WFS1-deficiency increases endoplasmic reticulum stress, impairs cell cycle progression and triggers the apoptotic pathway specifically in pancreatic β-cells

Takahiro Yamada, Hisamitsu Ishihara, Akira Tamura, Rui Takahashi, Suguru Yamaguchi, Daisuke Takei, Ai Tokita, Chihiro Satake, Fumi Tashiro, Hideki Katagiri, Hiroyuki Aburatani, Jun Ichi Miyazaki, Yoshitomo Oka

Research output: Contribution to journalArticlepeer-review

163 Citations (Scopus)

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 phosphorylation of RNA-dependent protein kinase-like ER kinase, 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 the ER stress response. In contrast, these changes are not observed in heart, skeletal muscle or brown adipose tissues with WFS1-deficiency. The increased ER stress response was accompanied by reduced BrdU incorporation and increased caspase-3 cleavage, indicating impaired cell cycle progression and accelerated apoptotic processes in the mutant islets. These changes are associated with increased expression of the cell cycle regulator p21CIP1 in wfs1-deficient islets and clonal β-cells. Treatment of islets with thapsigargin, an ER stress inducer, caused upregulation of p21CIP1. In addition, forced expression of p21CIP1 resulted in reduced MIN6 β-cell numbers, suggesting the ER stress-induced increase in p21CIP1 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 impaired cell cycle progression and increased apoptosis.

Original languageEnglish
Pages (from-to)1600-1609
Number of pages10
JournalHuman molecular genetics
Volume15
Issue number10
DOIs
Publication statusPublished - 2006 May 15

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Genetics(clinical)

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