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Diabetologia

Erschienen in:

01.02.2007 | Article

MAFA controls genes implicated in insulin biosynthesis and secretion

verfasst von: H. Wang, T. Brun, K. Kataoka, A. J. Sharma, C. B. Wollheim

Erschienen in: Diabetologia | Ausgabe 2/2007

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Abstract

Aims/hypothesis

Effects of the transcription factor v-maf musculoaponeurotic fibrosarcoma oncogene homologue A (MAFA) on the regulation of beta cell gene expression and function were investigated.

Materials and methods

INS-1 stable cell lines permitting inducible up- or downregulation of this transcription factor were established.

Results

MAFA overproduction enhanced and its dominant-negative mutant (DN-MAFA) diminished binding of the factor to the insulin promoter, correlating with insulin mRNA levels and cellular protein content. Glucose-stimulated insulin secretion was facilitated by MAFA and blunted by DN-MAFA. This is partly due to alterations in glucokinase production, the glucose sensor of beta cells. In addition, the expression of important beta cell genes, e.g. those encoding solute carrier family 2 (facilitated glucose transporter), member 2 (formerly known as GLUT2), pancreatic and duodenal homeobox factor 1 (PDX1), NK6 transcription factor-related, locus 1 (NKX6-1), glucagon-like peptide 1 receptor (GLP1R), prohormone convertase 1/3 (PCSK1) and pyruvate carboxylase (PC), was regulated positively by MAFA and negatively by DN-MAFA.

Conclusions/interpretation

The data suggest that MAFA is not only a key activator of insulin transcription, but also a master regulator of genes implicated in maintaining beta cell function, in particular metabolism–secretion coupling, proinsulin processing and GLP1R signalling. Our in vitro study provides molecular targets that explain the phenotype of recently reported Mafa-null mice. We also demonstrate that MAFA is produced specifically in beta cells of human islets. Glucose influenced DNA-binding activity of MAFA in rat islets in a bell-shaped manner. MAFA thus qualifies as a master regulator of beta-cell-specific gene expression and function.

Nur mit Berechtigung zugänglich

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 9:1009–1019PubMedCrossRef

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

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 99:6737–6742PubMedCrossRef

Matsuoka TA, Zhao L, Artner I et al (2003) Members of the large Maf transcription family regulate insulin gene transcription in islet beta cells. Mol Cell Biol 23:6049–6062PubMedCrossRef

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 277:49903–49910PubMedCrossRef

Kojima H, Fujimiya M, Matsumura K et al (2003) NeuroD-betacellulin gene therapy induces islet neogenesis in the liver and reverses diabetes in mice. Nat Med 9:596–603PubMedCrossRef

Ferber S, Halkin A, Cohen H et al (2000) Pancreatic and duodenal homeobox gene 1 induces expression of insulin genes in liver and ameliorates streptozotocin-induced hyperglycemia. Nat Med 6:568–572PubMedCrossRef

Kaneto H, Matsuoka TA, Nakatani Y et al (2005) A crucial role of MafA as a novel therapeutic target for diabetes. J Biol Chem 280:15047–15052PubMedCrossRef

Zalzman M, Gupta S, Giri RK et al (2003) Reversal of hyperglycemia in mice by using human expandable insulin-producing cells differentiated from fetal liver progenitor cells. Proc Natl Acad Sci USA 100:7253–7258PubMedCrossRef

10.

Kataoka K, Shioda S, Ando K, Sakagami K, Handa H, Yasuda K (2004) Differentially expressed Maf family transcription factors, c-Maf and MafA, activate glucagon and insulin gene expression in pancreatic islet alpha- and beta-cells. J Mol Endocrinol 32:9–20PubMedCrossRef

11.

Artner I, Le Lay J, Hang Y et al (2006) MafB: an activator of the glucagon gene expressed in developing islet alpha- and beta-cells. Diabetes 55:297–304PubMedCrossRef

12.

Nishimura W, Kondo T, Salameh T et al (2006) A switch from MafB to MafA expression accompanies differentiation to pancreatic beta-cells. Dev Biol 293:526–539PubMedCrossRef

13.

Tsuchiya M, Taniguchi S, Yasuda K et al (2006) Potential roles of large mafs in cell lineages and developing pancreas. Pancreas 32:408–416PubMedCrossRef

14.

Kitamura YI, Kitamura T, Kruse JP et al (2005) FoxO1 protects against pancreatic beta cell failure through NeuroD and MafA induction. Cell Metab 2:153–163PubMedCrossRef

15.

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 280:32413–32418PubMedCrossRef

16.

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

17.

Pino MF, Ye DZ, Linning KD et al (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 19:1343–1360PubMedCrossRef

18.

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 136:873–876PubMed

19.

Ueki K, Okada T, Hu J et al (2006) Total insulin and IGF-I resistance in pancreatic beta cells causes overt diabetes. Nat Genet 38:583–588PubMedCrossRef

20.

Wang H, Maechler P, Ritz-Laser B et al (2001) Pdx1 level defines pancreatic gene expression pattern and cell lineage differentiation. J Biol Chem 276:25279–25286PubMedCrossRef

21.

Wang H, Iezzi M, Theander S et al (2005) Suppression of Pdx-1 perturbs proinsulin processing, insulin secretion and GLP-1 signalling in INS-1 cells. Diabetologia 48:720–731PubMedCrossRef

22.

Ahlgren U, Johnson J, Johnson 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 12:1763–1768PubMed

23.

Li Y, Cao X, Li LX, Brubaker PL, Edlund H, Drucker DJ (2005) Beta-cell Pdx1 expression is essential for the glucoregulatory, proliferative, and cytoprotective actions of glucagon-like peptide-1. Diabetes 54:482–491PubMedCrossRef

24.

Gossen M, Freundlieb S, Bender G, Muller G, Hillen W, Bujard H (1995) Transcriptional activation by tetracyclines in mammalian cells. Science 268:1766–1769PubMedCrossRef

25.

Wang H, Iynedjian PB (1997) Modulation of glucose responsiveness of insulinoma beta-cells by graded overexpression of glucokinase. Proc Natl Acad Sci USA 94:4372–4377PubMedCrossRef

26.

Wang H, Maechler P, Hagenfeldt KA, Wollheim CB (1998) Dominant-negative suppression of HNF-1alpha function results in defective insulin gene transcription and impaired metabolism-secretion coupling in a pancreatic beta-cell line. EMBO J 17:6701–6713PubMedCrossRef

27.

Zhu X, Zhou A, Dey A et al (2002) Disruption of PC1/3 expression in mice causes dwarfism and multiple neuroendocrine peptide processing defects. Proc Natl Acad Sci USA 99:10293–10298PubMedCrossRef

28.

Preitner F, Ibberson M, Franklin I et al (2004) Gluco-incretins control insulin secretion at multiple levels as revealed in mice lacking GLP-1 and GIP receptors. J Clin Invest 113:635–645PubMedCrossRef

29.

Mirmira RG, Watada H, German MS (2000) Beta-cell differentiation factor Nkx6-1 contains distinct DNA binding interference and transcriptional repression domains. J Biol Chem 275:14743–14751PubMedCrossRef

30.

Watada H, Mirmira RG, Leung J, German MS (2000) Transcriptional and transcriptional regulation of beta-cell differentiation factor Nkx6-1. J Biol Chem 275:34224–34230PubMedCrossRef

31.

Schisler JC, Jensen PB, Taylor DG et al (2005) The Nkx6-1 homeodomain transcription factor suppresses glucagon expression and regulates glucose-stimulated insulin secretion in islet beta cells. Proc Natl Acad Sci USA 102:7297–7302PubMedCrossRef

32.

Iype T, Francis J, Garmey JC et al (2005) Mechanism of insulin gene regulation by the pancreatic transcription factor Pdx-1: application of pre-mrna analysis and chromatin immunoprecipitation to assess formation of functional transcriptional complexes. J Biol Chem 280:16798–16807PubMedCrossRef

33.

Zhu X, Orci L, Carroll R, Norrbom C, Ravazzola M, Steiner DF (2002) Severe block in processing of proinsulin to insulin accompanied by elevation of des-64,65 proinsulin intermediates in islets of mice lacking prohormone convertase 1/3. Proc Natl Acad Sci USA 99:10299–10304PubMedCrossRef

34.

Naya FJ, Huang H-P, Qiu Y et al (1997) Diabetes, defective pancreatic morphogenesis, and abnormal enteroendocrine differentiation in BETA2/NeuroD-deficient mice. Genes Dev 11:2323–2334PubMed

35.

Wang H, Hagenfeldt-Johansson K, Otten LA, Gauthier BR, Herrera PL, Wollheim CB (2002) Experimental models of transcription factor-associated maturity-onset diabetes of the young. Diabetes 51(Suppl 3):S333–S342PubMedCrossRef

36.

Wang H, Maechler P, Antinozzi PA, Hagenfeldt KA, Wollheim CB (2000) Hepatocyte nuclear factor 4alpha regulates the expression of pancreatic beta-cell genes implicated in glucose metabolism and nutrient-induced insulin secretion. J Biol Chem 275:35953–35959PubMedCrossRef

37.

Thorens B (2001) GLUT2 in pancreatic and extra-pancreatic gluco-detection (review). Mol Membr Biol 18:265–273PubMedCrossRef

38.

Schuit F, De Vos A, Farfari S et al (1997) Metabolic fate of glucose in purified islet cells. Glucose-regulated anaplerosis in beta cells. J Biol Chem 272:18572–18579PubMedCrossRef

39.

Lu D, Mulder H, Zhao P et al (2002) 13C NMR isotopomer analysis reveals a connection between pyruvate cycling and glucose-stimulated insulin secretion (GSIS). Proc Natl Acad Sci USA 99:2708–2713PubMedCrossRef

40.

Matschinsky FM (1996) Banting Lecture 1995. A lesson in metabolic regulation inspired by the glucokinase glucose sensor paradigm. Diabetes 45:223–241PubMedCrossRef

41.

Zhang CY, Baffy G, Perret P et al (2001) Uncoupling protein-2 negatively regulates insulin secretion and is a major link between obesity, beta cell dysfunction, and type 2 diabetes. Cell 105:745–755PubMedCrossRef

42.

Wang J, Silva JP, Gustafsson CM, Rustin P, Larsson NG (2001) Increased in vivo apoptosis in cells lacking mitochondrial DNA gene expression. Proc Natl Acad Sci USA 98:4038–4043PubMedCrossRef

43.

Clayton PT, Eaton S, Aynsley-Green A et al (2001) Hyperinsulinism in short-chain l-3-hydroxyacyl-CoA dehydrogenase deficiency reveals the importance of beta-oxidation in insulin secretion. J Clin Invest 108:457–465PubMedCrossRef

44.

Ishihara H, Wang H, Drewes LR, Wollheim CB (1999) Overexpression of monocarboxylate transporter and lactate dehydrogenase alters insulin secretory responses to pyruvate and lactate in beta cells. J Clin Invest 104:1621–1629PubMedCrossRef

45.

Sekine N, Cirulli V, Regazzi R et al (1994) Low lactate dehydrogenase and high mitochondrial glycerol phosphate dehydrogenase in pancreatic beta-cells. Potential role in nutrient sensing. J Biol Chem 269:4895–4902PubMed

46.

Zhao L, Guo M, Matsuoka TA et al (2005) The islet beta cell-enriched MafA activator is a key regulator of insulin gene transcription. J Biol Chem 280:11887–11894PubMedCrossRef

47.

Zhang C, Moriguchi T, Kajihara M et al (2005) MafA is a key regulator of glucose-stimulated insulin secretion. Mol Cell Biol 25:4969–4976PubMedCrossRef

48.

Samaras SE, Zhao L, Means A, Henderson E, Matsuoka TA, Stein R (2003) The islet beta cell-enriched RIPE3b1/Maf transcription factor regulates pdx-1 expression. J Biol Chem 278:12263–12270PubMedCrossRef

49.

Newgard CB (2002) While tinkering with the beta-cell...metabolic regulatory mechanisms and new therapeutic strategies: American Diabetes Association Lilly Lecture, 2001. Diabetes 51:3141–3150PubMedCrossRef

50.

Horvath A, Szabadkai G, Varnai P et al (1998) Voltage dependent calcium channels in adrenal glomerulosa cells and in insulin producing cells. Cell Calcium 23:33–42PubMedCrossRef

Titel: MAFA controls genes implicated in insulin biosynthesis and secretion
verfasst von: H. Wang
T. Brun
K. Kataoka
A. J. Sharma
C. B. Wollheim
Publikationsdatum: 01.02.2007
Verlag: Springer-Verlag
Erschienen in: Diabetologia / Ausgabe 2/2007
Print ISSN: 0012-186X
Elektronische ISSN: 1432-0428
DOI: https://doi.org/10.1007/s00125-006-0490-2

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Materials and methods

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