Abstract
Hepatic expression of insulin-like growth factor-binding protein-1 (IGFBP-1) is rapidly and completely inhibited by insulin. The signalling pathway that mediates this effect of insulin requires the activation of phosphoinositide 3-kinase (PI 3-kinase). Many of the cellular actions of insulin, including activation of PI 3-kinase, can be 'mimicked' by oxidative stresses, such as H(2)O(2). In the present study, we demonstrate that H(2)O(2) does not 'mimic' but rather antagonizes insulin repression of IGFBP-1 gene expression in H4IIE cells. This effect is accompanied by a decrease in the insulin-induced activation of mammalian target of rapamycin (mTOR)-dependent signalling. However, insulin-induced phosphorylation and regulation of protein kinase B, glycogen synthase kinase-3 and FKHR (forkhead in rhabdomyosarcoma) are not affected by H(2)O(2) in the same cells. In addition, H(2)O(2) strongly activates the p42/p44 mitogen-activated protein kinases, but the presence of PD184352 (an inhibitor of this pathway) does not block the effect of H(2)O(2) on IGFBP-1 gene expression. Our results support the view that the insulin-mediated repression of IGFBP-1 gene expression is partly mTOR-dependent, and demonstrate that H(2)O(2) selectively antagonizes mTOR-dependent insulin action. The implications for the use of H(2)O(2)-generating agents as therapeutics for the treatment of insulin resistance, as well as the role of oxidative stress in the development of insulin resistance, are discussed.
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- Ayala J. E., Streeper R. S., Desgrosellier J. S., Durham S. K., Suwanichkul A., Svitek C. A., Goldman J. K., Barr F. G., Powell D. R., O'Brien R. M. Conservation of an insulin response unit between mouse and human glucose-6-phosphatase catalytic subunit gene promoters: transcription factor FKHR binds the insulin response sequence. Diabetes. 1999 Sep;48(9):1885–1889. doi: 10.2337/diabetes.48.9.1885. [DOI] [PubMed] [Google Scholar]
- Band C. J., Posner B. I. Phosphatidylinositol 3'-kinase and p70s6k are required for insulin but not bisperoxovanadium 1,10-phenanthroline (bpV(phen)) inhibition of insulin-like growth factor binding protein gene expression. Evidence for MEK-independent activation of mitogen-activated protein kinase by bpV(phen). J Biol Chem. 1997 Jan 3;272(1):138–145. doi: 10.1074/jbc.272.1.138. [DOI] [PubMed] [Google Scholar]
- Barker C. W., Fagan J. B., Pasco D. S. Down-regulation of P4501A1 and P4501A2 mRNA expression in isolated hepatocytes by oxidative stress. J Biol Chem. 1994 Feb 11;269(6):3985–3990. [PubMed] [Google Scholar]
- Blair A. S., Hajduch E., Litherland G. J., Hundal H. S. Regulation of glucose transport and glycogen synthesis in L6 muscle cells during oxidative stress. Evidence for cross-talk between the insulin and SAPK2/p38 mitogen-activated protein kinase signaling pathways. J Biol Chem. 1999 Dec 17;274(51):36293–36299. doi: 10.1074/jbc.274.51.36293. [DOI] [PubMed] [Google Scholar]
- Bradford M. M. A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding. Anal Biochem. 1976 May 7;72:248–254. doi: 10.1016/0003-2697(76)90527-3. [DOI] [PubMed] [Google Scholar]
- Cichy S. B., Uddin S., Danilkovich A., Guo S., Klippel A., Unterman T. G. Protein kinase B/Akt mediates effects of insulin on hepatic insulin-like growth factor-binding protein-1 gene expression through a conserved insulin response sequence. J Biol Chem. 1998 Mar 13;273(11):6482–6487. doi: 10.1074/jbc.273.11.6482. [DOI] [PubMed] [Google Scholar]
- Cross D. A., Alessi D. R., Cohen P., Andjelkovich M., Hemmings B. A. Inhibition of glycogen synthase kinase-3 by insulin mediated by protein kinase B. Nature. 1995 Dec 21;378(6559):785–789. doi: 10.1038/378785a0. [DOI] [PubMed] [Google Scholar]
- Czech M. P., Lawrence J. C., Jr, Lynn W. S. Hexose transport in isolated brown fat cells. A model system for investigating insulin action on membrane transport. J Biol Chem. 1974 Sep 10;249(17):5421–5427. [PubMed] [Google Scholar]
- Dickens M., Svitek C. A., Culbert A. A., O'Brien R. M., Tavaré J. M. Central role for phosphatidylinositide 3-kinase in the repression of glucose-6-phosphatase gene transcription by insulin. J Biol Chem. 1998 Aug 7;273(32):20144–20149. doi: 10.1074/jbc.273.32.20144. [DOI] [PubMed] [Google Scholar]
- Freeman D. J., Norrie J., Sattar N., Neely R. D., Cobbe S. M., Ford I., Isles C., Lorimer A. R., Macfarlane P. W., McKillop J. H. Pravastatin and the development of diabetes mellitus: evidence for a protective treatment effect in the West of Scotland Coronary Prevention Study. Circulation. 2001 Jan 23;103(3):357–362. doi: 10.1161/01.cir.103.3.357. [DOI] [PubMed] [Google Scholar]
- Gingras A. C., Raught B., Sonenberg N. Regulation of translation initiation by FRAP/mTOR. Genes Dev. 2001 Apr 1;15(7):807–826. doi: 10.1101/gad.887201. [DOI] [PubMed] [Google Scholar]
- Guo S., Rena G., Cichy S., He X., Cohen P., Unterman T. Phosphorylation of serine 256 by protein kinase B disrupts transactivation by FKHR and mediates effects of insulin on insulin-like growth factor-binding protein-1 promoter activity through a conserved insulin response sequence. J Biol Chem. 1999 Jun 11;274(24):17184–17192. doi: 10.1074/jbc.274.24.17184. [DOI] [PubMed] [Google Scholar]
- Hadari Y. R., Tzahar E., Nadiv O., Rothenberg P., Roberts C. T., Jr, LeRoith D., Yarden Y., Zick Y. Insulin and insulinomimetic agents induce activation of phosphatidylinositol 3'-kinase upon its association with pp185 (IRS-1) in intact rat livers. J Biol Chem. 1992 Sep 5;267(25):17483–17486. [PubMed] [Google Scholar]
- Hayes G. R., Lockwood D. H. Role of insulin receptor phosphorylation in the insulinomimetic effects of hydrogen peroxide. Proc Natl Acad Sci U S A. 1987 Nov;84(22):8115–8119. doi: 10.1073/pnas.84.22.8115. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Heffetz D., Rutter W. J., Zick Y. The insulinomimetic agents H2O2 and vanadate stimulate tyrosine phosphorylation of potential target proteins for the insulin receptor kinase in intact cells. Biochem J. 1992 Dec 1;288(Pt 2):631–635. doi: 10.1042/bj2880631. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Hutchison K. A., Matić G., Meshinchi S., Bresnick E. H., Pratt W. B. Redox manipulation of DNA binding activity and BuGR epitope reactivity of the glucocorticoid receptor. J Biol Chem. 1991 Jun 5;266(16):10505–10509. [PubMed] [Google Scholar]
- Jefferies H. B., Reinhard C., Kozma S. C., Thomas G. Rapamycin selectively represses translation of the "polypyrimidine tract" mRNA family. Proc Natl Acad Sci U S A. 1994 May 10;91(10):4441–4445. doi: 10.1073/pnas.91.10.4441. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Kops G. J., Burgering B. M. Forkhead transcription factors: new insights into protein kinase B (c-akt) signaling. J Mol Med (Berl) 1999 Sep;77(9):656–665. doi: 10.1007/s001099900050. [DOI] [PubMed] [Google Scholar]
- Koshio O., Akanuma Y., Kasuga M. Hydrogen peroxide stimulates tyrosine phosphorylation of the insulin receptor and its tyrosine kinase activity in intact cells. Biochem J. 1988 Feb 15;250(1):95–101. doi: 10.1042/bj2500095. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Krieger-Brauer H. I., Kather H. Human fat cells possess a plasma membrane-bound H2O2-generating system that is activated by insulin via a mechanism bypassing the receptor kinase. J Clin Invest. 1992 Mar;89(3):1006–1013. doi: 10.1172/JCI115641. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Lawrence J. C., Jr, Fadden P., Haystead T. A., Lin T. A. PHAS proteins as mediators of the actions of insulin, growth factors and cAMP on protein synthesis and cell proliferation. Adv Enzyme Regul. 1997;37:239–267. doi: 10.1016/s0065-2571(96)00016-7. [DOI] [PubMed] [Google Scholar]
- Lawrence J. C., Jr, Larner J. Activation of glycogen synthase in rat adipocytes by insulin and glucose involves increased glucose transport and phosphorylation. J Biol Chem. 1978 Apr 10;253(7):2104–2113. [PubMed] [Google Scholar]
- Leslie N. R., Biondi R. M., Alessi D. R. Phosphoinositide-regulated kinases and phosphoinositide phosphatases. Chem Rev. 2001 Aug;101(8):2365–2380. doi: 10.1021/cr000091i. [DOI] [PubMed] [Google Scholar]
- Lochhead P. A., Coghlan M., Rice S. Q., Sutherland C. Inhibition of GSK-3 selectively reduces glucose-6-phosphatase and phosphatase and phosphoenolypyruvate carboxykinase gene expression. Diabetes. 2001 May;50(5):937–946. doi: 10.2337/diabetes.50.5.937. [DOI] [PubMed] [Google Scholar]
- Lochhead P. A., Salt I. P., Walker K. S., Hardie D. G., Sutherland C. 5-aminoimidazole-4-carboxamide riboside mimics the effects of insulin on the expression of the 2 key gluconeogenic genes PEPCK and glucose-6-phosphatase. Diabetes. 2000 Jun;49(6):896–903. doi: 10.2337/diabetes.49.6.896. [DOI] [PubMed] [Google Scholar]
- Ludvigsen C., Jarett L. Similarities between insulin, hydrogen peroxide, concanavalin A, and anti-insulin receptor antibody stimulated glucose transport: increase in the number of transport sites. Metabolism. 1982 Mar;31(3):284–287. doi: 10.1016/0026-0495(82)90066-x. [DOI] [PubMed] [Google Scholar]
- Mahadev K., Wu X., Zilbering A., Zhu L., Lawrence J. T., Goldstein B. J. Hydrogen peroxide generated during cellular insulin stimulation is integral to activation of the distal insulin signaling cascade in 3T3-L1 adipocytes. J Biol Chem. 2001 Oct 11;276(52):48662–48669. doi: 10.1074/jbc.M105061200. [DOI] [PubMed] [Google Scholar]
- Morel Y., Barouki R. Repression of gene expression by oxidative stress. Biochem J. 1999 Sep 15;342(Pt 3):481–496. [PMC free article] [PubMed] [Google Scholar]
- O'Brien R. M., Granner D. K. Regulation of gene expression by insulin. Physiol Rev. 1996 Oct;76(4):1109–1161. doi: 10.1152/physrev.1996.76.4.1109. [DOI] [PubMed] [Google Scholar]
- Osawa H., Sutherland C., Robey R. B., Printz R. L., Granner D. K. Analysis of the signaling pathway involved in the regulation of hexokinase II gene transcription by insulin. J Biol Chem. 1996 Jul 12;271(28):16690–16694. doi: 10.1074/jbc.271.28.16690. [DOI] [PubMed] [Google Scholar]
- Patel S., Lochhead P. A., Rena G., Sutherland C. Antagonistic effects of phorbol esters on insulin regulation of insulin-like growth factor-binding protein-1 (IGFBP-1) but not glucose-6-phosphatase gene expression. Biochem J. 2001 Nov 1;359(Pt 3):611–619. doi: 10.1042/0264-6021:3590611. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Patel Satish, Lochhead Pamela A., Rena Graham, Fumagalli Stefano, Pende Mario, Kozma Sara C., Thomas George, Sutherland Calum. Insulin regulation of insulin-like growth factor-binding protein-1 gene expression is dependent on the mammalian target of rapamycin, but independent of ribosomal S6 kinase activity. J Biol Chem. 2002 Jan 9;277(12):9889–9895. doi: 10.1074/jbc.M109870200. [DOI] [PubMed] [Google Scholar]
- Pham F. H., Cole S. M., Clerk A. Regulation of cardiac myocyte protein synthesis through phosphatidylinositol 3' kinase and protein kinase B. Adv Enzyme Regul. 2001;41:73–86. doi: 10.1016/s0065-2571(00)00007-8. [DOI] [PubMed] [Google Scholar]
- Pham F. H., Sugden P. H., Clerk A. Regulation of protein kinase B and 4E-BP1 by oxidative stress in cardiac myocytes. Circ Res. 2000 Jun 23;86(12):1252–1258. doi: 10.1161/01.res.86.12.1252. [DOI] [PubMed] [Google Scholar]
- Prasad R. K., Ismail-Beigi F. Mechanism of stimulation of glucose transport by H2O2: role of phospholipase C. Arch Biochem Biophys. 1999 Feb 1;362(1):113–122. doi: 10.1006/abbi.1998.1026. [DOI] [PubMed] [Google Scholar]
- Shaw M., Cohen P., Alessi D. R. The activation of protein kinase B by H2O2 or heat shock is mediated by phosphoinositide 3-kinase and not by mitogen-activated protein kinase-activated protein kinase-2. Biochem J. 1998 Nov 15;336(Pt 1):241–246. doi: 10.1042/bj3360241. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Sutherland C., Campbell D. G., Cohen P. Identification of insulin-stimulated protein kinase-1 as the rabbit equivalent of rskmo-2. Identification of two threonines phosphorylated during activation by mitogen-activated protein kinase. Eur J Biochem. 1993 Mar 1;212(2):581–588. doi: 10.1111/j.1432-1033.1993.tb17696.x. [DOI] [PubMed] [Google Scholar]
- Sutherland C., O'Brien R. M., Granner D. K. Phosphatidylinositol 3-kinase, but not p70/p85 ribosomal S6 protein kinase, is required for the regulation of phosphoenolpyruvate carboxykinase (PEPCK) gene expression by insulin. Dissociation of signaling pathways for insulin and phorbol ester regulation of PEPCK gene expression. J Biol Chem. 1995 Jun 30;270(26):15501–15506. doi: 10.1074/jbc.270.26.15501. [DOI] [PubMed] [Google Scholar]
- Sutherland C., Tebbey P. W., Granner D. K. Oxidative and chemical stress mimic insulin by selectively inhibiting the expression of phosphoenolpyruvate carboxykinase in hepatoma cells. Diabetes. 1997 Jan;46(1):17–22. doi: 10.2337/diab.46.1.17. [DOI] [PubMed] [Google Scholar]
- Sutherland C., Waltner-Law M., Gnudi L., Kahn B. B., Granner D. K. Activation of the ras mitogen-activated protein kinase-ribosomal protein kinase pathway is not required for the repression of phosphoenolpyruvate carboxykinase gene transcription by insulin. J Biol Chem. 1998 Feb 6;273(6):3198–3204. doi: 10.1074/jbc.273.6.3198. [DOI] [PubMed] [Google Scholar]
- Tirosh A., Rudich A., Potashnik R., Bashan N. Oxidative stress impairs insulin but not platelet-derived growth factor signalling in 3T3-L1 adipocytes. Biochem J. 2001 May 1;355(Pt 3):757–763. doi: 10.1042/bj3550757. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Tomizawa M., Kumar A., Perrot V., Nakae J., Accili D., Rechler M. M., Kumaro A. Insulin inhibits the activation of transcription by a C-terminal fragment of the forkhead transcription factor FKHR. A mechanism for insulin inhibition of insulin-like growth factor-binding protein-1 transcription. J Biol Chem. 2000 Mar 10;275(10):7289–7295. doi: 10.1074/jbc.275.10.7289. [DOI] [PubMed] [Google Scholar]
- Van der Kaay J., Beck M., Gray A., Downes C. P. Distinct phosphatidylinositol 3-kinase lipid products accumulate upon oxidative and osmotic stress and lead to different cellular responses. J Biol Chem. 1999 Dec 10;274(50):35963–35968. doi: 10.1074/jbc.274.50.35963. [DOI] [PubMed] [Google Scholar]
- Wilden P. A., Broadway D. Combination of insulinomimetic agents H2O2 and vanadate enhances insulin receptor mediated tyrosine phosphorylation of IRS-1 leading to IRS-1 association with the phosphatidylinositol 3-kinase. J Cell Biochem. 1995 Jul;58(3):279–291. doi: 10.1002/jcb.240580303. [DOI] [PubMed] [Google Scholar]
- Xie Z., Li H., Liu L., Kahn B. B., Najjar S. M., Shah W. Metabolic regulation of Na(+)/P(i)-cotransporter-1 gene expression in H4IIE cells. Am J Physiol Endocrinol Metab. 2000 Apr;278(4):E648–E655. doi: 10.1152/ajpendo.2000.278.4.E648. [DOI] [PubMed] [Google Scholar]
- von Manteuffel S. R., Dennis P. B., Pullen N., Gingras A. C., Sonenberg N., Thomas G. The insulin-induced signalling pathway leading to S6 and initiation factor 4E binding protein 1 phosphorylation bifurcates at a rapamycin-sensitive point immediately upstream of p70s6k. Mol Cell Biol. 1997 Sep;17(9):5426–5436. doi: 10.1128/mcb.17.9.5426. [DOI] [PMC free article] [PubMed] [Google Scholar]