Endoplasmic Reticulum Stress-induced Activation of Activating Transcription Factor 6 Decreases Insulin Gene Expression Via Up-regulation of Orphan Nuclear Receptor Small Heterodimer Partner

Overview

Journal Endocrinology

Publisher Oxford University Press

Specialty Endocrinology

Date 2008 May 3

PMID 18450959

Citations 61

Authors

Hye-Young Seo

Yong Deuk Kim

Kyeong-Min Lee

Ae-Kyung Min

Mi-Kyung Kim

Hye-Soon Kim

Kyu-Chang Won

Joong-Yeol Park

Ki-Up Lee

Hueng-Sik Choi

Keun-Gyu Park

In-Kyu Lee

Affiliations

Soon will be listed here.

Abstract

The highly developed endoplasmic reticulum (ER) structure of pancreatic beta-cells is a key factor in beta-cell function. Here we examined whether ER stress-induced activation of activating transcription factor (ATF)-6 impairs insulin gene expression via up-regulation of the orphan nuclear receptor small heterodimer partner (SHP; NR0B2), which has been shown to play a role in beta-cell dysfunction. We examined whether ER stress decreases insulin gene expression, and this process is mediated by ATF6. A small interfering RNA that targeted SHP was used to determine whether the effect of ATF6 on insulin gene expression is mediated by SHP. We also measured the expression level of ATF6 in pancreatic islets in Otsuka Long Evans Tokushima Fatty rats, a rodent model of type 2 diabetes. High glucose concentration (30 mmol/liter glucose) increased ER stress in INS-1 cells. ER stress induced by tunicamycin, thapsigargin, or dithiotreitol decreased insulin gene transcription. ATF6 inhibited insulin promoter activity, whereas X-box binding protein-1 and ATF4 did not. Adenovirus-mediated overexpression of active form of ATF6 in INS-1 cells impaired insulin gene expression and secretion. ATF6 also down-regulated pancreatic duodenal homeobox factor-1 and RIPE3b1/MafA gene expression and repressed the cooperative action of pancreatic duodenal homeobox factor-1, RIPE3b1/MafA, and beta-cell E box transactivator 2 in stimulating insulin transcription. The ATF6-induced suppression of insulin gene expression was associated with up-regulation of SHP gene expression. Finally, we found that expression of ATF6 was increased in the pancreatic islets of diabetic Otsuka Long Evans Tokushima Fatty rats, compared with their lean, nondiabetic counterparts, Long-Evans Tokushima Otsuka rats. Collectively, this study shows that ER stress-induced activation of ATF6 plays an important role in the development of beta-cell dysfunction.

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References

Hsieh Y, Su I, Lei H, Lai M, Chang W, Huang W . Differential endoplasmic reticulum stress signaling pathways mediated by iNOS. Biochem Biophys Res Commun. 2007; 359(3):643-8. DOI: 10.1016/j.bbrc.2007.05.154. View

Okita K, Yang Q, Yamagata K, Hangenfeldt K, Miyagawa J, Kajimoto Y . Human insulin gene is a target gene of hepatocyte nuclear factor-1alpha (HNF-1alpha) and HNF-1beta. Biochem Biophys Res Commun. 1999; 263(2):566-9. DOI: 10.1006/bbrc.1999.1412. View

Yoshida H, Okada T, Haze K, Yanagi H, Yura T, Negishi M . ATF6 activated by proteolysis binds in the presence of NF-Y (CBF) directly to the cis-acting element responsible for the mammalian unfolded protein response. Mol Cell Biol. 2000; 20(18):6755-67. PMC: 86199. DOI: 10.1128/MCB.20.18.6755-6767.2000. View

Pirot P, Naamane N, Libert F, Magnusson N, Orntoft T, Cardozo A . Global profiling of genes modified by endoplasmic reticulum stress in pancreatic beta cells reveals the early degradation of insulin mRNAs. Diabetologia. 2007; 50(5):1006-14. DOI: 10.1007/s00125-007-0609-0. View

Ye J, Rawson R, Komuro R, Chen X, Dave U, Prywes R . ER stress induces cleavage of membrane-bound ATF6 by the same proteases that process SREBPs. Mol Cell. 2001; 6(6):1355-64. DOI: 10.1016/s1097-2765(00)00133-7. View

Borgius L, Steffensen K, Gustafsson J, Treuter E . Glucocorticoid signaling is perturbed by the atypical orphan receptor and corepressor SHP. J Biol Chem. 2002; 277(51):49761-6. DOI: 10.1074/jbc.M205641200. View

Kim J, Chu K, Kim H, Seong H, Park K, Sanyal S . Orphan nuclear receptor small heterodimer partner, a novel corepressor for a basic helix-loop-helix transcription factor BETA2/neuroD. Mol Endocrinol. 2004; 18(4):776-90. DOI: 10.1210/me.2003-0311. View

Harding H, Ron D . Endoplasmic reticulum stress and the development of diabetes: a review. Diabetes. 2002; 51 Suppl 3:S455-61. DOI: 10.2337/diabetes.51.2007.s455. View

Brendel C, Schoonjans K, Botrugno O, Treuter E, Auwerx J . The small heterodimer partner interacts with the liver X receptor alpha and represses its transcriptional activity. Mol Endocrinol. 2002; 16(9):2065-76. DOI: 10.1210/me.2001-0194. View

10.

Qiu Y, Guo M, Huang S, Stein R . Insulin gene transcription is mediated by interactions between the p300 coactivator and PDX-1, BETA2, and E47. Mol Cell Biol. 2002; 22(2):412-20. PMC: 139753. DOI: 10.1128/MCB.22.2.412-420.2002. View

11.

Haze K, Yoshida H, Yanagi H, Yura T, Mori K . Mammalian transcription factor ATF6 is synthesized as a transmembrane protein and activated by proteolysis in response to endoplasmic reticulum stress. Mol Biol Cell. 1999; 10(11):3787-99. PMC: 25679. DOI: 10.1091/mbc.10.11.3787. View

12.

Namba T, Ishihara T, Tanaka K, Hoshino T, Mizushima T . Transcriptional activation of ATF6 by endoplasmic reticulum stressors. Biochem Biophys Res Commun. 2007; 355(2):543-8. DOI: 10.1016/j.bbrc.2007.02.004. View

13.

Yoshida H, Haze K, Yanagi H, Yura T, Mori K . Identification of the cis-acting endoplasmic reticulum stress response element responsible for transcriptional induction of mammalian glucose-regulated proteins. Involvement of basic leucine zipper transcription factors. J Biol Chem. 1998; 273(50):33741-9. DOI: 10.1074/jbc.273.50.33741. View

14.

Robertson R, Zhang H, Pyzdrowski K, Walseth T . Preservation of insulin mRNA levels and insulin secretion in HIT cells by avoidance of chronic exposure to high glucose concentrations. J Clin Invest. 1992; 90(2):320-5. PMC: 443105. DOI: 10.1172/JCI115865. View

15.

Lee A, Iwakoshi N, Glimcher L . XBP-1 regulates a subset of endoplasmic reticulum resident chaperone genes in the unfolded protein response. Mol Cell Biol. 2003; 23(21):7448-59. PMC: 207643. DOI: 10.1128/MCB.23.21.7448-7459.2003. View

16.

Yusta B, Baggio L, Estall J, Koehler J, Holland D, Li H . GLP-1 receptor activation improves beta cell function and survival following induction of endoplasmic reticulum stress. Cell Metab. 2006; 4(5):391-406. DOI: 10.1016/j.cmet.2006.10.001. View

17.

Olbrot M, Rud J, Moss L, Sharma A . Identification of beta-cell-specific insulin gene transcription factor RIPE3b1 as mammalian MafA. Proc Natl Acad Sci U S A. 2002; 99(10):6737-42. PMC: 124472. DOI: 10.1073/pnas.102168499. View

18.

Kim J, Kim H, Kim K, Park Y, Seong H, Park K . Orphan nuclear receptor small heterodimer partner represses hepatocyte nuclear factor 3/Foxa transactivation via inhibition of its DNA binding. Mol Endocrinol. 2004; 18(12):2880-94. DOI: 10.1210/me.2004-0211. View

19.

Poitout V, Olson L, Robertson R . Chronic exposure of betaTC-6 cells to supraphysiologic concentrations of glucose decreases binding of the RIPE3b1 insulin gene transcription activator. J Clin Invest. 1996; 97(4):1041-6. PMC: 507151. DOI: 10.1172/JCI118496. View

20.

Oyadomari S, Koizumi A, Takeda K, Gotoh T, Akira S, Araki E . Targeted disruption of the Chop gene delays endoplasmic reticulum stress-mediated diabetes. J Clin Invest. 2002; 109(4):525-32. PMC: 150879. DOI: 10.1172/JCI14550. View