2005 Fiscal Year Final Research Report Summary
Elucidation of diabetes-related genes
| Project/Area Number |
13204062
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| Research Category |
Grant-in-Aid for Scientific Research on Priority Areas
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| Allocation Type | Single-year Grants |
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| Review Section |
Biological Sciences
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| Research Institution | Tohoku University |
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Principal Investigator |
OKA Yoshitomo Tohoku University Graduate School of Medicine, Division of Molecular Metabolism and Diabetes, Professor, 大学院医学系研究科, 教授 (70175256)
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| Co-Investigator(Kenkyū-buntansha) |
KATAGIRI Hideki Tohoku University Graduate School of Medicine, Division of Advanced Therapeutics for Metabolic Diseases, Professor, 大学院医学系研究科, 教授 (00344664)
HINOKIO Yoshinori Tohoku University Hospital, Division of Molecular Diabetes and Metabolism, Lecture, 病院・講師 (10282071)
ISHIHARA Hisamitsu Tohoku University Hospital, Division of Molecular Diabetes and Metabolism, Research Associate, 病院・助手 (60361086)
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| Project Period (FY) |
2001 – 2005
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| Keywords | Diabetes / Insulin secretion / pancreatic B cell / Wolfram syndrome / Endoplasmic reticulum stress / cell cycle |
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| Research Abstract |
Wolfram syndrome, an autosomal recessive disorder associated with diabetes mellitus and optic atrophy is caused by mutations in the WFS1 gene encoding an endoplasmic reticulum (ER) membrane protein. We herein report that pancreatic islets of wfs1-deficient mice exhibit increases in PKR-like ER kinase phosphorylation, chaperone gene expressions and active XBP1 protein levels, indicating an enhanced ER stress response. We established wfsl-deficient MIN6 clonal β-cells by crossing wfsl-deficient mice with mice expressing simian virus 40 large T antigen in β-cells. These cells show essentially the same alterations in ER stress responses as wfsl-deficient islets, which were reversed by re-expression of WFS1 protein or overexpression of GRP78, a master regulator of ER stress. In contrast, these changes are observed neither in heart, skeletal muscle, nor brown adipose tissues with WFS1-deficiency. The enhanced ER stress results in increased caspase 3 cleavage and reduced BrdU incorporation, indicating accelerated apoptotic processes and impaired cell cycle progression in the mutant islets. These changes are associated with increased expression of p21^<CIP1> in wfsl-deficient islets and clonal β-cells. Treatment of islets with thapsigargin, an ER stress inducer increased p21^<CIP1> expression, and forced expression of p21^<CIP1> reduced MIN6 β-cell numbers, suggesting that the ER stress-induced increase in p21^<CIP1> expression to be involved in β-cell loss in the mutant islets. These data indicate that WFS1-deficiency activates the ER stress response specifically in β-cells, causing β-cell loss through increased apoptosis and impaired cell cycle progression.
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