake (300 nm = 33% +/- 12% p < 0.05), and this process was not effected by farnesyl transferase inhibition. Gycosylation inhibitors mimicked the effect of statin treatment (tunicamycin p < 0.001, castanospermine p < 0.05, deoxymannojirimycin p < 0.05), and there was insulin proreceptor accumulation. These data imply that HMG-CoA reductase inhibitors disrupt IGF-I signaling by combined effects on Ras prenylation and IGF receptor glycosylation, whereas insulin signaling is only affected by disrupted receptor glycosylation.
Editor: United States
Idioma: Inglês

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Abrogation of insulin-like growth factor-I (IGF-I) and insulin action by mevalonic acid depletion: synergy between protein prenylation and receptor glycosylation pathways

Siddals, Kirk W ; Marshman, Emma ; Westwood, Melissa ; Gibson, J Martin

United States

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