Endocrinol Metab.  2017 Mar;32(1):11-17. 10.3803/EnM.2017.32.1.11.

Recent Insights into Insulin-Like Growth Factor Binding Protein 2 Transcriptional Regulation

• Shin M
• Kang HS
• Park JH
• Bae JH
• Song DK
• Im SS

• KMID: 2413280
• DOI: http://doi.org/10.3803/EnM.2017.32.1.11

Abstract

Insulin-like growth factor binding proteins (IGFBPs) are major regulators of insulin-like growth factor bioavailability and activity in metabolic signaling. Seven IGFBP family isoforms have been identified. Recent studies have shown that IGFBPs play a pivotal role in metabolic signaling and disease, including the pathogenesis of obesity, diabetes, and cancer. Although many studies have documented the various roles played by IGFBPs, transcriptional regulation of IGFBPs is not well understood. In this review, we focus on the regulatory mechanisms of IGFBP gene expression, and we summarize the findings of transcription factor activity in the IGFBP promoter region.

Keyword

Insulin-like growth factor binding protein 2; Transcriptional regulation; Metabolic diseases; Liver

MeSH Terms

Biological Availability
Gene Expression
Humans
Insulin-Like Growth Factor Binding Protein 2*
Insulin-Like Growth Factor Binding Proteins
Liver
Metabolic Diseases
Obesity
Promoter Regions, Genetic
Protein Isoforms
Transcription Factors
Insulin-Like Growth Factor Binding Protein 2
Insulin-Like Growth Factor Binding Proteins
Protein Isoforms
Transcription Factors

Figure

• 

  Fig. 1 Insulin-like growth factor binding protein 2 (IGFBP-2) expression profile from Genecards database (www.genecards.org).

• 

  Fig. 2 Homology comparison of the insulin-like growth factor binding protein 2 (IGFBP-2) promoter region between species which show highly conserved regions with yellow color. (A) Alignment of human, mouse and rat IGFBP-2 promoter sequences between −1,000 and 1 bp from transcription start site. (B) Similarity plots of aligned IGFBP-2 promoter sequences between species.

• 

  Fig. 3 Comparison of insulin-like growth factor binding protein 2 (IGFBP-2) exon regions between species which represent highly conserved regions with yellow color. (A) Alignment of human, mouse and rat IGFBP-2 exon sequences. (B) Similarity plots of aligned IGFBP-2 amino acids sequences between species.

• 

  Fig. 4 Summary of transaction factor binding to the promoter regions of the insulin-like growth factor binding protein 2 (IGFBP-2) gene for human and mouse. PPAR, peroxisome proliferation-activator receptor; PPRE, PPAR response element; C/EBPα, CCAAT-enhancer-binding protein α; RXRα, retinoid X receptor α.

Reference

1. Wheatcroft SB, Kearney MT. IGF-dependent and IGF-independent actions of IGF-binding protein-1 and -2: implications for metabolic homeostasis. Trends Endocrinol Metab. 2009; 20:153–162.

2. Kim HS, Nagalla SR, Oh Y, Wilson E, Roberts CT Jr, Rosenfeld RG. Identification of a family of low-affinity insulin-like growth factor binding proteins (IGFBPs): characterization of connective tissue growth factor as a member of the IGFBP superfamily. Proc Natl Acad Sci U S A. 1997; 94:12981–12986.

3. Clemmons DR. The relative roles of growth hormone and IGF-1 in controlling insulin sensitivity. J Clin Invest. 2004; 113:25–27.

4. Schoen TJ, Mazuruk K, Waldbillig RJ, Potts J, Beebe DC, Chader GJ, et al. Cloning and characterization of a chick embryo cDNA and gene for IGF-binding protein-2. J Mol Endocrinol. 1995; 15:49–59.

5. Shimasaki S, Ling N. Identification and molecular characterization of insulin-like growth factor binding proteins (IGFBP-1, -2, -3, -4, -5 and -6). Prog Growth Factor Res. 1991; 3:243–266.

6. Kibbey MM, Jameson MJ, Eaton EM, Rosenzweig SA. Insulin-like growth factor binding protein-2: contributions of the C-terminal domain to insulin-like growth factor-1 binding. Mol Pharmacol. 2006; 69:833–845.

7. Clemmons DR, Snyder DK, Busby WH Jr. Variables controlling the secretion of insulin-like growth factor binding protein-2 in normal human subjects. J Clin Endocrinol Metab. 1991; 73:727–733.

8. Feldser D, Agani F, Iyer NV, Pak B, Ferreira G, Semenza GL. Reciprocal positive regulation of hypoxia-inducible factor 1alpha and insulin-like growth factor 2. Cancer Res. 1999; 59:3915–3918.

9. Kang HS, Kim MY, Kim SJ, Lee JH, Kim YD, Seo YK, et al. Regulation of IGFBP-2 expression during fasting. Biochem J. 2015; 467:453–460.

10. Kang HS, Cho HC, Lee JH, Oh GT, Koo SH, Park BH, et al. Metformin stimulates IGFBP-2 gene expression through PPARalpha in diabetic states. Sci Rep. 2016; 6:23665.

11. Li Z, Picard F. Modulation of IGFBP2 mRNA expression in white adipose tissue upon aging and obesity. Horm Metab Res. 2010; 42:787–791.

12. Ruan W, Lai M. Insulin-like growth factor binding protein: a possible marker for the metabolic syndrome? Acta Diabetol. 2010; 47:5–14.

13. Frystyk J. Free insulin-like growth factors: measurements and relationships to growth hormone secretion and glucose homeostasis. Growth Horm IGF Res. 2004; 14:337–375.

14. Swiderski K, Martins KJ, Chee A, Trieu J, Naim T, Gehrig SM, et al. Skeletal muscle-specific overexpression of IGFBP-2 promotes a slower muscle phenotype in healthy but not dystrophic mdx mice and does not affect the dystrophic pathology. Growth Horm IGF Res. 2016; 30-31:1–10.

15. Johnson MH, de Mejia EG. Phenolic compounds from fermented berry beverages modulated gene and protein expression to increase insulin secretion from pancreatic beta-cells in vitro. J Agric Food Chem. 2016; 64:2569–2581.

16. Li Z, Miard S, Laplante M, Sonenberg N, Picard F. Insulin stimulates IGFBP-2 expression in 3T3-L1 adipocytes through the PI3K/mTOR pathway. Mol Cell Endocrinol. 2012; 358:63–68.

17. Mireuta M, Darnel A, Pollak M. IGFBP-2 expression in MCF-7 cells is regulated by the PI3K/AKT/mTOR pathway through Sp1-induced increase in transcription. Growth Factors. 2010; 28:243–255.

18. Dunlap SM, Celestino J, Wang H, Jiang R, Holland EC, Fuller GN, et al. Insulin-like growth factor binding protein 2 promotes glioma development and progression. Proc Natl Acad Sci U S A. 2007; 104:11736–11741.

19. Tombolan L, Orso F, Guzzardo V, Casara S, Zin A, Bonora M, et al. High IGFBP2 expression correlates with tumor severity in pediatric rhabdomyosarcoma. Am J Pathol. 2011; 179:2611–2624.

20. Grimberg A, Coleman CM, Shi Z, Burns TF, MacLachlan TK, Wang W, et al. Insulin-like growth factor factor binding protein-2 is a novel mediator of p53 inhibition of insulin-like growth factor signaling. Cancer Biol Ther. 2006; 5:1408–1414.

21. Pannett AA, Thakker RV. Multiple endocrine neoplasia type 1. Endocr Relat Cancer. 1999; 6:449–473.

22. La P, Schnepp RW, Petersen CD, Silva AC, Hua X. Tumor suppressor menin regulates expression of insulin-like growth factor binding protein 2. Endocrinology. 2004; 145:3443–3450.

23. Rehfeldt C, Renne U, Sawitzky M, Binder G, Hoeflich A. Increased fat mass, decreased myofiber size, and a shift to glycolytic muscle metabolism in adolescent male transgenic mice overexpressing IGFBP-2. Am J Physiol Endocrinol Metab. 2010; 299:E287–E298.

24. Chua CY, Liu Y, Granberg KJ, Hu L, Haapasalo H, Annala MJ, et al. IGFBP2 potentiates nuclear EGFR-STAT3 signaling. Oncogene. 2016; 35:738–747.

25. Allen RE, Boxhorn LK. Regulation of skeletal muscle satellite cell proliferation and differentiation by transforming growth factor-beta, insulin-like growth factor I, and fibroblast growth factor. J Cell Physiol. 1989; 138:311–315.

26. Lynch GS, Cuffe SA, Plant DR, Gregorevic P. IGF-I treatment improves the functional properties of fast- and slow-twitch skeletal muscles from dystrophic mice. Neuromuscul Disord. 2001; 11:260–268.

27. Schertzer JD, van der Poel C, Shavlakadze T, Grounds MD, Lynch GS. Muscle-specific overexpression of IGF-I improves E-C coupling in skeletal muscle fibers from dystrophic mdx mice. Am J Physiol Cell Physiol. 2008; 294:C161–C168.

28. Aguirre GA, De Ita JR, de la Garza RG, Castilla-Cortazar I. Insulin-like growth factor-1 deficiency and metabolic syndrome. J Transl Med. 2016; 14:3.

29. Renehan AG, Frystyk J, Flyvbjerg A. Obesity and cancer risk: the role of the insulin-IGF axis. Trends Endocrinol Metab. 2006; 17:328–336.

30. Heald AH, Kaushal K, Siddals KW, Rudenski AS, Anderson SG, Gibson JM. Insulin-like growth factor binding protein-2 (IGFBP-2) is a marker for the metabolic syndrome. Exp Clin Endocrinol Diabetes. 2006; 114:371–376.

31. Levi J, Huynh FK, Denroche HC, Neumann UH, Glavas MM, Covey SD, et al. Hepatic leptin signalling and subdiaphragmatic vagal efferents are not required for leptin-induced increases of plasma IGF binding protein-2 (IGFBP-2) in ob/ob mice. Diabetologia. 2012; 55:752–762.