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Targeting phosphorylation of eukaryotic initiation factor-2α to treat human disease.

Publication ,  Journal Article
Fullwood, MJ; Zhou, W; Shenolikar, S
Published in: Prog Mol Biol Transl Sci
2012

The unfolded protein response, also known as endoplasmic reticulum (ER) stress, has been implicated in numerous human diseases, including atherosclerosis, cancer, diabetes, and neurodegenerative disorders. Protein misfolding activates one or more of the three ER transmembrane sensors to initiate a complex network of signaling that transiently suppresses protein translation while also enhancing protein folding and proteasomal degradation of misfolded proteins to ensure full recovery from ER stress. Gene disruption studies in mice have provided critical insights into the role of specific signaling components and pathways in the differing responses of animal tissues to ER stress. These studies have emphasized an important contribution of translational repression to sustained insulin synthesis and β-cell viability in experimental models of type-2 diabetes. This has focused attention on the recently discovered small-molecule inhibitors of eIF2α phosphatases that prolong eIF2α phosphorylation to reduce cell death in several animal models of human disease. These compounds show significant cytoprotection in cellular and animal models of neurodegenerative disorders, highlighting a potential strategy for future development of drugs to treat human protein misfolding disorders.

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Published In

Prog Mol Biol Transl Sci

DOI

EISSN

1878-0814

Publication Date

2012

Volume

106

Start / End Page

75 / 106

Location

Netherlands

Related Subject Headings

  • Unfolded Protein Response
  • Thiourea
  • Protein Processing, Post-Translational
  • Protein Folding
  • Protein Biosynthesis
  • Proteasome Endopeptidase Complex
  • Phosphorylation
  • Phosphoprotein Phosphatases
  • Neurodegenerative Diseases
  • Neoplasms
 

Citation

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Fullwood, M. J., Zhou, W., & Shenolikar, S. (2012). Targeting phosphorylation of eukaryotic initiation factor-2α to treat human disease. Prog Mol Biol Transl Sci, 106, 75–106. https://doi.org/10.1016/B978-0-12-396456-4.00005-5
Fullwood, Melissa J., Wei Zhou, and Shirish Shenolikar. “Targeting phosphorylation of eukaryotic initiation factor-2α to treat human disease.Prog Mol Biol Transl Sci 106 (2012): 75–106. https://doi.org/10.1016/B978-0-12-396456-4.00005-5.
Fullwood MJ, Zhou W, Shenolikar S. Targeting phosphorylation of eukaryotic initiation factor-2α to treat human disease. Prog Mol Biol Transl Sci. 2012;106:75–106.
Fullwood, Melissa J., et al. “Targeting phosphorylation of eukaryotic initiation factor-2α to treat human disease.Prog Mol Biol Transl Sci, vol. 106, 2012, pp. 75–106. Pubmed, doi:10.1016/B978-0-12-396456-4.00005-5.
Fullwood MJ, Zhou W, Shenolikar S. Targeting phosphorylation of eukaryotic initiation factor-2α to treat human disease. Prog Mol Biol Transl Sci. 2012;106:75–106.

Published In

Prog Mol Biol Transl Sci

DOI

EISSN

1878-0814

Publication Date

2012

Volume

106

Start / End Page

75 / 106

Location

Netherlands

Related Subject Headings

  • Unfolded Protein Response
  • Thiourea
  • Protein Processing, Post-Translational
  • Protein Folding
  • Protein Biosynthesis
  • Proteasome Endopeptidase Complex
  • Phosphorylation
  • Phosphoprotein Phosphatases
  • Neurodegenerative Diseases
  • Neoplasms