{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,27]],"date-time":"2026-09-27T04:11:09Z","timestamp":1790482269934,"version":"4.1.0"},"reference-count":48,"publisher":"MDPI AG","issue":"21","license":[{"start":{"date-parts":[[2022,11,5]],"date-time":"2022-11-05T00:00:00Z","timestamp":1667606400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Takeda Science foundation and Banyu Life Science foundation","award":["25461357"],"award-info":[{"award-number":["25461357"]}]},{"name":"Takeda Science foundation and Banyu Life Science foundation","award":["16K09752"],"award-info":[{"award-number":["16K09752"]}]},{"name":"Takeda Science foundation and Banyu Life Science foundation","award":["19H03710"],"award-info":[{"award-number":["19H03710"]}]},{"name":"Takeda Science foundation and Banyu Life Science foundation","award":["20K08887"],"award-info":[{"award-number":["20K08887"]}]},{"name":"Takeda Science foundation and Banyu Life Science foundation","award":["19H03710"],"award-info":[{"award-number":["19H03710"]}]},{"name":"Takeda Science foundation and Banyu Life Science foundation","award":["25461357"],"award-info":[{"award-number":["25461357"]}]},{"name":"Takeda Science foundation and Banyu Life Science foundation","award":["16K09752"],"award-info":[{"award-number":["16K09752"]}]},{"name":"Takeda Science foundation and Banyu Life Science foundation","award":["19H03710"],"award-info":[{"award-number":["19H03710"]}]},{"name":"Takeda Science foundation and Banyu Life Science foundation","award":["20K08887"],"award-info":[{"award-number":["20K08887"]}]},{"name":"Takeda Science foundation and Banyu Life Science foundation","award":["19H03710"],"award-info":[{"award-number":["19H03710"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Endoplasmic reticulum (ER) stress is a key pathogenic factor in type 1 and 2 diabetes. Glycogen synthase kinase 3 (Gsk-3) contributes to \u03b2-cell loss in mice. However, the mechanism by which Gsk-3 leads \u03b2-cell death remains unclear. ER stress was pharmacologically induced in mouse primary islets and insulinoma cells. We used insulinoma cells derived from Akita mice as a model of genetic ER stress. Gsk-3 activity was blocked by treating with Gsk-3 inhibitors or by introducing catalytically inactive Gsk-3\u03b2. Gsk-3 inhibition prevented proteasomal degradation of activating transcriptional factor 4 (ATF4) and alleviated apoptosis. We found that ATF4-S214 was phosphorylated by Gsk-3, and that this was required for a binding of ATF4 with \u03b2TrCP, which mediates polyubiquitination. The anti-apoptotic effect of Gsk-3 inhibition was attenuated by introducing DN-ATF4 or by knockdown of ATF4. Mechanistically, Gsk-3 inhibition modulated transcription targets of ATF4 and in turn facilitated dephosphorylation of eIF2\u03b1, altering the protein translational dynamism under ER stress. These observations were reproduced in the Akita mouse-derived cells. Thus, these results reveal the role of Gsk-3 in the regulation of the integrated stress response, and provide a rationale for inhibiting this enzyme to prevent \u03b2-cell death under ER stress conditions.<\/jats:p>","DOI":"10.3390\/ijms232113586","type":"journal-article","created":{"date-parts":[[2022,11,8]],"date-time":"2022-11-08T11:56:36Z","timestamp":1667908596000},"page":"13586","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":13,"title":["Gsk-3-Mediated Proteasomal Degradation of ATF4 Is a Proapoptotic Mechanism in Mouse Pancreatic \u03b2-Cells"],"prefix":"10.3390","volume":"23","author":[{"given":"Yuko","family":"Nagao","sequence":"first","affiliation":[{"name":"Division of Endocrinology, Metabolism, Haematological Sciences and Therapeutics, Graduate School of Medicine, Yamaguchi University, Ube 755-8505, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kikuko","family":"Amo-Shiinoki","sequence":"additional","affiliation":[{"name":"Division of Endocrinology, Metabolism, Haematological Sciences and Therapeutics, Graduate School of Medicine, Yamaguchi University, Ube 755-8505, Japan"},{"name":"Department of Diabetes Research, School of Medicine, Yamaguchi University, Ube 755-8505, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hiroko","family":"Nakabayashi","sequence":"additional","affiliation":[{"name":"Division of Endocrinology, Metabolism, Haematological Sciences and Therapeutics, Graduate School of Medicine, Yamaguchi University, Ube 755-8505, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Masayuki","family":"Hatanaka","sequence":"additional","affiliation":[{"name":"Division of Endocrinology, Metabolism, Haematological Sciences and Therapeutics, Graduate School of Medicine, Yamaguchi University, Ube 755-8505, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Manabu","family":"Kondo","sequence":"additional","affiliation":[{"name":"Division of Endocrinology, Metabolism, Haematological Sciences and Therapeutics, Graduate School of Medicine, Yamaguchi University, Ube 755-8505, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kimie","family":"Matsunaga","sequence":"additional","affiliation":[{"name":"Division of Endocrinology, Metabolism, Haematological Sciences and Therapeutics, Graduate School of Medicine, Yamaguchi University, Ube 755-8505, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Masahiro","family":"Emoto","sequence":"additional","affiliation":[{"name":"Division of Endocrinology, Metabolism, Haematological Sciences and Therapeutics, Graduate School of Medicine, Yamaguchi University, Ube 755-8505, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shigeru","family":"Okuya","sequence":"additional","affiliation":[{"name":"Health Administration Centre, Organisation for University Education, Yamaguchi University, Yamaguchi 753-8511, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yukio","family":"Tanizawa","sequence":"additional","affiliation":[{"name":"Division of Endocrinology, Metabolism, Haematological Sciences and Therapeutics, Graduate School of Medicine, Yamaguchi University, Ube 755-8505, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9802-0584","authenticated-orcid":false,"given":"Katsuya","family":"Tanabe","sequence":"additional","affiliation":[{"name":"Division of Endocrinology, Metabolism, Haematological Sciences and Therapeutics, Graduate School of Medicine, Yamaguchi University, Ube 755-8505, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,11,5]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"92","DOI":"10.1111\/nyas.12031","article-title":"Islet \u03b2 cell mass in diabetes and how it relates to function, birth, and death","volume":"1281","author":"Weir","year":"2013","journal-title":"Ann. 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