The DOI matches its Crossref record; 56 of the 56 references it cites were found in a registry or an index.
Translation Attenuation through eIF2α Phosphorylation Prevents Oxidative Stress and Maintains the Differentiated State in β Cells
Open accessAbstract
SUMMARY Accumulation of unfolded protein within the endoplasmic reticulum (ER) lumen attenuates mRNA translation through activation of the protein kinase PERK and subsequent phosphorylation of eukaryotic initiation factor 2 on Ser51 of the alpha subunit (eIF2α). Genetic disruption of the PERK/eIF2α pathway in humans and mice produces severe pancreatic beta cell deficiency and post-natal lethality. To elucidate the role of eIF2α phosphorylation in beta cells, we have rescued the lethality of homozygous eIF2α Ser51Ala mice by expression of a loxP-flanked wild-type eIF2α transgene. Beta cell-specific transgene deletion to prevent eIF2α phosphorylation caused a severe diabetic phenotype due to heightened, unregulated proinsulin translation, defective intracellular trafficking of secretory and plasma membrane proteins, increased oxidative damage, reduced expression of stress response and beta cell-specific genes, and apoptosis. However, glucose intolerance and beta cell death in these mice were attenuated by antioxidant treatment. We conclude that phosphorylation of eIF2α coordinately attenuates mRNA translation, prevents oxidative stress, and optimizes ER protein folding to support insulin production in the beta cell. These findings that show increased proinsulin synthesis causes oxidative stress leading to beta cell failure may reflect events in the beta cell loss associated with insulin resistance in type 2 diabetes.
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Cites
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Cited by
Endoplasmic reticulum stress and the inflammatory basis of metabolic disease
Hotamisligil, G. S. (2010) · Cell · doi:10.1016/j.cell.2010.02.034 · Cited by 2,802
The integrated stress response
Pakos‐Zebrucka, K., Koryga, I., Mnich, K., Ljujic, M., Samali, A., & Gorman, A. M. (2016) · The EMBO Reports · doi:10.15252/embr.201642195 · Cited by 2,659
Mechanisms, regulation and functions of the unfolded protein response
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Self-citationER stress-induced cell death mechanisms
Sano, R., & Reed, J. C. (2013) · Biochimica et Biophysica Acta (BBA) - Molecular Cell Research · doi:10.1016/j.bbamcr.2013.06.028 · Cited by 1,988
ER-stress-induced transcriptional regulation increases protein synthesis leading to cell death
Han, J., Back, S. H., Hur, J., Lin, Y.-H., Gildersleeve, R., Shan, J., Yuan, C. L., Krokowski, D., Wang, S., Hatzoglou, M., et al. (2013) · Nature Cell Biology · doi:10.1038/ncb2738 · Cited by 1,691
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Metadata
- Authors
- Back, S. H., Scheuner, D., Han, J., Song, B., Ribick, M., Wang, J., Gildersleeve, R. D., Pennathur, S., & Kaufman, R. J.
- Venue
- Cell Metabolism
- Publisher
- Elsevier BV
- Published
- 2009-07
- Volume
- 10
- Issue
- 1
- Pages
- 13-26
- ISSN
- 1550-4131 (ISSN-L)
- OpenAlex
- W2034567067
- Cited by
- 366
- References
- 56
- FWCI
- 10.52
- Type
- journal article
- Language
- en
- Open access
- bronze
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- Back, S. H., Scheuner, D., Han, J., Song, B., Ribick, M., Wang, J., Gildersleeve, R. D., Pennathur, S., & Kaufman, R. J. (2009). Translation Attenuation through eIF2α Phosphorylation Prevents Oxidative Stress and Maintains the Differentiated State in β Cells. Cell Metabolism. https://doi.org/10.1016/j.cmet.2009.06.002
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