| Budget Amount *help |
¥15,000,000 (Direct Cost: ¥15,000,000)
Fiscal Year 2006: ¥6,700,000 (Direct Cost: ¥6,700,000)
Fiscal Year 2005: ¥8,300,000 (Direct Cost: ¥8,300,000)
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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. Herein, we 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 wfs1-deficient MIN6 clonal (β-cells by crossing wfs1-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 wfs1-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 WFS 1-deficiency. The enhanced ER stress results in increased caspase 3 cleavage and reduced BrdU incorporation in the mutant islets, indicating accelerated apoptotic processes and impaired cell cycle progression in the mutant islets. These changes are associated with increased expression of p21^<CIP1> in wfs1-deficient islets and clonal β-cells. Treatment of islets with thapsigargin, an ER stress inducer, caused upregulation of p21^<CIP1>, and forced expression of p21^<CIP1> resulted in reduction in 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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