Transcriptional Regulation of the Insulin Receptor Gene Promoter

  • Catherine McKeon
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 343)


The human insulin receptor is a membrane bound glycoprotein which is found on the surface of most cells. Like many growth factor receptors, the insulin receptor is a tyrosine kinase. The receptor is a heterotetramer composed of 2 alpha-and 2 beta-subunits. The alpha-subunit is located extracellularly where it binds insulin while the beta-subunit spans the membrane and contains the tyrosine kinase domain. The presence of this receptor is probably necessary for normal cell growth. Specialized cells such as myocytes and adipocytes have evolved mechanisms to elevate levels of this protein on their surface which allows these cells to be especially sensitive to the effects of insulin. In addition, the number of insulin receptor has been shown to be regulated by systemic factors such as hormones1 and nutrients such as glucose.2 Many investigators have cloned and analyzed the human insulin receptor promoter in an attempt to identify individual elements which are responsible for these effects. In this review, I will summarize the progress in this field and will discuss some of the conflicting data which has resulted.


HepG2 Cell Insulin Receptor Consensus Binding Site Insulin Receptor Gene Human Insulin Receptor 
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  1. 1.
    I.G. Fantus, G.A. Saviolakis, J.A. Hedo and P. Gorden, Mechanism of glucorticoid-induced increase in insulin receptors of cultured human lymphocytes, J. Biol. Chem. 257:8277 (1982).PubMedGoogle Scholar
  2. 2.
    J.R. Levy, G. Krystal, P. Glickman and F. Dastvan, Effects of media conditions, insulin, and dexamethasone on insulin-receptor mRNA and promoter activity in HepG2 cells, Diabetes. 40:58 (1991).PubMedCrossRefGoogle Scholar
  3. 3.
    A. Ullrich, J.R. Bell, E.Y. Chen, R. Herrera, L.M. Petruzzelli, T.J. Dull, A. Gray,L. Coussens, Y.-C. Liao, M. Tsubokawa, A. Mason, P.H. Seeburg, C. Grunfeld, O.M. Rosen and J. Ramachandran, Human insulin receptor and its relationship to the tyrosine kinase family of oncogenes, Nature. 313:756 (1985).PubMedCrossRefGoogle Scholar
  4. 4.
    Y. Ebina, L. Ellis, K. Jarnagin, M. Edery, L. Graf, E. Clauser, J. Ou, F. Masiarz,Y.W. Kan , I.D. Goldfine, R.A. Roth and W.J. Rutter, The human insulin receptor cDNA: the structural basis for hormone-activated transmembrane signalling, Cell. 40:747 (1985).PubMedCrossRefGoogle Scholar
  5. 5.
    S. Seino, M. Seino, S. Nishi and G. Bell, Structure of the human insulin receptor gene and characterization of its promoter, Proc. Natl. Acad. Sci. USA. 86:114 (1989).PubMedCrossRefGoogle Scholar
  6. 6.
    D.S. Tewari, D.M. Cook and R. Taub, Characterization of the promoter region and 3′ end of the human insulin receptor gene, J. Biol. Chem. 264:16238 (1989).PubMedGoogle Scholar
  7. 7.
    D.E. Moller, A. Yokota, J.F. Caro and J.S. Flier, Tissue-specific expression of two alternatively spliced insulin receptor mRNAs in man. Mol. Endocrinol. 3:1263 (1989).PubMedCrossRefGoogle Scholar
  8. 8.
    S. Seino and G.I. Bell, Alternative splicing of human insulin receptor messenger RNA. Biochem. Biophys. Res. Comm. 159:312 (1989).PubMedCrossRefGoogle Scholar
  9. 9.
    L. Mosthaf, J. Eriksson, H. Haring, L. Groop, E. Widen and A. Ullrich, Insulin receptor isotype expression correlates with risk of non-insulin-dependent diabetes, Proc. Natl. Acad. Sci. USA. 90:2633 (1993).PubMedCrossRefGoogle Scholar
  10. 10.
    E. Araki, F. Shimada, H. Uzawa, M. Mori and Y. Ebina, Characterization of the promoter region of the human insulin receptor gene, J Biol Chem. 262:16186 (1987).PubMedGoogle Scholar
  11. 11.
    P.W. Mamula, K. Wong, B.A. Maddux, A.R. McDonald and I.D. Goldfine, Sequence and analysis of promoter region of human insulin-receptor gene, Diabetes. 37:1241 (1988).PubMedCrossRefGoogle Scholar
  12. 12.
    C. McKeon, V. Moncada, T. Pham, P. Salvatore, T. Kadowaki, D. Accili and S.I. Taylor, Structural and functional analysis of the insulin receptor promoter, Mol. Endocrinol. 4:647 (1990).PubMedCrossRefGoogle Scholar
  13. 13.
    E. Sibley, T. Kastelic, T.J. Kelly and M.D. Lane, Characterization of the mouse insulin receptor gene promoter, Proc. Natl. Acad. Sci. USA. 86:9732 (1989).PubMedCrossRefGoogle Scholar
  14. 14.
    J.K. Lee, J.W.O. Tam, M.J. Tsai and S.Y. Tsai, Identification of cis-and transacting factors regulating the expression of the human insulin receptor gene, J. Biol. Chem. 267:4638 (1992).PubMedGoogle Scholar
  15. 15.
    K.E. Cameron, J. Resnik and N.J.G. Webster, Transcriptional regulation of the human insulin receptor promoter, J. Biol. Chem. 267:17375 (1992).PubMedGoogle Scholar
  16. 16.
    H. Chen, G.E. Walker, S.I. Taylor and C. McKeon, Characterization of the proximal enhancer of the insulin receptor gene, Endocrinology. 130(Suppl):111 (1992).CrossRefGoogle Scholar
  17. 17.
    H. Chen, G.E. Walker and C. McKeon, The proximal enhancer of the insulin receptor gene binds the transcription factor Sp1, Endocrinology. in press, (1993).Google Scholar
  18. 18.
    E. Araki, T. Murakami, T. Shirotani, F. Kanai, Y. Shinohara, F. Shimada, F.Mori, M. Shichiri and Y. Ebina, A cluster of four Spl binding sites required for efficient expression of the human insulin receptor gene, J. Biol. Chem. 266:3944 (1991).PubMedGoogle Scholar
  19. 19.
    D.G. Rouiller, C. McKeon, S.I. Taylor and P. Gorden, Hormonal regulation of insulin receptor gene expression: Hydrocortisone and insulin act by different mechanisms, J. Biol. Chem. 263:13185 (1988).PubMedGoogle Scholar
  20. 20.
    A.R. McDonald, A.S. Maddox, Y. Okabayashi, K.Y. Wong, D.M. Hawley, CD.Logson and I.D. Goldfine, Regulation of insulin receptor mRNA levels by glucocorticoids, Diabetes. 36:779 (1987).PubMedCrossRefGoogle Scholar
  21. 21.
    A.R. McDonald and I.D. Goldfine, Glucocorticoid regulation of insulin receptor gene transcription in IM-9 cultured lymphocytes, J Clin Invest. 81:499 (1988).PubMedCrossRefGoogle Scholar
  22. 22.
    A. Brunetti, B.A. Maddox, K.Y. Wong and I.D. Goldfine, Muscle cell differentiation is associated with increased insulin receptor biosynthesis and messenger RNA levels, J. Clin. Invest. 83:192 (1989).PubMedCrossRefGoogle Scholar
  23. 23.
    F. Beguinot, C.R. Kahn, A.C. Moses and R.J. Smith, The development of insulin receptors and responsiveness is an early marker of differentiation in the muscle cell line L6, Endocinology. 118:446 (1986).CrossRefGoogle Scholar
  24. 24.
    A. Brunetti, K.Y. Wong, P.A. Goodman and I.D. Goldfine, Identification of nuclear binding proteins for the insulin receptor promoter, Endocrinology. 128(Suppl):222 (1991).Google Scholar
  25. 25.
    H. Green and M. Meath, An established pre-adipose cell line and its differentiation in culture, Cell. 3:127 (1974).PubMedCrossRefGoogle Scholar
  26. 26.
    C. McKeon, T. Pham and G.E. Walker, A region in the intron of the insulin receptor gene is responsible for induction during adipocyte differentiation, Endocrinology. 128(suppl):231 (1991).CrossRefGoogle Scholar
  27. 27.
    C. McKeon and T. Pham, Transactivation of the human insulin receptor gene by the CCAAT/Enhancer binding protein, Biochem. Biophy. Res. Commun. 174:721 (1991).CrossRefGoogle Scholar
  28. 28.
    R.J. Christy, V.W. Yang, J. Ntambi M., D.E. Geiman, W.H. Landschulz, A.D. Friedman, Y. Nakabeppu, T.J. Kelly and M.D. Lane, Differentiation-induced gene expression in 3T3-L1 preadipocytes: CCAAT/enhancer binding protein interacts with and activates the promoters of two adipocyte-specific genes, Genes Devel. 3:1323 (1989).PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 1994

Authors and Affiliations

  • Catherine McKeon
    • 1
  1. 1.Metabolic Diseases and Gene Therapy Research Program, National Institute of Diabetes and Kidney and Digestive DiseasesNational Institutes of HealthBethesdaUSA

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