| Wolfram syndrome 1 gene negatively regulates ER stress signaling in rodent and human cells. | |
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MedLine Citation:
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PMID: 20160352 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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Wolfram syndrome is an autosomal-recessive disorder characterized by insulin-dependent diabetes mellitus, caused by nonautoimmune loss of beta cells, and neurological dysfunctions. We have previously shown that mutations in the Wolfram syndrome 1 (WFS1) gene cause Wolfram syndrome and that WFS1 has a protective function against ER stress. However, it remained to be determined how WFS1 mitigates ER stress. Here we have shown in rodent and human cell lines that WFS1 negatively regulates a key transcription factor involved in ER stress signaling, activating transcription factor 6alpha (ATF6alpha), through the ubiquitin-proteasome pathway. WFS1 suppressed expression of ATF6alpha target genes and repressed ATF6alpha-mediated activation of the ER stress response element (ERSE) promoter. Moreover, WFS1 stabilized the E3 ubiquitin ligase HRD1, brought ATF6alpha to the proteasome, and enhanced its ubiquitination and proteasome-mediated degradation, leading to suppression of ER stress signaling. Consistent with these data, beta cells from WFS1-deficient mice and lymphocytes from patients with Wolfram syndrome exhibited dysregulated ER stress signaling through upregulation of ATF6alpha and downregulation of HRD1. These results reveal a role for WFS1 in the negative regulation of ER stress signaling and in the pathogenesis of diseases involving chronic, unresolvable ER stress, such as pancreatic beta cell death in diabetes. |
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Authors:
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Sonya G Fonseca; Shinsuke Ishigaki; Christine M Oslowski; Simin Lu; Kathryn L Lipson; Rajarshi Ghosh; Emiko Hayashi; Hisamitsu Ishihara; Yoshitomo Oka; M Alan Permutt; Fumihiko Urano |
Publication Detail:
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Type: Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't Date: 2010-02-15 |
Journal Detail:
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Title: The Journal of clinical investigation Volume: 120 ISSN: 1558-8238 ISO Abbreviation: J. Clin. Invest. Publication Date: 2010 Mar |
Date Detail:
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Created Date: 2010-03-04 Completed Date: 2010-03-31 Revised Date: 2012-04-25 |
Medline Journal Info:
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Nlm Unique ID: 7802877 Medline TA: J Clin Invest Country: United States |
Other Details:
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Languages: eng Pagination: 744-55 Citation Subset: AIM; IM |
Affiliation:
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Program in Gene Function and Expression, University of Massachusetts Medical School, Worcester, MA 01605-2324, USA. |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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Activating Transcription Factor 6
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genetics,
metabolism Animals COS Cells Calmodulin-Binding Proteins / genetics, metabolism* Cell Line, Tumor Cercopithecus aethiops Endoplasmic Reticulum / genetics, metabolism, pathology Gene Expression Regulation / genetics Humans Insulin-Secreting Cells / metabolism*, pathology Membrane Proteins / genetics, metabolism* Mice Proteasome Endopeptidase Complex / genetics, metabolism Rats Signal Transduction* Trans-Activators / genetics, metabolism Ubiquitin / genetics, metabolism Ubiquitin-Protein Ligases / genetics, metabolism Ubiquitination / genetics Unfolded Protein Response* Wolfram Syndrome / genetics, metabolism*, pathology |
| Grant Support | |
ID/Acronym/Agency:
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5 P30 DK32520/DK/NIDDK NIH HHS; R01 DK067493/DK/NIDDK NIH HHS; R01 DK067493/DK/NIDDK NIH HHS; R01 DK067493-07/DK/NIDDK NIH HHS; R01 DK067493-08/DK/NIDDK NIH HHS |
| Chemical | |
Reg. No./Substance:
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0/ATF6 protein, human; 0/Activating Transcription Factor 6; 0/Atf6 protein, mouse; 0/Calmodulin-Binding Proteins; 0/Membrane Proteins; 0/Trans-Activators; 0/Ubiquitin; 0/WFS1 protein, rat; 0/wolframin protein; EC 3.4.25.1/Proteasome Endopeptidase Complex; EC 6.3.2.-/HRD1 protein, mouse; EC 6.3.2.19/SYVN1 protein, human; EC 6.3.2.19/Ubiquitin-Protein Ligases; EC 6.3.2.19/synoviolin protein, rat |
| Comments/Corrections | |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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