Original article. Transcription factors regulate Forkhead box O1 gene promoter activity in pancreatic β-cells

Open access

Abstract

Background: Transcription factors of the Forkhead box O (Fox O) family have important roles in cellular proliferation, apoptosis, differentiation, and stress resistance. In pancreatic β-cells, FoxO1 protein plays an important role in β-cells development. The molecular mechanism of transcriptional regulation of basal FoxO1 gene expression in pancreatic β-cells is not fully understood.

Objectives: Explore the potential transcription factors regulating FoxO1 promoter activity using pancreatic β-cell line (RINm5F cells)

Methods: Promoter screening method, luciferase reporter gene analysis, transient expression assay system, and deletion analysis of a -974/-18 bp 5’ upstream region of the mouse FoxO1 gene were used in this study.

Results: An inhibition domain (-974/-321) and an activation domain (-321/-18) was identified through deletion analysis of a -974/-18 bp 5’ upstream region of the mouse FoxO1 gene. Using the promoter screening method, several transcription factors were selected. Luciferase reporter studies showed that these factors could regulate FoxO1 promoter activity in RINm5F cells. Among these factors, cAMP response-element binding protein (CREB) could positively regulate FoxO1 promoter activity. Signal transducer and activator of transcription 1 (STAT1) played a negative role on FoxO1 promoter. In addition, ETS oncogene family member Elk-1 did not affect the FoxO1 promoter activity.

Conclusion: Two transcription factors (CREB and STAT1) could effectively regulate the mouse FoxO1 gene promoter activity.

If the inline PDF is not rendering correctly, you can download the PDF file here.

  • 1. Kitamura T Nakae J Kitamura Y Kido Y Biggs WH 3rd Wright CV et al. The forkhead transcription factor Foxo1 links insulin signaling to Pdx1 regulation of pancreatic beta cell growth. J Clin Invest. 2002; 110: 1839-47.

  • 2. Sussel L Kalamaras J Hartigan OCDJ Meneses JJ Pedersen RA Rubenstein JL et al. Mice lacking the homeodomain transcription factor Nkx2.2 have diabetes due to arrested differentiation of pancreatic beta cells. Development. 1998; 125:2213-21.

  • 3. Sander M Sussel L Conners J Scheel D Kalamaras J Dela Cruz F et al. Homeobox gene Nkx6.1 lies downstream of Nkx2.2 in the major pathway of betacell formation in the pancreas. Development. 2000; 127: 5533-40.

  • 4. Wang J Elghazi L Parker SE Kizilocak H Asano M Sussel L et al. The concerted activities of Pax4 and Nkx2.2 are essential to initiate pancreatic beta-cell differentiation. Dev Biol. 2004; 266:178-89.

  • 5. Kawamori D Kaneto H Nakatani Y Matsuoka TA Matsuhisa M Hori M et al. The forkhead transcription factor Foxo1 bridges the JNK pathway and the transcription factor PDX-1 through its intracellular translocation. J Biol Chem. 2006; 281:1091-8.

  • 6. Hennige AM Ozcan U Okada T Jhala US Schubert M White MF et al. Alterations in growth and apoptosis of insulin receptor substrate-1-deficient beta-cells. Am J Physiol Endocrinol Metab. 2005; 289:E337-46.

  • 7. Wither DJ Gutierrez JS Towery H Burks DJ Ren JM Previs S et al. Disruption of IRS-2 causes type 2 diabetes in mice. Nature. 1998; 391:900-4.

  • 8. Kulkarni RN Bruning JC Winnay JN Postic C Magnuson MA Kahn CR. Tissue-specific knockout of the insulin receptor in pancreatic beta cells creates an insulin secretory defect similar to that in type 2 diabetes. Cell. 1999; 96:329-39.

  • 9. Hennige AM Burks DJ Ozcan U Kulkarni RN Ye J Park S et al. Upregulation of insulin receptor substrate-2 in pancreatic beta cells prevents diabetes. J Clin Invest. 2003; 112:1521-32.

  • 10. Brunet A Bonni A Zigmond MJ Lin MZ Juo P Hu LS et al. Akt promotes cell survival by phosphorylating and inhibiting a forkhead transcription factor. Cell. 1999; 96:857-68.

  • 11. Zhang XF Zhang JJ Yang XM Han X. Several transcription factors regulate COX-2 gene expression in pancreatic -cells. Mol Biol Rep. 2007; 34: 199-206.

  • 12. Impey S McCorkle SR Cha-Molstad H Dwyer JM Yochum GS. Defining the CREB regulon: a genomewide analysis of transcription factor regulatory regions. Cell. 2004; 119:1041-54.

  • 13. Maiese K Chong ZZ Shang YC. OutFOXOing disease and disability: The therapeutic potential of targeting FoxO proteins. Trends Mol Med. 2008; 14:219-27.

  • 14. Guo S Rena G Cichy S He X Cohen P Unterman T. Phosphorylation of serine 256 by protein kinase B disrupts transactivation by FKHR and mediates effects of insulin on insulin-like growth factor-binding protein-1 promoter activity through a conserved insulin response sequence. J Biol Chem. 1999; 274:17184-92.

  • 15. Nakae J Park BC Accili D. Insulin stimulates phosphorylation of the forkhead transcription factor FKHR on serine 253 through a Wortmannin-sensitive pathway. J Biol Chem. 1999; 274:15982-5.

  • 16. Kamei Y Miura S Suzuki M Kai Y Mizukami J Taniguchi T et al. Skeletal muscle FOXO1 (FKHR) transgenic mice have less skeletal muscle mass downregulated Type I (slow twitch/red muscle) fiber genes and impaired glycemic control. J Biol Chem. 2004; 279: 41114-23.

  • 17. Zhang X Yong W Lv J Zhu Y Zhang J Chen F et al. Inhibition of forkhead box O1 protects pancreatic betacells against dexamethasone-induced dysfunction. Endocrinology. 2009; 150: 4065-73.

  • 18. Cardenas C Muller M Jaimovich E. Carrasco Depolarization of skeletal muscle cells induces phosphorylation of cAMP response element binding protein via calcium and protein kinase Calpha. J Biol Chem. 2004; 279:39122-31.

  • 19. Wu GY Deisseroth K Tsien RW. Activity-dependent CREB phosphorylation: convergence of a fast sensitive calmodulin kinase pathway and a slow less sensitive mitogen-activated protein kinase pathway. Proc Natl Acad Sci USA. 2001; 98:2808-13.

  • 20. Togo T. Long-term potentiation of wound-induced exocytosis and plasma membrane repair is dependent on cAMP-response element-mediated transcription via a protein kinase C- and p38 MAPK-dependent pathway. J Biol Chem. 2004; 279:44996-5003.

  • 21. Mitsuru O Dennis JC Roxana MM Amilcar FM Terry GU Peter R. Signal transducer and activator of transcription (Stat) 5b-mediated inhibition of insulinlike growth factor binding protein-1 gene transcription: a mechanism for repression of gene expression by growth hormone. Mol Endocrinol. 2007; 21: 1443-57.

  • 22. Sharrocks AD Brown AL Ling Y. The ETS-domain transcription factor family. Int J Biochem Cell Biol. 1997; 29:1371-87.

  • 23. Buchwalter G Gross C Wasylyk B. Ets ternary complex transcription factors. Gene. 2004; 324:1-14.

  • 24. Kasza A O’Donnell A Gascoigne K Zeef LA Hayes A Sharrocks AD. The ETS domain transcription factor Elk-1 regulates the expression of its partner protein SRF. J Biol Chem. 2005; 280:1149-55.

Search
Journal information
Impact Factor
IMPACT FACTOR 2018: 0.2
5-year IMPACT FACTOR: 0.293

CiteScore 2018: 0.30

SCImago Journal Rank (SJR) 2018: 0.172
Source Normalized Impact per Paper (SNIP) 2018: 0.237

Cited By
Metrics
All Time Past Year Past 30 Days
Abstract Views 0 0 0
Full Text Views 126 81 5
PDF Downloads 82 67 4