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Science 307 (5711): 935-939

Copyright © 2005 by the American Association for the Advancement of Science

A Selective Inhibitor of eIF2{alpha} Dephosphorylation Protects Cells from ER Stress

Michael Boyce,1 Kevin F. Bryant,2* Céline Jousse,3* Kai Long,4* Heather P. Harding,3 Donalyn Scheuner,5 Randal J. Kaufman,5 Dawei Ma,4 Donald M. Coen,2 David Ron,3 Junying Yuan1{dagger}

Abstract: Most protein phosphatases have little intrinsic substrate specificity, making selective pharmacological inhibition of specific dephosphorylation reactions a challenging problem. In a screen for small molecules that protect cells from endoplasmic reticulum (ER) stress, we identified salubrinal, a selective inhibitor of cellular complexes that dephosphorylate eukaryotic translation initiation factor 2 subunit {alpha} (eIF2{alpha}). Salubrinal also blocks eIF2{alpha} dephosphorylation mediated by a herpes simplex virus protein and inhibits viral replication. These results suggest that selective chemical inhibitors of eIF2{alpha} dephosphorylation may be useful in diseases involving ER stress or viral infection. More broadly, salubrinal demonstrates the feasibility of selective pharmacological targeting of cellular dephosphorylation events.

1 Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA.
2 Department of Biological Chemistry and Molecular Pharmacology and Committee on Virology, Harvard Medical School, Boston, MA 02115, USA.
3 Skirball Institute, New York University School of Medicine, New York, NY 10016, USA.
4 Shanghai Institute of Organic Chemistry, Shanghai, China.
5 Department of Biological Chemistry and Howard Hughes Medical Institute, University of Michigan Medical Center, Ann Arbor, MI 48109, USA.

* These authors contributed equally to this work.

{dagger} To whom correspondence should be addressed. E-mail: jyuan{at}hms.harvard.edu


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Reexpression of Human Somatostatin Receptor Gene 2 Gene Mediated by Oncolytic Adenovirus Increases Antitumor Activity of Tumor Necrosis Factor-Related Apoptosis-Inducing Ligand against Pancreatic Cancer.
Z. Zhang, Y. Huang, K. Newman, J. Gu, X. Zhang, H. Wu, M. Zhao, Z. Xianyu, and X. Liu (2009)
Clin. Cancer Res. 15, 5154-5160
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Activation of the Akt-NF-{kappa}B Pathway by Subtilase Cytotoxin through the ATF6 Branch of the Unfolded Protein Response.
H. Yamazaki, N. Hiramatsu, K. Hayakawa, Y. Tagawa, M. Okamura, R. Ogata, T. Huang, S. Nakajima, J. Yao, A. W. Paton, et al. (2009)
J. Immunol. 183, 1480-1487
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Targeting Protein Serine/Threonine Phosphatases for Drug Development.
J. L. McConnell and B. E. Wadzinski (2009)
Mol. Pharmacol. 75, 1249-1261
   Abstract »    Full Text »    PDF »
Translational reprogramming following UVB irradiation is mediated by DNA-PKcs and allows selective recruitment to the polysomes of mRNAs encoding DNA repair enzymes.
I. R. Powley, A. Kondrashov, L. A. Young, H. C. Dobbyn, K. Hill, I. G. Cannell, M. Stoneley, Y.-W. Kong, J. A. Cotes, G. C.M. Smith, et al. (2009)
Genes & Dev. 23, 1207-1220
   Abstract »    Full Text »    PDF »
ER stress protects from retinal degeneration.
C. S. Mendes, C. Levet, G. Chatelain, P. Dourlen, A. Fouillet, M.-L. Dichtel-Danjoy, A. Gambis, H. D. Ryoo, H. Steller, and B. Mollereau (2009)
EMBO J. 28, 1296-1307
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PLAB induction in fenretinide-induced apoptosis of ovarian cancer cells occurs via a ROS-dependent mechanism involving ER stress and JNK activation.
V. Appierto, P. Tiberio, M. G. Villani, E. Cavadini, and F. Formelli (2009)
Carcinogenesis 30, 824-831
   Abstract »    Full Text »    PDF »
Early endosomes and endosomal coatomer are required for autophagy.
M. Razi, E. Y.W. Chan, and S. A. Tooze (2009)
J. Cell Biol. 185, 305-321
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Human Cytomegalovirus Protein pUL38 Induces ATF4 Expression, Inhibits Persistent JNK Phosphorylation, and Suppresses Endoplasmic Reticulum Stress-Induced Cell Death.
B. Xuan, Z. Qian, E. Torigoi, and D. Yu (2009)
J. Virol. 83, 3463-3474
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Cross-Talk between Integrins and Oncogenes Modulates Chemosensitivity.
J. C. Puigvert, S. Huveneers, L. Fredriksson, M. o. h. Veld, B. van de Water, and E. H. J. Danen (2009)
Mol. Pharmacol. 75, 947-955
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Canonical Initiation Factor Requirements of the Myc Family of Internal Ribosome Entry Segments.
K. A. Spriggs, L. C. Cobbold, C. L. Jopling, R. E. Cooper, L. A. Wilson, M. Stoneley, M. J. Coldwell, D. Poncet, Y.-C. Shen, S. J. Morley, et al. (2009)
Mol. Cell. Biol. 29, 1565-1574
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Severe Acute Respiratory Syndrome Coronavirus Triggers Apoptosis via Protein Kinase R but Is Resistant to Its Antiviral Activity.
V. Krahling, D. A. Stein, M. Spiegel, F. Weber, and E. Muhlberger (2009)
J. Virol. 83, 2298-2309
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ERAD inhibitors integrate ER stress with an epigenetic mechanism to activate BH3-only protein NOXA in cancer cells.
Q. Wang, H. Mora-Jensen, M. A. Weniger, P. Perez-Galan, C. Wolford, T. Hai, D. Ron, W. Chen, W. Trenkle, A. Wiestner, et al. (2009)
PNAS 106, 2200-2205
   Abstract »    Full Text »    PDF »
Inhibition of eIF2{alpha} Dephosphorylation Maximizes Bortezomib Efficiency and Eliminates Quiescent Multiple Myeloma Cells Surviving Proteasome Inhibitor Therapy.
D. M. Schewe and J. A. Aguirre-Ghiso (2009)
Cancer Res. 69, 1545-1552
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