Publication Date:
2005-02-12
Description:
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 (eIF2alpha). Salubrinal also blocks eIF2alpha dephosphorylation mediated by a herpes simplex virus protein and inhibits viral replication. These results suggest that selective chemical inhibitors of eIF2alpha 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.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Boyce, Michael -- Bryant, Kevin F -- Jousse, Celine -- Long, Kai -- Harding, Heather P -- Scheuner, Donalyn -- Kaufman, Randal J -- Ma, Dawei -- Coen, Donald M -- Ron, David -- Yuan, Junying -- AI19838/AI/NIAID NIH HHS/ -- AI26077/AI/NIAID NIH HHS/ -- DDK42394/DK/NIDDK NIH HHS/ -- DK47119/DK/NIDDK NIH HHS/ -- ES08681/ES/NIEHS NIH HHS/ -- GM64703/GM/NIGMS NIH HHS/ -- NS35138/NS/NINDS NIH HHS/ -- R37-AG012859/AG/NIA NIH HHS/ -- New York, N.Y. -- Science. 2005 Feb 11;307(5711):935-9.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/15705855" target="_blank"〉PubMed〈/a〉
Keywords:
Animals
;
Antigens, Differentiation
;
Apoptosis/*drug effects
;
Cell Cycle Proteins
;
Cell Line
;
Cinnamates/*pharmacology/toxicity
;
*Cytoprotection
;
Dose-Response Relationship, Drug
;
Endoplasmic Reticulum/*metabolism
;
Enzyme Inhibitors/pharmacology
;
Eukaryotic Initiation Factor-2/*metabolism
;
Genes, Reporter
;
Herpesvirus 1, Human/drug effects/physiology
;
Keratitis, Herpetic/drug therapy/virology
;
Male
;
Mice
;
Oxazoles/pharmacology/toxicity
;
PC12 Cells
;
Phosphoprotein Phosphatases/metabolism
;
Phosphorylation
;
Protein Folding
;
Protein Kinases/metabolism
;
Protein Phosphatase 1
;
Proteins/metabolism
;
Rats
;
Thiourea/*analogs & derivatives/*pharmacology/toxicity
;
Tunicamycin/pharmacology
;
Viral Proteins/metabolism
;
Virus Replication/drug effects
Print ISSN:
0036-8075
Electronic ISSN:
1095-9203
Topics:
Biology
,
Chemistry and Pharmacology
,
Computer Science
,
Medicine
,
Natural Sciences in General
,
Physics
