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Selective inhibition of eukaryotic translation initiation factor 2 alpha dephosphorylation potentiates fatty acid-induced endoplasmic reticulum stress and causes pancreatic beta-cell dysfunction and apoptosis

(2007) JOURNAL OF BIOLOGICAL CHEMISTRY. 282(6). p.3989-3997
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Abstract
Free fatty acids cause pancreatic beta-cell apoptosis and may contribute to beta-cell loss in type 2 diabetes via the induction of endoplasmic reticulum stress. Reductions in eukaryotic translation initiation factor (eIF) 2 alpha phosphorylation trigger P-cell failure and diabetes. Salubrinal selectively inhibits eIF2 alpha dephosphorylation, protects other cells against endoplasmic reticulum stress-mediated apoptosis, and has been proposed as a beta-cell protector. Unexpectedly, salubrinal induced apoptosis in primary beta-cells, and it potentiated the deleterious effects of oleate and palmitate. Salubrinal induced a marked eIF2 alpha phosphorylation and potentiated the inhibitory effects of free fatty acids on protein synthesis and insulin release. The synergistic activation of the PERK-eIF2 alpha branch of the endoplasmic reticulum stress response, but not of the IRE1 and activating transcription factor-6 pathways, led to a marked induction of activating transcription factor-4 and the pro-apoptotic transcription factor CHOP. Our findings demonstrate that excessive eIF2 alpha phosphorylation is poorly tolerated by beta-cells and exacerbates free fatty acid-induced apoptosis. This modifies the present paradigm regarding the beneficial role of eIF2 alpha phosphorylation in beta-cells and must be taken into consideration when designing therapies to protect beta-cells in type 2 diabetes.
Keywords
WOLCOTT-RALLISON-SYNDROME, MESSENGER-RNA, MONOCYTE CHEMOATTRACTANT PROTEIN-1, FACTOR-KAPPA-B, UNFOLDED PROTEIN RESPONSE, INSULIN-PRODUCING CELLS, ER STRESS, GLUCOSE-HOMEOSTASIS, PROMOTES SURVIVAL, ISLET CELLS

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Citation

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MLA
Cnop, Miriam et al. “Selective Inhibition of Eukaryotic Translation Initiation Factor 2 Alpha Dephosphorylation Potentiates Fatty Acid-induced Endoplasmic Reticulum Stress and Causes Pancreatic Beta-cell Dysfunction and Apoptosis.” JOURNAL OF BIOLOGICAL CHEMISTRY 282.6 (2007): 3989–3997. Print.
APA
Cnop, M., Ladrière, L., Hekerman, P., Ortis, F., Cardozo, A. K., Dogusan, Z., Flamez, D., et al. (2007). Selective inhibition of eukaryotic translation initiation factor 2 alpha dephosphorylation potentiates fatty acid-induced endoplasmic reticulum stress and causes pancreatic beta-cell dysfunction and apoptosis. JOURNAL OF BIOLOGICAL CHEMISTRY, 282(6), 3989–3997.
Chicago author-date
Cnop, Miriam, Laurence Ladrière, Paul Hekerman, Fernanda Ortis, Alessandra K Cardozo, Zeynep Dogusan, Daisy Flamez, Michael Boyce, Jun-Ying Yuan, and Décio L Eizirik. 2007. “Selective Inhibition of Eukaryotic Translation Initiation Factor 2 Alpha Dephosphorylation Potentiates Fatty Acid-induced Endoplasmic Reticulum Stress and Causes Pancreatic Beta-cell Dysfunction and Apoptosis.” Journal of Biological Chemistry 282 (6): 3989–3997.
Chicago author-date (all authors)
Cnop, Miriam, Laurence Ladrière, Paul Hekerman, Fernanda Ortis, Alessandra K Cardozo, Zeynep Dogusan, Daisy Flamez, Michael Boyce, Jun-Ying Yuan, and Décio L Eizirik. 2007. “Selective Inhibition of Eukaryotic Translation Initiation Factor 2 Alpha Dephosphorylation Potentiates Fatty Acid-induced Endoplasmic Reticulum Stress and Causes Pancreatic Beta-cell Dysfunction and Apoptosis.” Journal of Biological Chemistry 282 (6): 3989–3997.
Vancouver
1.
Cnop M, Ladrière L, Hekerman P, Ortis F, Cardozo AK, Dogusan Z, et al. Selective inhibition of eukaryotic translation initiation factor 2 alpha dephosphorylation potentiates fatty acid-induced endoplasmic reticulum stress and causes pancreatic beta-cell dysfunction and apoptosis. JOURNAL OF BIOLOGICAL CHEMISTRY. 2007;282(6):3989–97.
IEEE
[1]
M. Cnop et al., “Selective inhibition of eukaryotic translation initiation factor 2 alpha dephosphorylation potentiates fatty acid-induced endoplasmic reticulum stress and causes pancreatic beta-cell dysfunction and apoptosis,” JOURNAL OF BIOLOGICAL CHEMISTRY, vol. 282, no. 6, pp. 3989–3997, 2007.
@article{847079,
  abstract     = {Free fatty acids cause pancreatic beta-cell apoptosis and may contribute to beta-cell loss in type 2 diabetes via the induction of endoplasmic reticulum stress. Reductions in eukaryotic translation initiation factor (eIF) 2 alpha phosphorylation trigger P-cell failure and diabetes. Salubrinal selectively inhibits eIF2 alpha dephosphorylation, protects other cells against endoplasmic reticulum stress-mediated apoptosis, and has been proposed as a beta-cell protector. Unexpectedly, salubrinal induced apoptosis in primary beta-cells, and it potentiated the deleterious effects of oleate and palmitate. Salubrinal induced a marked eIF2 alpha phosphorylation and potentiated the inhibitory effects of free fatty acids on protein synthesis and insulin release. The synergistic activation of the PERK-eIF2 alpha branch of the endoplasmic reticulum stress response, but not of the IRE1 and activating transcription factor-6 pathways, led to a marked induction of activating transcription factor-4 and the pro-apoptotic transcription factor CHOP. Our findings demonstrate that excessive eIF2 alpha phosphorylation is poorly tolerated by beta-cells and exacerbates free fatty acid-induced apoptosis. This modifies the present paradigm regarding the beneficial role of eIF2 alpha phosphorylation in beta-cells and must be taken into consideration when designing therapies to protect beta-cells in type 2 diabetes.},
  author       = {Cnop, Miriam and Ladrière, Laurence and Hekerman, Paul and Ortis, Fernanda and Cardozo, Alessandra K and Dogusan, Zeynep and Flamez, Daisy and Boyce, Michael and Yuan, Jun-Ying and Eizirik, Décio L},
  issn         = {0021-9258},
  journal      = {JOURNAL OF BIOLOGICAL CHEMISTRY},
  keywords     = {WOLCOTT-RALLISON-SYNDROME,MESSENGER-RNA,MONOCYTE CHEMOATTRACTANT PROTEIN-1,FACTOR-KAPPA-B,UNFOLDED PROTEIN RESPONSE,INSULIN-PRODUCING CELLS,ER STRESS,GLUCOSE-HOMEOSTASIS,PROMOTES SURVIVAL,ISLET CELLS},
  language     = {eng},
  number       = {6},
  pages        = {3989--3997},
  title        = {Selective inhibition of eukaryotic translation initiation factor 2 alpha dephosphorylation potentiates fatty acid-induced endoplasmic reticulum stress and causes pancreatic beta-cell dysfunction and apoptosis},
  url          = {http://dx.doi.org/10.1074/jbc.M607627200},
  volume       = {282},
  year         = {2007},
}

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