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Transcriptional Regulation of Insulin Gene Expression

  • Chapter
Pancreatic Beta Cell in Health and Disease

Abstract

The insulin gene is expressed exclusively in the beta cells of the islet of Langerhans. The release of this polypeptide hormone into the bloodstream, principally in response to elevated glucose levels, is essential for controlling carbohydrate metabolism in peripheral tissues. A fundamental cause of diabetes, a disease that affects millions of people and is a major cause of morbidity and mortality, is the inability of beta cells to produce sufficient amounts of insulin, resulting in hyperglycemia. A large effort is underway to identify and characterize the transcriptional regulators of genes, like insulin, that are important in islet beta cell function. It is hoped that this knowledge will provide information into how beta cell function is disrupted in type 2 diabetic individuals, and to provide a foundation for cell-based therapies that may be effective in diabetes treatment. Many of the cis-acting sequences, essential in directing both selective and glucose-inducible transcription within the 5′-flanking region of the insulin gene, have been defined and several of the key trans-activators isolated, including PAX-6, PDX-1, MafA, and BETA2/NeuroD1. In addition, the inactivation of genes encoding these regulatory proteins in mice has established that most play a role in islet cell differentiation during pancreas development. In this review, the regulatory role of the islet-enriched transcription factors of the insulin gene will be discussed, with a focus on their role in adult beta cell function.

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References

  1. Matschinsky FM (1990) Glucokinase as glucose sensor and metabolic signal generator in pancreatic beta-cells and hepatocytes. Diabetes 39:647–652

    Article  PubMed  CAS  Google Scholar 

  2. Poitout V, Hagman D, Stein R, Artner I, Robertson RP, Harmon JS (2006) Regulation of the insulin gene by glucose and fatty acids. J Nutr 136:873–876

    PubMed  CAS  Google Scholar 

  3. Horikawa Y, Oda N, Cox NJ, Li X, Orho-Melander M, Hara M, Hinokio Y, Lindner TH, Mashima H, Schwarz PE, del Bosque-Plata L, Horikawa Y, Oda Y, Yoshiuchi I, Colilla S, Polonsky KS, Wei S, Concannon P, Iwasaki N, Schulze J, Baier LJ, Bogardus C, Groop L, Boerwinkle E, Hanis CL, Bell GI (2000) Genetic variation in the gene encoding calpain-10 is associated with type 2 diabetes mellitus. Nat Genet 26:163–175

    Article  PubMed  CAS  Google Scholar 

  4. Hattersley AT (1998) Maturity-onset diabetes of the young: clinical heterogeneity explained by genetic heterogeneity. Diabetes Med 15:15–24

    Article  CAS  Google Scholar 

  5. Froguel P, Vaxillaire M, Sun F, Velho G, Zouali H, Butel MO, Lesage S, Vionnet N, Clement K, Fougerousse F, Tanizawa T, Weissenbach J, Beckmann JS, Lathrop JM, Passa PH, Permutt MA, Cohen D (1992) Close linkage of glucokinase locus on chromosome 7p to early-onset non-insulin-dependent diabetes mellitus. Nature 356:162–164

    Article  PubMed  CAS  Google Scholar 

  6. Malecki MT (2005) Genetics of type 2 diabetes mellitus. Diabetes Res Clin Pract 68Suppl 1:S10–S21

    Article  PubMed  CAS  Google Scholar 

  7. Dumonteil E, Laser B, Constant I, Philippe J (1998) Differential regulation of the glucagon and insulin I gene promoters by the basic helix-loop-helix transcription factors E47 and BETA2. J Biol Chem 273:19945–19954

    Article  PubMed  CAS  Google Scholar 

  8. Ohlsson H, Karlsson K, Edlund T (1993) IPF1, a homeodomain-containing transactivator of the insulin gene. EMBO J 12:4251–4259

    PubMed  CAS  Google Scholar 

  9. Melloul D, Marshak S, Cerasi E (2002) Regulation of insulin gene transcription. Diabetologia 45:309–326

    Article  PubMed  CAS  Google Scholar 

  10. Hanahan D (1985) Heritable formation of pancreatic beta-cell tumours in transgenic mice expressing recombinant insulin/simian virus 40 oncogenes. Nature 315:115–122

    Article  PubMed  CAS  Google Scholar 

  11. Bucchini D, Ripoche MA, Stinnakre MG, Desbois P, Lores P, Monthioux E, Absil J, Lepesant JA, Pictet R, Jami J (1986) Pancreatic expression of human insulin gene in transgenic mice. Proc Natl Acad Sci USA 83:2511–2515

    Article  PubMed  CAS  Google Scholar 

  12. Selden RF, Skoskiewicz MJ, Howie KB, Russell PS, Goodman HM (1986) Regulation of human insulin gene expression in transgenic mice. Nature 321:525–528

    Article  PubMed  CAS  Google Scholar 

  13. Soares MB, Schon E, Henderson A, Karathanasis SK, Cate R, Zeitlin S, Chirgwin J, Efstratiadis A (1985) RNA-mediated gene duplication: the rat preproinsulin I gene is a functional retroposon. Mol Cell Biol 5:2090–2103

    PubMed  CAS  Google Scholar 

  14. Fromont-Racine M, Bucchini D, Madsen O, Desbois P, Linde S, Nielsen JH, Saulnier C, Ripoche MA, Jami J, Pictet R (1990) Effect of 5′-flanking sequence deletions on expression of the human insulin gene in transgenic mice. Mol Endocrinol 4: 669–677

    PubMed  CAS  Google Scholar 

  15. Crowe DT, Tsai MJ (1989) Mutagenesis of the rat insulin II 5′-flanking region defines sequences important for expression in HIT cells. Mol Cell Biol 9:1784–1789

    PubMed  CAS  Google Scholar 

  16. Edlund T, Walker MD, Barr PJ, Rutter WJ (1985) Cell-specific expression of the rat insulin gene: evidence for role of two distinct 5′ flanking elements. Science 230: 912–916

    Article  PubMed  CAS  Google Scholar 

  17. Melloul D, Ben-Neriah Y, Cerasi E (1993) Glucose modulates the binding of an isletspecific factor to a conserved sequence within the rat I and the human insulin promoters. Proc Natl Acad Sci USA 90:3865–3869

    Article  PubMed  CAS  Google Scholar 

  18. Sharma A, Stein R (1994) Glucose-induced transcription of the insulin gene is mediated by factors required for beta-cell-type-specific expression. Mol Cell Biol 14:871–879

    PubMed  CAS  Google Scholar 

  19. Whelan J, Poon D, Weil PA, Stein R (1989) Pancreatic beta-cell-type-specific expression of the rat insulin II gene is controlled by positive and negative cellular transcriptional elements. Mol Cell Biol 9:3253–3259

    PubMed  CAS  Google Scholar 

  20. Stein R (1993) Factors regulating insulin gene transcription. Trends Endocrinol Metab 4:96–100

    Article  CAS  PubMed  Google Scholar 

  21. Leibiger IB, Leibiger B, Moede T, Berggren PO (1998) Exocytosis of insulin promotes insulin gene transcription via the insulin receptor/PI-3 kinase/p70 s6 kinase and CaM kinase pathways. Mol Cell 1:933–938

    Article  PubMed  CAS  Google Scholar 

  22. Wu H, MacFarlane WM, Tadayyon M, Arch JR, James RF, Docherty K (1999) Insulin stimulates pancreatic-duodenal homeobox factor-1 (PDX1) DNA-binding activity and insulin promoter activity in pancreatic beta cells. Biochem J 344 Pt 3:813–818

    Article  PubMed  CAS  Google Scholar 

  23. Aspinwall CA, Lakey JR, Kennedy RT (1999) Insulin-stimulated insulin secretion in single pancreatic beta cells. J Biol Chem 274:6360–6365

    Article  PubMed  CAS  Google Scholar 

  24. Withers DJ, Gutierrez JS, Towery H, Burks DJ, Ren JM, Previs S, Zhang Y, Bernal D, Pons S, Shulman GI, Bonner-Weir S, White MF (1998) Disruption of IRS-2 causes type 2 diabetes in mice. Nature 391:900–904

    Article  PubMed  CAS  Google Scholar 

  25. Ueki K, Okada T, Hu J, Liew CW, Assmann A, Dahlgren GM, Peters JL, Shackman JG, Zhang M, Artner I, Satin LS, Stein R, Holzenberger M, Kennedy RT, Kahn CR, Kulkarni RN (2006) Total insulin and IGF-I resistance in pancreatic beta cells causes overt diabetes. Nat Genet 38:583–588

    Article  PubMed  CAS  Google Scholar 

  26. Sander M, Neubuser A, Kalamaras J, Ee HC, Martin GR, German MS (1997) Genetic analysis reveals that PAX6 is required for normal transcription of pancreatic hormone genes and islet development. Genes Dev 11:1662–1673

    Article  PubMed  CAS  Google Scholar 

  27. Ahlgren U, Jonsson J, Edlund H (1996) The morphogenesis of the pancreatic mesenchyme is uncoupled from that of the pancreatic epithelium in IPF1/PDX1-deficient mice. Development 122:1409–1416

    PubMed  CAS  Google Scholar 

  28. Naya FJ, Huang HP, Qiu Y, Mutoh H, DeMayo FJ, Leiter AB, Tsai MJ (1997) Diabetes, defective pancreatic morphogenesis, and abnormal enteroendocrine differentiation in BETA2/neuroD-deficient mice. Genes Dev 11:2323–2334

    Article  PubMed  CAS  Google Scholar 

  29. Zhang C, Moriguchi T, Kajihara M, Esaki R, Harada A, Shimohata H, Oishi H, Hamada M, Morito N, Hasegawa K, Kudo T, Engel JD, Yamamoto M, Takahashi S (2005) MafA is a key regulator of glucose-stimulated insulin secretion. Mol Cell Biol 25:4969–4976

    Article  PubMed  CAS  Google Scholar 

  30. Bell GI, Polonsky KS (2001) Diabetes mellitus and genetically programmed defects in beta-cell function. Nature 414:788–791

    Article  PubMed  CAS  Google Scholar 

  31. Steiner DF, Chan SJ, Welsh JM, Kwok SC (1985) Structure and evolution of the insulin gene. Annu Rev Genet 19:463–484

    Article  PubMed  CAS  Google Scholar 

  32. Knepel W, Vallejo M, Chafitz JA, Habener JF (1991) The pancreatic islet-specific glucagon G3 transcription factors recognize control elements in the rat somatostatin and insulin-I genes. Mol Endocrinol 5:1457–1466

    PubMed  CAS  Google Scholar 

  33. Sosa-Pineda B, Chowdhury K, Torres M, Oliver G, Gruss P (1997) The Pax4 gene is essential for differentiation of insulin-producing beta cells in the mammalian pancreas. Nature 386:399–402

    Article  PubMed  CAS  Google Scholar 

  34. Fujitani Y, Kajimoto Y, Yasuda T, Matsuoka TA, Kaneto H, Umayahara Y, Fujita N, Watada H, Miyazaki JI, Yamasaki Y, Hori M (1999) Identification of a portable repression domain and an E1A-responsive activation domain in Pax4: a possible role of Pax4 as a transcriptional repressor in the pancreas. Mol Cell Biol 19:8281–8291

    PubMed  CAS  Google Scholar 

  35. Smith SB, Ee HC, Conners JR, German MS (1999) Paired-homeodomain transcription factor PAX4 acts as a transcriptional repressor in early pancreatic development. Mol Cell Biol 19:8272–8280

    PubMed  CAS  Google Scholar 

  36. Sosa-Pineda, B (2004) The gene Pax4 is an essential regulator of pancreatic beta-cell development. Mol Cells 18:289–294

    PubMed  CAS  Google Scholar 

  37. Sander M, Griffen SC, Huang J, German MS (1998) A novel glucose-responsive element in the human insulin gene functions uniquely in primary cultured islets. Proc Natl Acad Sci USA 95:11572–11577

    Article  PubMed  CAS  Google Scholar 

  38. Boam DS, Clark AR, Docherty K (1990) Positive and negative regulation of the human insulin gene by multiple trans-acting factors. J Biol Chem 265:8285–8296

    PubMed  CAS  Google Scholar 

  39. Le Lay J, Stein R (2006) Involvement of PDX-1 in activation of human insulin gene transcription. J Endocrinol 188:287–294

    Article  PubMed  CAS  Google Scholar 

  40. Pino MF, Ye DZ, Linning KD, Green CD, Wicksteed B, Poitout V, Olson LK (2005) Elevated glucose attenuates human insulin gene promoter activity in INS-1 pancreatic beta-cells via reduced nuclear factor binding to the A5/core and Z element. Mol Endocrinol 19:1343–1360

    Article  PubMed  CAS  Google Scholar 

  41. Gehring WJ, Affolter M, Burglin T (1994) Homeodomain proteins. Annu Rev Biochem 63:487–526

    Article  PubMed  CAS  Google Scholar 

  42. Trainor PA, Krumlauf R (2001) Hox genes, neural crest cells and branchial arch patterning. Curr Opin Cell Biol 13:698–705

    Article  PubMed  CAS  Google Scholar 

  43. Leonard J, Peers B, Johnson T, Ferreri K, Lee S, Montminy MR (1993) Characterization of somatostatin transactivating factor-1, a novel homeobox factor that stimulates somatostatin expression in pancreatic islet cells. Mol Endocrinol 7:1275–1283

    Article  PubMed  CAS  Google Scholar 

  44. Miller CP, McGehee RE Jr, Habener JF (1994) IDX-1: a new homeodomain transcription factor expressed in rat pancreatic islets and duodenum that transactivates the somatostatin gene. EMBO J 13:1145–1156

    PubMed  CAS  Google Scholar 

  45. Rudnick A, Ling TY, Odagiri H, Rutter WJ, German MS (1994) Pancreatic beta cells express a diverse set of homeobox genes. Proc Natl Acad Sci USA 91:12203–12207

    Article  PubMed  CAS  Google Scholar 

  46. German MS, Wang J, Chadwick RB, Rutter WJ (1992) Synergistic activation of the insulin gene by a LIM-homeo domain protein and a basic helix-loop-helix protein: building a functional insulin mini-enhancer complex. Genes Dev 6:2165–2176

    Article  PubMed  CAS  Google Scholar 

  47. Karlsson O, Thor S, Norberg T, Ohlsson H, Edlund T (1990) Insulin gene enhancer binding protein Isl-1 is a member of a novel class of proteins containing both a homeo-and a Cys-His domain. Nature 344:879–882

    Article  PubMed  CAS  Google Scholar 

  48. Rosanas-Urgell A, Marfany G, Garcia-Fernandez J (2005) Pdx1-related homeodomain transcription factors are distinctly expressed in mouse adult pancreatic islets. Mol Cell Endocrinol 237:59–66

    Article  PubMed  CAS  Google Scholar 

  49. Chawengsaksophak K, James R, Hammond VE, Kontgen F, Beck F (1997) Homeosis and intestinal tumours in Cdx2 mutant mice. Nature 386:84–87

    Article  PubMed  CAS  Google Scholar 

  50. Ahlgren U, Pfaff SL, Jessell TM, Edlund T, Edlund H (1997) Independent requirement for ISL1 in formation of pancreatic mesenchyme and islet cells. Nature 385:257–260

    Article  PubMed  CAS  Google Scholar 

  51. Ohlsson H, Thor S, Edlund T (1991) Novel insulin promoter-and enhancer-binding proteins that discriminate between pancreatic alpha-and beta-cells. Mol Endocrinol 5:897–904

    Article  PubMed  CAS  Google Scholar 

  52. Thor S, Ericson J, Brannstrom T, Edlund T (1991) The homeodomain LIM protein Isl-1 is expressed in subsets of neurons and endocrine cells in the adult rat. Neuron 7:881–889

    Article  PubMed  CAS  Google Scholar 

  53. Leonard J, Serup P, Gonzalez G, Edlund T, Montminy M (1992) The LIM family transcription factor Isl-1 requires cAMP response element binding protein to promote somatostatin expression in pancreatic islet cells. Proc Natl Acad Sci USA 89: 6247–6251

    Article  PubMed  CAS  Google Scholar 

  54. Wang M, Drucker DJ (1995) The LIM domain homeobox gene isl-1 is a positive regulator of islet cell-specific proglucagon gene transcription. J Biol Chem 270:12646–12652

    Article  PubMed  CAS  Google Scholar 

  55. Wang M, Drucker DJ (1996) Activation of amylin gene transcription by LIM domain homeobox gene isl-1. Mol Endocrinol 10:243–251

    Article  PubMed  CAS  Google Scholar 

  56. Peshavaria M, Gamer L, Henderson E, Teitelman G, Wright CV, Stein R (1994) XIHbox 8, an endoderm-specific Xenopus homeodomain protein, is closely related to a mammalian insulin gene transcription factor. Mol Endocrinol 8: 806–816

    Article  PubMed  CAS  Google Scholar 

  57. Petersen HV, Serup P, Leonard J, Michelsen BK, Madsen OD (1994) Transcriptional regulation of the human insulin gene is dependent on the homeodomain protein STF1/IPF1 acting through the CT boxes. Proc Natl Acad Sci USA 91:10465–10469

    Article  PubMed  CAS  Google Scholar 

  58. Peers B, Leonard J, Sharma S, Teitelman G, Montminy MR (1994) Insulin expression in pancreatic islet cells relies on cooperative interactions between the helix loop helix factor E47 and the homeobox factor STF-1. Mol Endocrinol 8:1798–1806

    Article  PubMed  CAS  Google Scholar 

  59. Guz Y, Montminy MR, Stein R, Leonard J, Gamer LW, Wright CV, Teitelman G (1995) Expression of murine STF-1, a putative insulin gene transcription factor, in beta cells of pancreas, duodenal epithelium and pancreatic exocrine and endocrine progenitors during ontogeny. Development 121:11–18

    PubMed  CAS  Google Scholar 

  60. Wu KL, Gannon M, Peshavaria M, Offield MF, Henderson E, Ray M, Marks A, Gamer LW, Wright CV, Stein R (1997) Hepatocyte nuclear factor 3beta is involved in pancreatic beta-cell-specific transcription of the pdx-1 gene. Mol Cell Biol 17: 6002–6013

    PubMed  CAS  Google Scholar 

  61. Watada H, Kajimoto Y, Miyagawa J, Hanafusa T, Hamaguchi K, Matsuoka T, Yamamoto K, Matsuzawa Y, Kawamori R, Yamasaki Y (1996) PDX-1 induces insulin and glucokinase gene expressions in alphaTC1 clone 6 cells in the presence of betacellulin. Diabetes 45:1826–1831

    Article  PubMed  CAS  Google Scholar 

  62. Watada H, Kajimoto Y, Umayahara Y, Matsuoka T, Kaneto H, Fujitani Y, Kamada T, Kawamori R, Yamasaki Y (1996) The human glucokinase gene beta-cell-type promoter: an essential role of insulin promoter factor 1/PDX-1 in its activation in HIT-T15 cells. Diabetes 45:1478–1488

    Article  PubMed  CAS  Google Scholar 

  63. Bretherton-Watt D, Gore N, Boam DS (1996) Insulin upstream factor 1 and a novel ubiquitous factor bind to the human islet amyloid polypeptide/amylin gene promoter. Biochem J 313 (Pt 2):495–502

    PubMed  CAS  Google Scholar 

  64. Watada H, Kajimoto Y, Kaneto H, Matsuoka T, Fujitani Y, Miyazaki J, Yamasaki Y (1996) Involvement of the homeodomain-containing transcription factor PDX-1 in islet amyloid polypeptide gene transcription. Biochem Biophys Res Commun 229:746–751

    Article  PubMed  CAS  Google Scholar 

  65. Waeber G, Thompson N, Nicod P, Bonny C (1996) Transcriptional activation of the GLUT2 gene by the IPF-1/STF-1/IDX-1 homeobox factor. Mol Endocrinol 10: 1327–1334

    Article  PubMed  CAS  Google Scholar 

  66. Cissell MA, Zhao L, Sussel L, Henderson E, Stein R (2003) Transcription factor occupancy of the insulin gene in vivo. Evidence for direct regulation by Nkx2.2. J Biol Chem 278:751–756

    Article  PubMed  CAS  Google Scholar 

  67. Serup P, Jensen J, Andersen FG, Jorgensen MC, Blume N, Holst JJ, Madsen OD (1996) Induction of insulin and islet amyloid polypeptide production in pancreatic islet glucagonoma cells by insulin promoter factor 1. Proc Natl Acad Sci USA 93:9015–9020

    Article  PubMed  CAS  Google Scholar 

  68. Elrick LJ, Docherty K (2001) Phosphorylation-dependent nucleocytoplasmic shuttling of pancreatic duodenal homeobox-1. Diabetes 50:2244–2252

    Article  PubMed  CAS  Google Scholar 

  69. Rafiq I, Kennedy HJ, Rutter GA (1998) Glucose-dependent translocation of insulin promoter factor-1 (IPF-1) between the nuclear periphery and the nucleoplasm of single MIN6 beta-cells. J Biol Chem 273:23241–23247

    Article  PubMed  CAS  Google Scholar 

  70. Chakrabarti SK, Francis J, Ziesmann SM, Garmey JC, Mirmira RG (2003) Covalent histone modifications underlie the developmental regulation of insulin gene transcription in pancreatic beta cells. J Biol Chem 278:23617–23623

    Article  PubMed  CAS  Google Scholar 

  71. Docherty HM, Hay CW, Ferguson LA, Barrow J, Durward E, Docherty K (2005) Relative contribution of PDX-1, MafA and E47/beta2 to the regulation of the human insulin promoter. Biochem J 389:813–820

    Article  PubMed  CAS  Google Scholar 

  72. Mosley AL, Ozcan S (2003) Glucose regulates insulin gene transcription by hyperacetylation of histone h4. J Biol Chem 278:19660–19666

    Article  PubMed  CAS  Google Scholar 

  73. Francis J, Chakrabarti SK, Garmey JC, Mirmira RG (2005) Pdx-1 links histone H3-Lys-4 methylation to RNA polymerase II elongation during activation of insulin transcription. J Biol Chem 280:36244–36253

    Article  PubMed  CAS  Google Scholar 

  74. Ahlgren U, Jonsson J, Jonsson L, Simu K, Edlund H (1998) Beta-cell-specific inactivation of the mouse Ipf1/Pdx1 gene results in loss of the beta-cell phenotype and maturity onset diabetes. Genes Dev 12:1763–1768

    Article  PubMed  CAS  Google Scholar 

  75. Shieh SY, Tsai MJ (1991) Cell-specific and ubiquitous factors are responsible for the enhancer activity of the rat insulin II gene. J Biol Chem 266:16708–16714

    PubMed  CAS  Google Scholar 

  76. Zhao L, Cissell MA, Henderson E, Colbran R, Stein R (2000) The RIPE3b1 activator of the insulin gene is composed of a protein(s) of approximately 43 kDa, whose DNA binding activity is inhibited by protein phosphatase treatment. J Biol Chem 275: 10532–10537

    Article  PubMed  CAS  Google Scholar 

  77. Shieh SY, Stellrecht CM, Tsai MJ (1995) Molecular characterization of the rat insulin enhancer-binding complex 3b2. Cloning of a binding factor with putative helicase motifs. J Biol Chem 270:21503–21508

    Article  PubMed  CAS  Google Scholar 

  78. Kataoka K, Han SI, Shioda S, Hirai M, Nishizawa M, Handa H (2002) MafA is a glucose-regulated and pancreatic beta-cell-specific transcriptional activator for the insulin gene. J Biol Chem 277:49903–49910

    Article  PubMed  CAS  Google Scholar 

  79. Matsuoka TA, Zhao L, Artner I, Jarrett HW, Friedman D, Means A, Stein R (2003) Members of the large Maf transcription family regulate insulin gene transcription in islet beta cells. Mol Cell Biol 23:6049–6062

    Article  PubMed  CAS  Google Scholar 

  80. Olbrot M, Rud J, Moss LG, Sharma A (2002) Identification of beta-cell-specific insulin gene transcription factor RIPE3b1 as mammalian MafA. Proc Natl Acad Sci USA 99:6737–6742

    Article  PubMed  CAS  Google Scholar 

  81. Matsuoka TA, Artner I, Henderson E, Means A, Sander M, Stein R (2004) The MafA transcription factor appears to be responsible for tissue-specific expression of insulin. Proc Natl Acad Sci USA 101:2930–2933

    Article  PubMed  CAS  Google Scholar 

  82. Zhao L, Guo M, Matsuoka TA, Hagman DK, Parazzoli SD, Poitout V, Stein R (2005) The islet beta cell-enriched MafA activator is a key regulator of insulin gene transcription. J Biol Chem 280:11887–11894

    Article  PubMed  CAS  Google Scholar 

  83. Hagman DK, Hays LB, Parazzoli SD, Poitout V (2005) Palmitate inhibits insulin gene expression by altering PDX-1 nuclear localization and reducing MafA expression in isolated rat islets of Langerhans. J Biol Chem 280:32413–32418

    Article  PubMed  CAS  Google Scholar 

  84. Harmon JS, Stein R, Robertson RP (2005) Oxidative stress-mediated, posttranslational loss of MafA protein as a contributing mechanism to loss of insulin gene expression in glucotoxic beta cells. J Biol Chem 280:11107–11113

    Article  PubMed  CAS  Google Scholar 

  85. Artner I, Le Lay J, Hang Y, Elghazi Y, Schisler JC, Henderson E, Sosa-Pineda B, Stein R (2006) MafB: an activator of the glucagon gene expressed in developing islet alpha-and beta-cells. Diabetes 55:297–304

    Article  PubMed  CAS  Google Scholar 

  86. Nishimura W, Kondo T, Salameh T, El Khattabi I, Dodge R, Bonner-Weir S, Sharma A (2006) A switch from MafB to MafA expression accompanies differentiation to pancreatic beta-cells. Dev Biol 293:526–539

    Article  PubMed  CAS  Google Scholar 

  87. German MS, Moss LG, Wang J, Rutter WJ (1992) The insulin and islet amyloid polypeptide genes contain similar cell-specific promoter elements that bind identical beta-cell nuclear complexes. Mol Cell Biol 12:1777–17788

    PubMed  CAS  Google Scholar 

  88. Peshavaria M, Henderson E, Sharma A, Wright CV, Stein R (1997) Functional characterization of the transactivation properties of the PDX-1 homeodomain protein. Mol Cell Biol 17:3987–3996

    PubMed  CAS  Google Scholar 

  89. Naya FJ, Stellrecht CM, Tsai MJ (1995) Tissue-specific regulation of the insulin gene by a novel basic helix-loop-helix transcription factor. Genes Dev 9:1009–1019

    Article  PubMed  CAS  Google Scholar 

  90. Whelan J, Cordle SR, Henderson E, Weil PA, Stein R (1990) Identification of a pancreatic beta-cell insulin gene transcription factor that binds to and appears to activate cell-type-specific expression: its possible relationship to other cellular factors that bind to a common insulin gene sequence. Mol Cell Biol 10:1564–1572

    PubMed  CAS  Google Scholar 

  91. Buskin JN, Hauschka SD (1989) Identification of a myocyte nuclear factor that binds to the muscle-specific enhancer of the mouse muscle creatine kinase gene. Mol Cell Biol 9:2627–2640

    PubMed  CAS  Google Scholar 

  92. Ephrussi A, Church GM, Tonegawa S, Gilbert W (1985) B lineage-specific interactions of an immunoglobulin enhancer with cellular factors in vivo. Science 227: 134–140

    Article  PubMed  CAS  Google Scholar 

  93. Davis RL, Weintraub H, Lassar AB (1987) Expression of a single transfected cDNA converts fibroblasts to myoblasts. Cell 51:987–1000

    Article  PubMed  CAS  Google Scholar 

  94. Braun T, Buschhausen-Denker G, Bober E, Tannich E, Arnold HH (1989) A novel human muscle factor related to but distinct from MyoD1 induces myogenic conversion in 10T1/2 fibroblasts. EMBO J 8:701–709

    PubMed  CAS  Google Scholar 

  95. Brennan TJ, Olson EN (1990) Myogenin resides in the nucleus and acquires high affinity for a conserved enhancer element on heterodimerization. Genes Dev 4: 582–595

    Article  PubMed  CAS  Google Scholar 

  96. Cabrera CV, Martinez-Arias A, Bate M (1987) The expression of three members of the achaete-scute gene complex correlates with neuroblast segregation in Drosophila. Cell 50:425–433

    Article  PubMed  CAS  Google Scholar 

  97. Lee JE, Hollenberg SM, Snider L, Turner DL, Lipnick N, Weintraub H (1995) Conversion of Xenopus ectoderm into neurons by NeuroD, a basic helix-loop-helix protein. Science 268:836–844

    Article  PubMed  CAS  Google Scholar 

  98. Peyton M, Moss LG, Tsai MJ (1994) Two distinct class A helix-loop-helix transcription factors, E2A and BETA1, form separate DNA binding complexes on the insulin gene E box. J Biol Chem 269:25936–25941

    PubMed  CAS  Google Scholar 

  99. Cordle SR, Henderson E, Masuoka H, Weil PA, Stein R (1991) Pancreatic beta-cell-type-specific transcription of the insulin gene is mediated by basic helix-loop-helix DNA-binding proteins. Mol Cell Biol 11:1734–1738

    PubMed  CAS  Google Scholar 

  100. German MS, Blanar MA, Nelson C, Moss LG, Rutter WJ (1991) Two related helix-loop-helix proteins participate in separate cell-specific complexes that bind the insulin enhancer. Mol Endocrinol 5:292–299

    PubMed  CAS  Google Scholar 

  101. Murre C, McCaw PS, Vaessin H, Caudy M, Jan LY, Jan YN, Cabrera CV, Buskin JN, Hauschka SD, Lassar AB, Weintraub H, Baltimore D (1989) Interactions between heterologous helix-loop-helix proteins generate complexes that bind specifically to a common DNA sequence. Cell 58:537–544

    Article  PubMed  CAS  Google Scholar 

  102. Sommer L, Ma Q, Anderson DJ (1996) neurogenins, a novel family of atonal-related bHLH transcription factors, are putative mammalian neuronal determination genes that reveal progenitor cell heterogeneity in the developing CNS and PNS. Mol Cell Neurosci 8:221–241

    Article  PubMed  CAS  Google Scholar 

  103. Weintraub H (1993) The MyoD family and myogenesis: redundancy, networks, and thresholds. Cell 75:1241–1244

    Article  PubMed  CAS  Google Scholar 

  104. Mutoh H, Fung BP, Naya FJ, Tsai MJ, Nishitani J, Leiter AB (1997) The basic helix-loop-helix transcription factor BETA2/NeuroD is expressed in mammalian enteroendocrine cells and activates secretin gene expression. Proc Natl Acad Sci USA 94: 3560–3564

    Article  PubMed  CAS  Google Scholar 

  105. Poulin G, Turgeon B, Drouin J (1997) NeuroD1/beta2 contributes to cell-specific transcription of the proopiomelanocortin gene. Mol Cell Biol 17:6673–6682

    PubMed  CAS  Google Scholar 

  106. Chae JH, Stein GH, Lee JE (2004) NeuroD: the predicted and the surprising. Mol Cells 18:271–288

    PubMed  CAS  Google Scholar 

  107. Rindi G, Ratineau C, Ronco A, Candusso ME, Tsai M, Leiter AB (1999) Targeted ablation of secretin-producing cells in transgenic mice reveals a common differentiation pathway with multiple enteroendocrine cell lineages in the small intestine. Development 126:4149–4156

    PubMed  CAS  Google Scholar 

  108. Huang HP, Chu K, Nemoz-Gaillard E, Elberg D, Tsai MJ (2002) Neogenesis of beta-cells in adult BETA2/NeuroD-deficient mice. Mol Endocrinol 16:541–551

    Article  PubMed  CAS  Google Scholar 

  109. German MS, Wang J (1994) The insulin gene contains multiple transcriptional elements that respond to glucose. Mol Cell Biol 14:4067–4075

    PubMed  CAS  Google Scholar 

  110. Chakrabarti SK, James JC, Mirmira RG (2002) Quantitative assessment of gene targeting in vitro and in vivo by the pancreatic transcription factor, Pdx1. Importance of chromatin structure in directing promoter binding. J Biol Chem 277:13286–13293

    Article  PubMed  CAS  Google Scholar 

  111. Qiu Y, Guo M, Huang S, Stein R (2002) Insulin gene transcription is mediated by interactions between the p300 coactivator and PDX-1, BETA2, and E47. Mol Cell Biol 22:412–420

    Article  PubMed  CAS  Google Scholar 

  112. Qiu Y, Sharma A, Stein R (1998) p300 mediates transcriptional stimulation by the basic helix-loop-helix activators of the insulin gene. Mol Cell Biol 18:2957–2964

    PubMed  CAS  Google Scholar 

  113. Emens LA, Landers DW, Moss LG (1992) Hepatocyte nuclear factor 1 alpha is expressed in a hamster insulinoma line and transactivates the rat insulin I gene. Proc Natl Acad Sci USA 89:7300–7304

    Article  PubMed  CAS  Google Scholar 

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Authors and Affiliations

  1. Department of Molecular Physiology and Biophysics, Vanderbilt University Medical Center, 723 Light Hall, Nashville, TN, 37232, USA

    Isabella Artner & Roland Stein

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  1. Isabella Artner
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  2. Roland Stein
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Editors and Affiliations

  1. Division of Cellular and Molecular Medicine, Department of Physiology and Cell Biology, Kobe University Graduate School of Medicine, 7-5-1 Kusunoki-cho, Chuo-ku, Kobe, 650-0017, Japan

    Susumu Seino M.D., D.M. Sci. (Professor) (Professor)

  2. Medicine and Human Genetics, The University of Chicago, 5841 South Maryland Avenue, Chicago, IL, 60637, USA

    Graeme I. Bell Ph.D. (Louis Block Distinguished Service Professor) (Louis Block Distinguished Service Professor)

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© 2008 Springer

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Artner, I., Stein, R. (2008). Transcriptional Regulation of Insulin Gene Expression. In: Seino, S., Bell, G.I. (eds) Pancreatic Beta Cell in Health and Disease. Springer, Tokyo. https://doi.org/10.1007/978-4-431-75452-7_2

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