Skip to main content
SpringerLink
Log in

An indirect role for upstream stimulatory factor in glucose-mediated induction of pyruvate kinase and S14 gene expression

  • Published:
Molecular and Cellular Biochemistry Aims and scope Submit manuscript

Abstract

Transcription of the L-type pyruvate kinase (L-PK) and S14 genes is induced in hepatocytes in response to increased glucose metabolism. The regulatory sequences of these genes responsible for induction by glucose have been mapped to related E-box containing motifs in the promoters. Similarly, L-PK promoter activity is stimulated in a differentiated pancreatic β-cell line, INS-1, in response to elevated glucose. By mutational analysis, we demonstrate that the sequence requirements for glucose induction in the INS-1 cell are identical to those observed in the hepatocyte, suggesting that the same transcriptional factor(s) is responsible for regulation of L-PK expression in the two cell types. One nuclear factor that binds to the glucose regulatory sequences of both of these genes is the Upstream Stimulatory Factor (USF), a ubiquitous E-box binding protein. Mice deleted for the USF2 gene display a severely delayed response to carbohydrate feeding (Valletet al. [26]). This observation, however, does not differentiate between a direct and an indirect role for USF in the process. To gain further insight into the possible involvement of USF in glucose signaling, we have used a recombinant adenoviral construct that expresses a dominant negative form of USF. This dominant negative can dimerize with endogenous USF and is shown to inhibit DNA binding of USF in hepatocytes and INS-1 cells. However, expression of the dominant negative USF did not block the ability of glucose to stimulate L-PK or S14 gene expression in hepatocytes or L-PK promoter activity in INS-1 cells. We conclude that USF does not act by binding to the glucose regulatory sequences of the S14 or L-PK genes and the role of USF in the process of glucose induction is indirect.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Hillgartner FB, Salati LM, Goodridge AG: Physiological and molecular mechanisms involved in nutritional regulation of fatty acid synthesis. Phys Rev 75: 47–76, 1995

    Google Scholar 

  2. Towle HC, Kaytor EN, Shih H-M: Regulation of the expression of lipogenic enzyme genes by carbohydrate. Annu Rev Nutr 17: 405–433, 1997

    Google Scholar 

  3. Girard J, Ferre P, Foufelle F: Mechanisms by which carbohydrates regulate expression of genes for glycolytic and lipogenic enzymes. Annu Rev Nutr 17: 325–352, 1997

    Google Scholar 

  4. Vaulont S, Kahn A: Transcriptional control of metabolic regulation genes by carbohydrates. FASEB J 8: 28–35, 1994

    Google Scholar 

  5. Jump DB, Oppenheimer JH: High basal expression and 3,5,3′-triiodothyronine regulation of messenger ribonucleic acid S14 in lipogenic tissues. Endocrinology 117: 2259–2266, 1985

    Google Scholar 

  6. Kinlaw WB, Church JL, Harmon J, Mariash CN: Direct evidence for a role of the "spot 14' protein in the regulation of lipid synthesis. J Biol Chem 270: 16615–16618, 1995

    Google Scholar 

  7. Vaulont S, Munich A, Decaux JF, Kahn A: Transcriptional and post-transcriptional regulation of L-type pyruvate kinase gene expression in rat liver. J Biol Chem 261: 7621–7625, 1986

    Google Scholar 

  8. Jump DB, Bell A, Santiago V: Thyroid hormone and dietary carbohydrate interact to regulate rat liver S14 gene transcription and chromatin structure. J Biol Chem 265: 3474–3478, 1990

    Google Scholar 

  9. Bergot M-O, Diaz-Guerra M-JM, Puzenat N, Raymondjean M, Kahn A: Cis-regulation of the L-type pyruvate kinase gene promoter by glucose, insulin and cyclic AMP. Nucl Acids Res 20: 1871–1878, 1992

    Google Scholar 

  10. Liu Z, Thompson KS, Towle HC: Carbohydrate regulation of the rat L-type pyruvate kinase gene requires two nuclear factors: LFA1 and a member of the c-myc family. J Biol Chem 268: 12787–12795, 1993

    Google Scholar 

  11. Shih H-M, Towle HC: Definition of the carbohydrate response element of the rat S14 gene: Context of the CACGTG motif determines the specificity of carbohydrate regulation. J Biol Chem 269: 9380–9387, 1994

    Google Scholar 

  12. Shih H-M, Liu Z, Towle HC: Two CACGTG motifs with proper spacing dictate the carbohydrate regulation of hepatic gene transcription. J Biol Chem 270: 21991–21997, 1995

    Google Scholar 

  13. Docherty K, Clark AR: Nutrient regulation of insulin gene expression. FASEB J 8: 20–27, 1994

    Google Scholar 

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

    Google Scholar 

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

    Google Scholar 

  16. Sharma A, Fusco-DeMane D, Henderson E, Efrat S, Stein R: The role of the insulin control element and RIPE3b1 activators in glucose-stimulated transcription of the insulin gene. Mol Endocrinol 9: 1468–1476, 1995

    Google Scholar 

  17. MacFarlane WM, Read ML, Gilligan M, Bujalska I, Docherty K: Glucose modulates the binding activity of the β-cell transcription factor IUF1 in a phosphorylation-dependent manner. Biochem J 303: 625–631, 1994

    Google Scholar 

  18. Marie S, Diaz-Guerra M-J, Miquerol L, Kahn A, Iynedjian PB: The pyruvate kinase gene as a model for studies of glucosedependent regulation of gene expression in the endocrine pancreatic beta-cell type. J Biol Chem 268: 23881–23890, 1993

    Google Scholar 

  19. Olson LK, Qian J, Poitout V: Glucose rapidly and reversibly decreases INS-1 cell insulin gene transcription via decrements in STF-1 and C1 activator transcription factor activity. Mol Endocrinol 12: 207–219, 1998

    Google Scholar 

  20. Atchley WR, Fitch WM: A natural classification of the basic helix-loop-helix class of transcription factors. Proc Natl Acad Sci USA 94: 5172–5176, 1997

    Google Scholar 

  21. Kadesch T: Consequences of heteromeric interactions among helix-loop-helix proteins. Cell Growth Differ 4: 49–55, 1993

    Google Scholar 

  22. Sirito M, Walker S, Lin Q, Kozlowski MT, Klein WH, Sawadogo M: Members of the USF family of helix-loop-helix proteins bind DNA as homo-as well as heterodimers. Gene Expr 2: 231–240, 1992

    Google Scholar 

  23. Viollet B, Lefrancois-Martinez A-M, Henrion A, Kahn A, Raymondjean M, Martinez A: Immunochemical characterization and transacting properties of upstream stimulatory factor isoforms. J Biol Chem 271: 1405–1415, 1996

    Google Scholar 

  24. Vaulont S, Puzenat N, Levrat F, Cognet M, Kahn A, Raymondjean M: Proteins binding to the liver-specific pyruvate kinase gene promoter: A unique combination of known factors. J Mol Biol 209: 205–219, 1989

    Google Scholar 

  25. Diaz Guerra M-JM, Bergot M-O, Martinez A, Cuif M-H, Kahn A, Raymondjean M: Functional characterization of the L-type pyruvate kinase gene glucose response complex. Mol Cell Biol 13: 7725–7733, 1993

    Google Scholar 

  26. Vallet VS, Henrion AA, Bucchini D, Casado M, Raymondjean M, Kahn A, Vaulont S: Glucose-dependent liver gene expression in upstream stimulatory factor 2-/-mice. J Biol Chem 272: 21944–21949, 1997

    Google Scholar 

  27. Kennedy HJ, Viollet B, Rafiq I, Kahn A, Rutter GA: Upstream stimulatory factor-2 (USF2) activity is required for glucose stimulation of L-pyruvate kinase promoter activity in single living islet β-cells. J Biol Chem 272: 20636–20640, 1997

    Google Scholar 

  28. Sirito M, Lin Q, Maity T, Sawadogo M: Ubiquitous expression of the 43-and 44kDa forms of transcription factor USF in mammalian cells. Nuc Acids Res 22: 427–433, 1994

    Google Scholar 

  29. Potter JJ, Cheneval D, Dang CV, Resar LMS, Mezey E, Yang VW: The upstream stimulatory factor binds to and activates the promoter of the rat class I alcohol dehydrogenase gene. J Biol Chem 266: 15457–15463, 1991

    Google Scholar 

  30. Viollet B, Kahn A, Raymondjean M: Protein kinase A-dependent phosphorylation modulates DNA-binding activity of Hepatocyte Nuclear Factor 4. Mol Cell Biol 17: 4208–4219, 1997

    Google Scholar 

  31. Kaytor EN, Shih H-M, Towle HC: Carbohydrate regulation of hepatic gene expression. Evidence against a role for the upstream stimulatory factor. J Biol Chem 272: 7525–7531, 1997

    Google Scholar 

  32. Lefrancois-Martinez A-M, Martinez A, Antoine B, Raymondjean M, Kahn A: Upstream stimulatory factor proteins are major components of the glucose response complex of the L-type pyruvate kinase gene promoter. J Biol Chem 270: 2640–2643, 1995

    Google Scholar 

  33. Shih H-M, Towle HC: Definition of the carbohydrate response element of the rat S14 gene: Evidence for a common factor required for carbohydrate regulation of hepatic genes. J Biol Chem 267: 13222–13228, 1992

    Google Scholar 

  34. Qian J, Kaytor EN, Towle HC, Olson LK: Upstream stimulatory factor regulates Pdx-1 gene expression in differentiated pancreatic β-cells. Biochem J 341: 315–322, 1999

    Google Scholar 

  35. Meier JL, Lui X, Sawadogo M, Straus SE: The cellular transcription factor USF cooperates with varicella-zoster virus immediate-early protein 62 to symmetrically activate a bidirectional viral promoter. Mol Cell Biol 14: 6896–6906, 1994

    Google Scholar 

  36. Becker TC, Noel RJ, Coats WS, Gomez-Foix AM, Alam T, Gerard RD, Newgard CB: Use of recombinant adenovirus for metabolic engineering of mammalian cells. Methods Cell Biol 43: 161–189, 1994

    Google Scholar 

  37. Schreiber E, Matthias P, Muller MM, Schaffner W: Rapid detection of octamer binding proteins with ‘mini extracts’ prepared from a small number of cells. Nuc Acids Res 17: 6419, 1989

    Google Scholar 

  38. Celi FS, Zenilman ME, Shuldiner AR: A rapid and versatile method to synthesize internal standards for competitive PCR. Nucl Acids Res 21: 1047, 1993

    Google Scholar 

  39. Asfari M, Janjic D, Meda P, Li G, Halban PA, Wollheim CB: Establishment of 2-mercaptoethanol-dependent differentiated insulin-secreting cell lines. Endocrinology 130: 167–178, 1992

    Google Scholar 

  40. Vallet VS, Casado M, Henrion AA, Bucchini D, Raymondjean M, Kahn A, Vaulont S: Defferential roles of upstream stimulatory factors 1 and 2 in the transcriptional response of liver genes to glucose. J Biol Chem 273: 20175–20179, 1998

    Google Scholar 

  41. Timchenko N, Wilson DR, Taylor LR, Abdelsayed S, Wilde M, Sawadogo M, Darlington GJ: Autoregulation of the human C/ EBP alpha gene by stimulation of upstream stimulatory factor binding. Mol Cell Biol 15: 1192–1202, 1995

    Google Scholar 

  42. Brown MS, Goldstein JL: The SREBP pathway: Regulation of cholesterol metabolism by proteolysis of a membrane-bound transcription factor. Cell 89: 331–340, 1997

    Google Scholar 

  43. Kim JB, Spotts GD, Halvorsen Y-D, Shih H-M, Ellenberger T, Towle HC, Spiegelman BM: Dual DNA binding specificity of ADD1/SREBP1 controlled by a single amino acid in the basic helix-loop-helix domain. Mol Cell Biol 15: 2582–2588, 1995

    Google Scholar 

  44. Lopez JM, Bennett MK, Sanchez HB, Rosenfeld JM, Osborne TF: Sterol regulation of acetyl coenzyme A carboxylase: A mechanism for coordinate control of cellular lipid. Proc Natl Acad Sci USA 93: 1049–1053, 1996

    Google Scholar 

  45. Magana MM, Osborne TF: Two tandem binding sites for sterol regulatory element binding proteins are required for sterol regulation of fatty-acid synthase promoter. J Biol Chem 271: 32689–32694, 1996

    Google Scholar 

  46. Ericsson J, Jackson SM, Kim JB, Spiegelman BM, Edwards PA: Idenfication of glycerol-3-phosphate acyltransferase as an adipocyte determination and differentiation factor 1-and sterol regulatory element-binding protein-responsive gene. J Biol Chem 272: 7298–7305, 1997

    Google Scholar 

  47. Tabor DE, Kim JB, Spiegelman BM, Edwards PA: Transcriptional activation of the stearoyl-CoA desaturase 2 gene by sterol regulatory element-binding protein/adipocyte determination and differentiation factor 1. J Biol Chem 273: 22052–22058, 1998

    Google Scholar 

  48. Kim JB, Sarraf P, Wright M, Yao KM, Mueller E, Solanes G, Lowell BB, Spiegelman BM: Nutritional and insulin regulation of fatty acid synthetase and leptin gene expression through ADD1/ SREBP1. J Clin Invest 101: 1–9, 1998

    Google Scholar 

  49. Shimano H, Horton JD, Hammer RE, Shimomura I, Brown MS, Goldstein JL: Overproduction of cholesterol and fatty acids causes massive liver enlargement in transgenic mice expressing truncated SREBP-1a. J Clin Invest 98: 1575–1584, 1996

    Google Scholar 

  50. Shimomura I, Shimano H, Korn BS, Bashmakov Y, Horton JD: Nuclear sterol regulatory element-binding proteins activate genes responsible for the entire program of unsaturated fatty acid biosynthesis in transgenic mouse liver. J Biol Chem 273: 35299–35306, 1998

    Google Scholar 

  51. Foretz M, Pacot C, Dugail I, Lemarchand P, Guichard C, Liepvre XL, Berthelier-Lubrano C, Spiegelman B, Kim JB, Ferre P, Foufelle F: ADD1/SREBP-1c is required in the activation of hepatic lipogenic gene expression by glucose. Mol Cell Biol 19: 3760–3768, 1999

    Google Scholar 

  52. Moriizumi S, Gourdon L, Lefrancois-Martinez A-M, Kahn A, Raymondjean M: Effect of different basic helix-loop-helix leucine zipper factors on the glucose respone unit of the L-type pyruvate kinase gene. Gene Expression 7: 103–113, 1998

    Google Scholar 

  53. Kim K-H: Regulation of acetyl-CoA carboxylase. Curr Top Cell Regul 22: 143–176, 1983

    Google Scholar 

  54. Yamada K, Tanaka T, Noguchi T: Characterization and purification of carbohydrate response element-binding protein of the rat L-type pyruvate kinase gene promoter. Biochem Biophys Res Commun 257: 44–49, 1999

    Google Scholar 

  55. Hasegawa J-I, Osatomi K, Wu R-F, Uyeda K: A novel factor binding to the glucose response elements of liver pyruvate kinase and fatty acid synthase genes. J Biol Chem 274: 1100–1107, 1999

    Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Biochemistry, Molecular Biology and Biophysics, University of Minnesota, MN, USA

    Elizabeth Kaytor & Howard Towle

  2. Department of Physiology, Michigan State University, East Lansing, MI, USA

    J. Qian & L. Olson

Authors
  1. Elizabeth Kaytor
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. J. Qian
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Howard Towle
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. L. Olson
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Kaytor, E., Qian, J., Towle, H. et al. An indirect role for upstream stimulatory factor in glucose-mediated induction of pyruvate kinase and S14 gene expression. Mol Cell Biochem 210, 13–21 (2000). https://doi.org/10.1023/A:1007006429041

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1023/A:1007006429041

Search

Navigation