Skip to main content
NCBI home page
Proceedings of the National Academy of Sciences of the United States of America logoLink to Proceedings of the National Academy of Sciences of the United States of America
. 1991 Aug 15;88(16):7224–7227. doi: 10.1073/pnas.88.16.7224

Insulin regulation of the glucagon gene is mediated by an insulin-responsive DNA element.

J Philippe 1
PMCID: PMC52266  PMID: 1651499

Abstract

Diabetes mellitus is characterized by insulin deficiency and high plasma glucagon levels, which can be normalized by insulin replacement. It has previously been reported that glucagon gene expression is negatively regulated by insulin at the transcriptional level. By transfection studies, I have now localized a DNA control element that mediates insulin effects on glucagon gene transcription. This element also confers insulin responsiveness to a heterologous promoter. DNA-binding proteins that specifically interact with this insulin-responsive element are found in both glucagon- and non-glucagon-producing cells; and the pattern of binding, as assessed by the gel retardation assay, is not modified by prior insulin treatment.

Full text

PDF
7224

Images in this article

7226Image
on p.7226
7226Image
on p.7226
7226Image
on p.7226

Selected References

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

  1. Blackshear P. J. Insulin-stimulated protein biosynthesis as a paradigm of protein kinase C-independent growth factor action. Clin Res. 1989 Jan;37(1):15–25. [PubMed] [Google Scholar]
  2. Chen L., Komiya I., Inman L., McCorkle K., Alam T., Unger R. H. Molecular and cellular responses of islets during perturbations of glucose homeostasis determined by in situ hybridization histochemistry. Proc Natl Acad Sci U S A. 1989 Feb;86(4):1367–1371. doi: 10.1073/pnas.86.4.1367. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Dignam J. D., Lebovitz R. M., Roeder R. G. Accurate transcription initiation by RNA polymerase II in a soluble extract from isolated mammalian nuclei. Nucleic Acids Res. 1983 Mar 11;11(5):1475–1489. doi: 10.1093/nar/11.5.1475. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Drucker D. J., Philippe J., Mojsov S. Proglucagon gene expression and posttranslational processing in a hamster islet cell line. Endocrinology. 1988 Oct;123(4):1861–1867. doi: 10.1210/endo-123-4-1861. [DOI] [PubMed] [Google Scholar]
  5. Henthorn P., Zervos P., Raducha M., Harris H., Kadesch T. Expression of a human placental alkaline phosphatase gene in transfected cells: use as a reporter for studies of gene expression. Proc Natl Acad Sci U S A. 1988 Sep;85(17):6342–6346. doi: 10.1073/pnas.85.17.6342. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Kahn C. R., White M. F. The insulin receptor and the molecular mechanism of insulin action. J Clin Invest. 1988 Oct;82(4):1151–1156. doi: 10.1172/JCI113711. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Keller S. A., Rosenberg M. P., Johnson T. M., Howard G., Meisler M. H. Regulation of amylase gene expression in diabetic mice is mediated by a cis-acting upstream element close to the pancreas-specific enhancer. Genes Dev. 1990 Aug;4(8):1316–1321. doi: 10.1101/gad.4.8.1316. [DOI] [PubMed] [Google Scholar]
  8. Knepel W., Jepeal L., Habener J. F. A pancreatic islet cell-specific enhancer-like element in the glucagon gene contains two domains binding distinct cellular proteins. J Biol Chem. 1990 May 25;265(15):8725–8735. [PubMed] [Google Scholar]
  9. Lee K. L., Isham K. R., Johnson A., Kenney F. T. Insulin enhances transcription of the tyrosine aminotransferase gene in rat liver. Arch Biochem Biophys. 1986 Aug 1;248(2):597–603. doi: 10.1016/0003-9861(86)90513-8. [DOI] [PubMed] [Google Scholar]
  10. Manley J. L., Fire A., Cano A., Sharp P. A., Gefter M. L. DNA-dependent transcription of adenovirus genes in a soluble whole-cell extract. Proc Natl Acad Sci U S A. 1980 Jul;77(7):3855–3859. doi: 10.1073/pnas.77.7.3855. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Meisler M. H., Howard G. Effects of insulin on gene transcription. Annu Rev Physiol. 1989;51:701–714. doi: 10.1146/annurev.ph.51.030189.003413. [DOI] [PubMed] [Google Scholar]
  12. Nasrin N., Ercolani L., Denaro M., Kong X. F., Kang I., Alexander M. An insulin response element in the glyceraldehyde-3-phosphate dehydrogenase gene binds a nuclear protein induced by insulin in cultured cells and by nutritional manipulations in vivo. Proc Natl Acad Sci U S A. 1990 Jul;87(14):5273–5277. doi: 10.1073/pnas.87.14.5273. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. O'Brien R. M., Lucas P. C., Forest C. D., Magnuson M. A., Granner D. K. Identification of a sequence in the PEPCK gene that mediates a negative effect of insulin on transcription. Science. 1990 Aug 3;249(4968):533–537. doi: 10.1126/science.2166335. [DOI] [PubMed] [Google Scholar]
  14. Philippe J., Drucker D. J., Knepel W., Jepeal L., Misulovin Z., Habener J. F. Alpha-cell-specific expression of the glucagon gene is conferred to the glucagon promoter element by the interactions of DNA-binding proteins. Mol Cell Biol. 1988 Nov;8(11):4877–4888. doi: 10.1128/mcb.8.11.4877. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Philippe J. Glucagon gene transcription is negatively regulated by insulin in a hamster islet cell line. J Clin Invest. 1989 Aug;84(2):672–677. doi: 10.1172/JCI114214. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Philippe J., Missotten M. Functional characterization of a cAMP-responsive element of the rat insulin I gene. J Biol Chem. 1990 Jan 25;265(3):1465–1469. [PubMed] [Google Scholar]
  17. Philippe J., Rochat S. Strict distance requirement for transcriptional activation by two regulatory elements of the glucagon gene. DNA Cell Biol. 1991 Mar;10(2):119–124. doi: 10.1089/dna.1991.10.119. [DOI] [PubMed] [Google Scholar]
  18. Prager D., Gebremedhin S., Melmed S. An insulin-induced DNA-binding protein for the human growth hormone gene. J Clin Invest. 1990 May;85(5):1680–1685. doi: 10.1172/JCI114620. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Prost E., Moore D. D. CAT vectors for analysis of eukaryotic promoters and enhancers. Gene. 1986;45(1):107–111. doi: 10.1016/0378-1119(86)90138-1. [DOI] [PubMed] [Google Scholar]
  20. Schreiber E., Matthias P., Müller M. M., Schaffner W. Identification of a novel lymphoid specific octamer binding protein (OTF-2B) by proteolytic clipping bandshift assay (PCBA). EMBO J. 1988 Dec 20;7(13):4221–4229. doi: 10.1002/j.1460-2075.1988.tb03319.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Selden R. F., Howie K. B., Rowe M. E., Goodman H. M., Moore D. D. Human growth hormone as a reporter gene in regulation studies employing transient gene expression. Mol Cell Biol. 1986 Sep;6(9):3173–3179. doi: 10.1128/mcb.6.9.3173. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Stumpo D. J., Stewart T. N., Gilman M. Z., Blackshear P. J. Identification of c-fos sequences involved in induction by insulin and phorbol esters. J Biol Chem. 1988 Feb 5;263(4):1611–1614. [PubMed] [Google Scholar]
  23. Takaki R., Ono J., Nakamura M., Yokogawa Y., Kumae S., Hiraoka T., Yamaguchi K., Hamaguchi K., Uchida S. Isolation of glucagon-secreting cell lines by cloning insulinoma cells. In Vitro Cell Dev Biol. 1986 Mar;22(3 Pt 1):120–126. doi: 10.1007/BF02623498. [DOI] [PubMed] [Google Scholar]
  24. Taub R., Roy A., Dieter R., Koontz J. Insulin as a growth factor in rat hepatoma cells. Stimulation of proto-oncogene expression. J Biol Chem. 1987 Aug 5;262(22):10893–10897. [PubMed] [Google Scholar]
  25. Weinstock R. S., Messina J. L. Transcriptional regulation of a rat hepatoma gene by insulin and protein kinase-C. Endocrinology. 1988 Jul;123(1):366–372. doi: 10.1210/endo-123-1-366. [DOI] [PubMed] [Google Scholar]
  26. Yamamoto K. K., Gonzalez G. A., Biggs W. H., 3rd, Montminy M. R. Phosphorylation-induced binding and transcriptional efficacy of nuclear factor CREB. Nature. 1988 Aug 11;334(6182):494–498. doi: 10.1038/334494a0. [DOI] [PubMed] [Google Scholar]

Articles from Proceedings of the National Academy of Sciences of the United States of America are provided here courtesy of National Academy of Sciences

RESOURCES