The Krüppel-like Zinc Finger Protein Glis3 Directly and Indirectly Activates Insulin Gene Transcription

Overview

Journal Nucleic Acids Res

Publisher Oxford University Press

Specialty Biochemistry

Date 2009 Mar 7

PMID 19264802

Citations 49

Authors

Yisheng Yang

Benny Hung-Junn Chang

Susan L Samson

Ming V Li

Lawrence Chan

Affiliations

Soon will be listed here.

Abstract

Glis3 is a member of the Krüppel-like family of transcription factors and is highly expressed in islet beta cells. Mutations in GLIS3 cause the syndrome of neonatal diabetes and congenital hypothyroidism (NDH). Our aim was to examine the role of Glis3 in beta cells, specifically with regard to regulation of insulin gene transcription. We demonstrate that insulin 2 (Ins2) mRNA expression in rat insulinoma 832/13 cells is markedly increased by wild-type Glis3 overexpression, but not by the NDH1 mutant. Furthermore, expression of both Ins1 and Ins2 mRNA is downregulated when Glis3 is knocked down by siRNA. Glis3 binds to the Ins2 promoter in the cell, detected by chromatin immunoprecipitation. Deletion analysis of Ins2 promoter identifies a sequence (5'-GTCCCCTGCTGTGAA-3') from -255 to -241 as the Glis3 response element and binding occur specifically via the Glis3 zinc finger region as revealed by mobility shift assays. Moreover, Glis3 physically and functionally interacts with Pdx1, MafA and NeuroD1 to modulate Ins2 promoter activity. Glis3 also may indirectly affect insulin promoter activity through upregulation of MafA and downregulation of Nkx6-1. This study uncovers a role of Glis3 for regulation of insulin gene expression and expands our understanding of its role in the beta cell.

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References

Clark A, Wilson M, Leibiger I, Scott V, Docherty K . A silencer and an adjacent positive element interact to modulate the activity of the human insulin promoter. Eur J Biochem. 1995; 232(2):627-32. View

Kim Y, Nakanishi G, Lewandoski M, Jetten A . GLIS3, a novel member of the GLIS subfamily of Krüppel-like zinc finger proteins with repressor and activation functions. Nucleic Acids Res. 2003; 31(19):5513-25. PMC: 206473. DOI: 10.1093/nar/gkg776. View

Hay C, Docherty K . Comparative analysis of insulin gene promoters: implications for diabetes research. Diabetes. 2006; 55(12):3201-13. DOI: 10.2337/db06-0788. View

Melloul D, Marshak S, Cerasi E . Regulation of insulin gene transcription. Diabetologia. 2002; 45(3):309-26. DOI: 10.1007/s00125-001-0728-y. View

Matsumura K, Chang B, Fujimiya M, Chen W, Kulkarni R, Eguchi Y . Aquaporin 7 is a beta-cell protein and regulator of intraislet glycerol content and glycerol kinase activity, beta-cell mass, and insulin production and secretion. Mol Cell Biol. 2007; 27(17):6026-37. PMC: 1952143. DOI: 10.1128/MCB.00384-07. View

Li M, Chen W, Poungvarin N, Imamura M, Chan L . Glucose-mediated transactivation of carbohydrate response element-binding protein requires cooperative actions from Mondo conserved regions and essential trans-acting factor 14-3-3. Mol Endocrinol. 2008; 22(7):1658-72. PMC: 2453601. DOI: 10.1210/me.2007-0560. View

Docherty H, Hay C, Ferguson L, Barrow J, Durward E, Docherty K . Relative contribution of PDX-1, MafA and E47/beta2 to the regulation of the human insulin promoter. Biochem J. 2005; 389(Pt 3):813-20. PMC: 1180732. DOI: 10.1042/BJ20041891. View

Artner I, Blanchi B, Raum J, Guo M, Kaneko T, Cordes S . MafB is required for islet beta cell maturation. Proc Natl Acad Sci U S A. 2007; 104(10):3853-8. PMC: 1803762. DOI: 10.1073/pnas.0700013104. View

Peshavaria M, Henderson E, Sharma A, Wright C, Stein R . Functional characterization of the transactivation properties of the PDX-1 homeodomain protein. Mol Cell Biol. 1997; 17(7):3987-96. PMC: 232251. DOI: 10.1128/MCB.17.7.3987. View

10.

Hohmeier H, Mulder H, Chen G, Prentki M, Newgard C . Isolation of INS-1-derived cell lines with robust ATP-sensitive K+ channel-dependent and -independent glucose-stimulated insulin secretion. Diabetes. 2000; 49(3):424-30. DOI: 10.2337/diabetes.49.3.424. View

11.

Senee V, Chelala C, Duchatelet S, Feng D, Blanc H, Cossec J . Mutations in GLIS3 are responsible for a rare syndrome with neonatal diabetes mellitus and congenital hypothyroidism. Nat Genet. 2006; 38(6):682-7. DOI: 10.1038/ng1802. View

12.

Beak J, Kang H, Kim Y, Jetten A . Functional analysis of the zinc finger and activation domains of Glis3 and mutant Glis3(NDH1). Nucleic Acids Res. 2008; 36(5):1690-702. PMC: 2275160. DOI: 10.1093/nar/gkn009. View

13.

Aramata S, Han S, Yasuda K, Kataoka K . Synergistic activation of the insulin gene promoter by the beta-cell enriched transcription factors MafA, Beta2, and Pdx1. Biochim Biophys Acta. 2005; 1730(1):41-6. DOI: 10.1016/j.bbaexp.2005.05.009. View

14.

Ohlsson H, Karlsson K, Edlund T . IPF1, a homeodomain-containing transactivator of the insulin gene. EMBO J. 1993; 12(11):4251-9. PMC: 413720. DOI: 10.1002/j.1460-2075.1993.tb06109.x. View

15.

Attanasio M, Uhlenhaut N, Sousa V, OToole J, Otto E, Anlag K . Loss of GLIS2 causes nephronophthisis in humans and mice by increased apoptosis and fibrosis. Nat Genet. 2007; 39(8):1018-24. DOI: 10.1038/ng2072. View

16.

Ritz-Laser B, Estreicher A, Klages N, Saule S, Philippe J . Pax-6 and Cdx-2/3 interact to activate glucagon gene expression on the G1 control element. J Biol Chem. 1999; 274(7):4124-32. DOI: 10.1074/jbc.274.7.4124. View

17.

Zhang F, Nakanishi G, Kurebayashi S, Yoshino K, Perantoni A, Kim Y . Characterization of Glis2, a novel gene encoding a Gli-related, Krüppel-like transcription factor with transactivation and repressor functions. Roles in kidney development and neurogenesis. J Biol Chem. 2001; 277(12):10139-49. DOI: 10.1074/jbc.M108062200. View

18.

Beak J, Kang H, Kim Y, Jetten A . Krüppel-like zinc finger protein Glis3 promotes osteoblast differentiation by regulating FGF18 expression. J Bone Miner Res. 2007; 22(8):1234-44. DOI: 10.1359/jbmr.070503. View

19.

Sander M, Sussel L, Conners J, Scheel D, Kalamaras J, Dela Cruz F . Homeobox gene Nkx6.1 lies downstream of Nkx2.2 in the major pathway of beta-cell formation in the pancreas. Development. 2000; 127(24):5533-40. DOI: 10.1242/dev.127.24.5533. View

20.

Mizushima S, Nagata S . pEF-BOS, a powerful mammalian expression vector. Nucleic Acids Res. 1990; 18(17):5322. PMC: 332193. DOI: 10.1093/nar/18.17.5322. View