| Inhibition of deoxyhypusine synthase enhances islet {beta} cell function and survival in the setting of endoplasmic reticulum stress and type 2 diabetes. | |
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MedLine Citation:
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PMID: 20956533 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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Islet β cell dysfunction resulting from inflammation, ER stress, and oxidative stress is a key determinant in the progression from insulin resistance to type 2 diabetes mellitus. It was recently shown that the enzyme deoxyhypusine synthase (DHS) promotes early cytokine-induced inflammation in the β cell. DHS catalyzes the conversion of lysine to hypusine, an amino acid that is unique to the translational elongation factor eIF5A. Here, we sought to determine whether DHS activity contributes to β cell dysfunction in models of type 2 diabetes in mice and β cell lines. A 2-week treatment of obese diabetic C57BLKS/J-db/db mice with the DHS inhibitor GC7 resulted in improved glucose tolerance, increased insulin release, and enhanced β cell mass. Thapsigargin treatment of β cells in vitro induces a picture of ER stress and apoptosis similar to that seen in db/db mice; in this setting, DHS inhibition led to a block in CHOP (CAAT/enhancer binding protein homologous protein) production despite >30-fold activation of Chop gene transcription. Blockage of CHOP translation resulted in reduction of downstream caspase-3 cleavage and near-complete protection of cells from apoptotic death. DHS inhibition appeared to prevent the cytoplasmic co-localization of eIF5A with the ER, possibly precluding the participation of eIF5A in translational elongation at ER-based ribosomes. We conclude that hypusination by DHS is required for the ongoing production of proteins, particularly CHOP, in response to ER stress in the β cell. |
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Authors:
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Reiesha D Robbins; Sarah A Tersey; Takeshi Ogihara; Dhananjay Gupta; Thomas B Farb; James Ficorilli; Krister Bokvist; Bernhard Maier; Raghavendra G Mirmira |
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Publication Detail:
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Type: Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't Date: 2010-10-18 |
Journal Detail:
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Title: The Journal of biological chemistry Volume: 285 ISSN: 1083-351X ISO Abbreviation: J. Biol. Chem. Publication Date: 2010 Dec |
Date Detail:
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Created Date: 2010-12-14 Completed Date: 2011-01-11 Revised Date: 2011-12-19 |
Medline Journal Info:
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Nlm Unique ID: 2985121R Medline TA: J Biol Chem Country: United States |
Other Details:
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Languages: eng Pagination: 39943-52 Citation Subset: IM |
Affiliation:
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Department of Pharmacology, University of Virginia, Charlottesville, Virginia 22904, USA. |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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Animals Apoptosis* Caspase 3 / genetics, metabolism Cell Survival / genetics Diabetes Mellitus, Type 2 / enzymology*, genetics, pathology Endoplasmic Reticulum / genetics, metabolism*, pathology Enzyme Inhibitors / pharmacology Insulin-Secreting Cells / enzymology*, pathology Mice Mice, Mutant Strains Oxidoreductases Acting on CH-NH Group Donors / genetics, metabolism* Peptide Chain Elongation, Translational / drug effects, genetics Peptide Initiation Factors / genetics, metabolism RNA-Binding Proteins / genetics, metabolism Thapsigargin / pharmacology Transcription Factor CHOP / biosynthesis, genetics Unfolded Protein Response* |
| Grant Support | |
ID/Acronym/Agency:
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F31 DK079420/DK/NIDDK NIH HHS; R01 DK60581/DK/NIDDK NIH HHS |
| Chemical | |
Reg. No./Substance:
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0/Ddit3 protein, mouse; 0/Enzyme Inhibitors; 0/Peptide Initiation Factors; 0/RNA-Binding Proteins; 0/eukaryotic translation initiation factor 5A; 147336-12-7/Transcription Factor CHOP; 67526-95-8/Thapsigargin; EC 1.5.-/Oxidoreductases Acting on CH-NH Group Donors; EC 1.5.1.-/deoxyhypusine synthase; EC 3.4.22.-/Casp3 protein, mouse; EC 3.4.22.-/Caspase 3 |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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