The unfolded protein response is required to maintain the integrity of the endoplasmic reticulum, prevent oxidative stress and preserve differentiation in β -cells
dc.contributor.author | Kaufman, R. J. | en_US |
dc.contributor.author | Back, S. H. | en_US |
dc.contributor.author | Song, B. | en_US |
dc.contributor.author | Han, J. | en_US |
dc.contributor.author | Hassler, J. | en_US |
dc.date.accessioned | 2011-01-31T18:01:19Z | |
dc.date.available | 2011-12-02T15:41:52Z | en_US |
dc.date.issued | 2010-10 | en_US |
dc.identifier.citation | Kaufman, R. J.; Back, S. H.; Song, B.; Han, J.; Hassler, J.; (2010). "The unfolded protein response is required to maintain the integrity of the endoplasmic reticulum, prevent oxidative stress and preserve differentiation in β -cells." Diabetes, Obesity and Metabolism 12(s2 The Stressed Beta-Cell: Proceedings of the 11th Servier-IGIS Symposium, St Jean Cap Ferrat, France, 25-28 March 2010 ): 99-107. <http://hdl.handle.net/2027.42/79390> | en_US |
dc.identifier.issn | 1462-8902 | en_US |
dc.identifier.issn | 1463-1326 | en_US |
dc.identifier.uri | https://hdl.handle.net/2027.42/79390 | |
dc.description.abstract | Diabetes is an epidemic of worldwide proportions caused by β -cell failure. Nutrient fluctuations and insulin resistance drive β -cells to synthesize insulin beyond their capacity for protein folding and secretion and thereby activate the unfolded protein response (UPR), an adaptive signalling pathway to promote cell survival upon accumulation of unfolded protein in the endoplasmic reticulum (ER). Protein kinase-like endoplasmic reticulum kinase (PERK) signals one component of the UPR through phosphorylation of eukaryotic initiation factor 2 on the α -subunit (eIF2 α ) to attenuate protein synthesis, thereby reducing the biosynthetic burden. β -Cells uniquely require PERK-mediated phosphorylation of eIF2 α to preserve cell function. Unabated protein synthesis in β -cells is sufficient to initiate a cascade of events, including oxidative stress, that are characteristic of β -cell failure observed in type 2 diabetes. In contrast to acute adaptive UPR activation, chronic activation increases expression of the proapoptotic transcription factor CAAT/enhancer-binding protein homologous protein (CHOP). Chop deletion in insulin-resistant mice profoundly increases β -cell mass and prevents β -cell failure to forestall the progression of diabetes. The findings suggest an unprecedented link by which protein synthesis and/or misfolding in the ER causes oxidative stress and should encourage the development of novel strategies to treat diabetes. | en_US |
dc.format.extent | 726953 bytes | |
dc.format.extent | 3106 bytes | |
dc.format.mimetype | application/pdf | |
dc.format.mimetype | text/plain | |
dc.publisher | Blackwell Publishing Ltd | en_US |
dc.subject.other | Antioxidant | en_US |
dc.subject.other | Apoptosis | en_US |
dc.subject.other | CHOP | en_US |
dc.subject.other | Eukaryotic Initiation Factor 2 | en_US |
dc.subject.other | Mitochondria | en_US |
dc.subject.other | PERK | en_US |
dc.subject.other | Protein Folding | en_US |
dc.subject.other | Translation | en_US |
dc.title | The unfolded protein response is required to maintain the integrity of the endoplasmic reticulum, prevent oxidative stress and preserve differentiation in β -cells | en_US |
dc.type | Article | en_US |
dc.rights.robots | IndexNoFollow | en_US |
dc.subject.hlbsecondlevel | Public Health (General) | en_US |
dc.subject.hlbtoplevel | Health Sciences | en_US |
dc.description.peerreviewed | Peer Reviewed | en_US |
dc.contributor.affiliationum | Howard Hughes Medical Institute, University of Michigan Medical Center, Ann Arbor, MI, USA | en_US |
dc.contributor.affiliationum | Department of Biological Chemistry, University of Michigan Medical Center, Ann Arbor, MI, USA | en_US |
dc.contributor.affiliationum | Department of Internal Medicine, University of Michigan Medical Center, Ann Arbor, MI, USA | en_US |
dc.identifier.pmid | 21029306 | en_US |
dc.description.bitstreamurl | http://deepblue.lib.umich.edu/bitstream/2027.42/79390/1/j.1463-1326.2010.01281.x.pdf | |
dc.identifier.doi | 10.1111/j.1463-1326.2010.01281.x | en_US |
dc.identifier.source | Diabetes, Obesity and Metabolism | en_US |
dc.owningcollname | Interdisciplinary and Peer-Reviewed |
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