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EXPERIMENTAL STUDY |
1 Health Service Center, Organization for University Education, Yamaguchi University, 2 Division of Neuroanatomy, Department of Neuroscience, and 3 Division of Molecular Analysis of Human Disorders, Department of Bio-Signal Analysis, Yamaguchi University Graduate School of Medicine, 1-1-1 Minami Kogushi, Ube, Yamaguchi 755-8505, Japan, 4 Department of Health and Environmental Sciences, Kyoto University Graduate School of Medicine, Kyoto, Japan, and 5 Division of Molecular Metabolism and Diabetes, Department of Internal Medicine, Tohoku University Graduate School of Medicine, Sendai, Japan
(Correspondence should be addressed to Y Tanizawa; Email: tanizawa{at}yamaguchi-u.ac.jp)
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 ß-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 ß-cell-derived MIN6 cells, and Akita mouse-derived Ins2 96Y/Y insulinoma cells. The human WFS1 gene promoter-luciferase reporter analysis was also conducted.
Result: Islet ß-cells were the major site of Wfs1 expression. This expression was also found in 
-cells, but not in 
-cells. WFS1 expression was transcriptionally up-regulated by ER stress-inducing chemical insults. Treatment of fibroblasts and MIN6 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 ß- and -cells in pancreatic islets, increases in response to ER stress, suggesting a functional link between Wfs1 and ER stress.
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T. Yamada, H. Ishihara, A. Tamura, R. Takahashi, S. Yamaguchi, D. Takei, A. Tokita, C. Satake, F. Tashiro, H. Katagiri, et al. WFS1-deficiency increases endoplasmic reticulum stress, impairs cell cycle progression and triggers the apoptotic pathway specifically in pancreatic {beta}-cells Hum. Mol. Genet., May 15, 2006; 15(10): 1600 - 1609. [Abstract] [Full Text] [PDF]
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