Skip to main content
PMC home page
Biochemical Journal logoLink to Biochemical Journal
. 2001 Aug 1;357(Pt 3):867–873. doi: 10.1042/0264-6021:3570867

Phorbol ester-induced activation of mitogen-activated protein kinase/extracellular-signal-regulated kinase kinase and extracellular-signal-regulated protein kinase decreases glucose-6-phosphatase gene expression.

D Schmoll 1, R Grempler 1, A Barthel 1, H G Joost 1, R Walther 1
PMCID: PMC1222018  PMID: 11463359

Abstract

Glucose-6-phosphatase (G6Pase) plays a central role in blood glucose homoeostasis, and insulin suppresses G6Pase gene expression by the activation of phosphoinositide 3-kinase (PI 3-kinase). Here, we show that the phorbol ester PMA decreases both basal and dexamethasone/cAMP-induced expression of a luciferase gene under the control of the G6Pase promoter in transiently transfected H4IIE hepatoma cells. This regulation was suppressed by the inhibitors of the mitogen-activated protein kinase/extracellular-signal-regulated kinase kinase (MEK), PD98059 and U0126, but not by the inhibitor of PI 3-kinase, LY294002. The co-expression of a constitutively active mutant of MEK mimicked the regulation of G6Pase promoter activity by PMA. The effect of PMA on both basal and induced G6Pase gene transcription was impaired by the overexpression of a dominant negative MEK construct, as well as by the expression of mitogen-activated protein kinase phosphatase-1. The mutation of the forkhead-binding sites within the insulin-response unit of the G6Pase promoter, which decreases the effect of insulin on G6Pase gene expression, did not alter the regulation of gene expression by PMA. The data show that PMA decreases G6Pase gene expression by the activation of MEK and extracellular-signal regulated protein kinase. With that, PMA mimics the effect of insulin on G6Pase gene expression by a different signalling pathway.

Full Text

The Full Text of this article is available as a PDF (163.5 KB).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Alessi D. R., Andjelkovic M., Caudwell B., Cron P., Morrice N., Cohen P., Hemmings B. A. Mechanism of activation of protein kinase B by insulin and IGF-1. EMBO J. 1996 Dec 2;15(23):6541–6551. [PMC free article] [PubMed] [Google Scholar]
  2. 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]
  3. Clore J. N., Stillman J., Sugerman H. Glucose-6-phosphatase flux in vitro is increased in type 2 diabetes. Diabetes. 2000 Jun;49(6):969–974. doi: 10.2337/diabetes.49.6.969. [DOI] [PubMed] [Google Scholar]
  4. Davies S. P., Reddy H., Caivano M., Cohen P. Specificity and mechanism of action of some commonly used protein kinase inhibitors. Biochem J. 2000 Oct 1;351(Pt 1):95–105. doi: 10.1042/0264-6021:3510095. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. 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]
  6. Fuller S. J., Davies E. L., Gillespie-Brown J., Sun H., Tonks N. K. Mitogen-activated protein kinase phosphatase 1 inhibits the stimulation of gene expression by hypertrophic agonists in cardiac myocytes. Biochem J. 1997 Apr 15;323(Pt 2):313–319. doi: 10.1042/bj3230313. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Gabbay R. A., Sutherland C., Gnudi L., Kahn B. B., O'Brien R. M., Granner D. K., Flier J. S. Insulin regulation of phosphoenolpyruvate carboxykinase gene expression does not require activation of the Ras/mitogen-activated protein kinase signaling pathway. J Biol Chem. 1996 Jan 26;271(4):1890–1897. doi: 10.1074/jbc.271.4.1890. [DOI] [PubMed] [Google Scholar]
  8. Gómez del Arco P., Martínez-Martínez S., Calvo V., Armesilla A. L., Redondo J. M. JNK (c-Jun NH2-terminal kinase) is a target for antioxidants in T lymphocytes. J Biol Chem. 1996 Oct 18;271(42):26335–26340. doi: 10.1074/jbc.271.42.26335. [DOI] [PubMed] [Google Scholar]
  9. Herbert T. P., Kilhams G. R., Batty I. H., Proud C. G. Distinct signalling pathways mediate insulin and phorbol ester-stimulated eukaryotic initiation factor 4F assembly and protein synthesis in HEK 293 cells. J Biol Chem. 2000 Apr 14;275(15):11249–11256. doi: 10.1074/jbc.275.15.11249. [DOI] [PubMed] [Google Scholar]
  10. Kolch W. Meaningful relationships: the regulation of the Ras/Raf/MEK/ERK pathway by protein interactions. Biochem J. 2000 Oct 15;351(Pt 2):289–305. [PMC free article] [PubMed] [Google Scholar]
  11. 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]
  12. Krstic M. D., Rogatsky I., Yamamoto K. R., Garabedian M. J. Mitogen-activated and cyclin-dependent protein kinases selectively and differentially modulate transcriptional enhancement by the glucocorticoid receptor. Mol Cell Biol. 1997 Jul;17(7):3947–3954. doi: 10.1128/mcb.17.7.3947. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Lee P. D., Giudice L. C., Conover C. A., Powell D. R. Insulin-like growth factor binding protein-1: recent findings and new directions. Proc Soc Exp Biol Med. 1997 Dec;216(3):319–357. doi: 10.3181/00379727-216-44182. [DOI] [PubMed] [Google Scholar]
  14. Massillon D. Regulation of the glucose-6-phosphatase gene by glucose occurs by transcriptional and post-transcriptional mechanisms. Differential effect of glucose and xylitol. J Biol Chem. 2000 Nov 21;276(6):4055–4062. doi: 10.1074/jbc.M007939200. [DOI] [PubMed] [Google Scholar]
  15. Nordlie R. C., Foster J. D., Lange A. J. Regulation of glucose production by the liver. Annu Rev Nutr. 1999;19:379–406. doi: 10.1146/annurev.nutr.19.1.379. [DOI] [PubMed] [Google Scholar]
  16. O'Brien R. M., Bonovich M. T., Forest C. D., Granner D. K. Signal transduction convergence: phorbol esters and insulin inhibit phosphoenolpyruvate carboxykinase gene transcription through the same 10-base-pair sequence. Proc Natl Acad Sci U S A. 1991 Aug 1;88(15):6580–6584. doi: 10.1073/pnas.88.15.6580. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Pagès G., Brunet A., L'Allemain G., Pouysségur J. Constitutive mutant and putative regulatory serine phosphorylation site of mammalian MAP kinase kinase (MEK1). EMBO J. 1994 Jul 1;13(13):3003–3010. doi: 10.1002/j.1460-2075.1994.tb06599.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Rasmussen H., Isales C. M., Calle R., Throckmorton D., Anderson M., Gasalla-Herraiz J., McCarthy R. Diacylglycerol production, Ca2+ influx, and protein kinase C activation in sustained cellular responses. Endocr Rev. 1995 Oct;16(5):649–681. doi: 10.1210/edrv-16-5-649. [DOI] [PubMed] [Google Scholar]
  19. Schaeffer H. J., Weber M. J. Mitogen-activated protein kinases: specific messages from ubiquitous messengers. Mol Cell Biol. 1999 Apr;19(4):2435–2444. doi: 10.1128/mcb.19.4.2435. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Schmoll D., Walker K. S., Alessi D. R., Grempler R., Burchell A., Guo S., Walther R., Unterman T. G. Regulation of glucose-6-phosphatase gene expression by protein kinase Balpha and the forkhead transcription factor FKHR. Evidence for insulin response unit-dependent and -independent effects of insulin on promoter activity. J Biol Chem. 2000 Nov 17;275(46):36324–36333. doi: 10.1074/jbc.M003616200. [DOI] [PubMed] [Google Scholar]
  21. Streeper R. S., Svitek C. A., Chapman S., Greenbaum L. E., Taub R., O'Brien R. M. A multicomponent insulin response sequence mediates a strong repression of mouse glucose-6-phosphatase gene transcription by insulin. J Biol Chem. 1997 May 2;272(18):11698–11701. doi: 10.1074/jbc.272.18.11698. [DOI] [PubMed] [Google Scholar]
  22. Trinh K. Y., O'Doherty R. M., Anderson P., Lange A. J., Newgard C. B. Perturbation of fuel homeostasis caused by overexpression of the glucose-6-phosphatase catalytic subunit in liver of normal rats. J Biol Chem. 1998 Nov 20;273(47):31615–31620. doi: 10.1074/jbc.273.47.31615. [DOI] [PubMed] [Google Scholar]
  23. Vanhaesebroeck B., Alessi D. R. The PI3K-PDK1 connection: more than just a road to PKB. Biochem J. 2000 Mar 15;346(Pt 3):561–576. [PMC free article] [PubMed] [Google Scholar]
  24. Zentner M. D., Lin H. H., Wen X., Kim K. J., Ann D. K. The amiloride-sensitive epithelial sodium channel alpha-subunit is transcriptionally down-regulated in rat parotid cells by the extracellular signal-regulated protein kinase pathway. J Biol Chem. 1998 Nov 13;273(46):30770–30776. doi: 10.1074/jbc.273.46.30770. [DOI] [PubMed] [Google Scholar]

Articles from Biochemical Journal are provided here courtesy of The Biochemical Society

RESOURCES