Endoplasmic reticulum stress induces Wfs1 gene expression in pancreatic β-cells via transcriptional activation

被引:73
作者
Ueda, K
Kawano, J
Takeda, K
Yujirj, T
Tanabe, K
Anno, T
Akiyama, M
Nozakj, J
Yoshinaga, T
Koizumi, A
Shinoda, K
Oka, Y
Tanizawa, Y
机构
[1] Yamaguchi Univ, Grad Sch Med, Div Mol Anal Human Disorders, Dept Bio Signal Anal, Ube, Yamaguchi 7558505, Japan
[2] Yamaguchi Univ, Grad Sch Med, Div Neuroanat, Dept Neurosci, Ube, Yamaguchi 7558505, Japan
[3] Yamaguchi Univ, Hlth Serv Ctr, Org Univ Educ, Ube, Yamaguchi 7558505, Japan
[4] Kyoto Univ, Grad Sch Med, Dept Hlth & Environm Sci, Kyoto, Japan
[5] Tohoku Univ, Grad Sch Med, Dept Internal Med, Div Mol Metab & Diabet, Sendai, Miyagi 980, Japan
关键词
D O I
10.1530/eje.1.01945
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
Objective: The WFS1 gene encodes an endoplasmic reticulum (ER) membrane-embedded protein. Homozygous WFS1 gene mutations cause Wolfram syndrome, characterized by insulin-deficient diabetes mellitus and optic atropy. Pancreatic beta-cells are selectively lost from the patient's islets. ER localization suggests that WFS1 protein has physiological functions in membrane trafficking, secretion, processing and/or regulation of ER calcium homeostasis. Disturbances or overloading of these functions induces ER stress responses, including apoptosis. We speculated that WFS1 protein might be involved in these ER stress responses. Design and methods: Islet expression of the Wfs1 protein was analyzed immunohistochemically. Induction of Wfs1 upon ER stress was examined by Northern and Western blot analyses using three different models: human skin fibroblasts, mouse pancreatic beta-cell-derived MIN6 cells, and Akita mouse-derived Ins2(96Y/Y) insulinoma cells. The human WFS I gene promoter-luciferase reporter analysis was also conducted. Result: Islet beta-cells were the major site of Wfs1 expression. This expression was also found in delta-cells, but not in alpha-cells. WFS1 expression was transcriptionally up-regulated by ER stress-inducing chemical insults. Treatment of fibroblasts and MlN6 cells with thapsigargin or tunicamycin increased WFS1 mRNA. WFS1 protein also increased in response to thapsigargin treatment in these cells. WFS1 gene expression was also increased in Ins2(96Y/Y) insulinoma cells. In these cells, ER stress was intrinsically induced by mutant insulin expression. The WFS1 gene promoter-luciferase reporter system revealed that the human WFS1 promoter was activated by chemically induced ER stress in MIN6 cells, and that the promoter was more active in Ins2(96Y/Y) cells than Ins2(wild/wild) cells. Conclusion: Wfs1 expression, which is localized to beta- and delta-cells in pancreatic islets, increases in response to ER stress, suggesting a functional link between Wfs1 and ER stress.
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收藏
页码:167 / 176
页数:10
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