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¹ Department of Molecular and Cellular Biology, Institute for Frontier Medical Sciences, Kyoto University, Kyoto 606-8397, Japan
² Department of Biophysics, Graduate School of Science, Kyoto University, Kyoto 606-8502, Japan
³ Department of Health and Environmental Sciences, Graduate School of Medicine and Faculty of Medicine, Kyoto University, Kyoto 606-8501, Japan
⁴ Department of Public health, Hyogo College of Medicine, Hyogo 663-8501, Japan
⁵ CREST, Japan Science and Technology Agency, Kawaguchi, Japan
⁶ PREST, Japan Science and Technology Agency, Kawaguchi, Japan

The dominant C96Y mutation of one of the two murine insulin genes, Ins2, causes diabetes mellitus in ‘Akita’ mice. Here we established pancreatic islet ß cell lines from heterozygous mice (Ins2^+/Akita). Western blot analysis of endoplasmic reticulum (ER) molecular chaperones indicated that Grp78, Grp94 and Orp150 are significantly increased in Ins2^+/Akita cells compared with wild-type (Ins2^+/+) cells. Reporter gene assays using the human GRP78 promoter with or without the ER stress response element (ERSE) showed that Ins2^+/Akita cells exhibit significantly stronger ERSE-dependent transcriptional activity than Ins2^+/+ cells. Transient over-expression of the Ins2 C96Y mutant in wild-type ß cells induces a stronger ERSE-dependent stress response than does wild-type Ins2 over-expression. The ERSE-binding transcription factor ATF6 is strongly activated in Ins2^+/Akita cells. The activity of a reporter containing the specific binding sequence of another ERSE-binding transcription factor, XBP1, is also enhanced in Ins2^+/Akita cells. Levels of active forms of XBP1 mRNA and protein are both markedly elevated in Ins2^+/Akita cells. These results indicate that this cell line is subject to continuous ER stress and that the Ins2 C96Y mutation induces the expression of ER chaperones through the activation of ATF6 and XBP1.

^* Correspondence: E-mail: nagata{at}frontier.kyoto-u.ac.jp

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