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  • 1
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    Selective inhibition of a regulatory subunit of protein phosphatase 1 restores proteostasis (2011)
    American Association for the Advancement of Science (AAAS)
    Details
    Publication Date: 2011-03-10
    Description: Many biological processes are regulated through the selective dephosphorylation of proteins. Protein serine-threonine phosphatases are assembled from catalytic subunits bound to diverse regulatory subunits that provide substrate specificity and subcellular localization. We describe a small molecule, guanabenz, that bound to a regulatory subunit of protein phosphatase 1, PPP1R15A/GADD34, selectively disrupting the stress-induced dephosphorylation of the alpha subunit of translation initiation factor 2 (eIF2alpha). Without affecting the related PPP1R15B-phosphatase complex and constitutive protein synthesis, guanabenz prolonged eIF2alpha phosphorylation in human stressed cells, adjusting the protein production rates to levels manageable by available chaperones. This favored protein folding and thereby rescued cells from protein misfolding stress. Thus, regulatory subunits of phosphatases are drug targets, a property used here to restore proteostasis in stressed cells.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Tsaytler, Pavel -- Harding, Heather P -- Ron, David -- Bertolotti, Anne -- 084812/Wellcome Trust/United Kingdom -- MC_U105185860/Medical Research Council/United Kingdom -- Medical Research Council/United Kingdom -- New York, N.Y. -- Science. 2011 Apr 1;332(6025):91-4. doi: 10.1126/science.1201396. Epub 2011 Mar 3.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉MRC Laboratory of Molecular Biology, Hills Road, Cambridge CB2 0QH, UK.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/21385720" target="_blank"〉PubMed〈/a〉
    Keywords: Adrenergic alpha-2 Receptor Agonists/*pharmacology ; Catalytic Domain/drug effects ; Cell Line ; Clonidine/pharmacology ; Endoplasmic Reticulum/drug effects/metabolism ; Enzyme Inhibitors/*pharmacology ; Eukaryotic Initiation Factor-2/metabolism ; Guanabenz/*pharmacology ; HeLa Cells ; Homeostasis ; Humans ; Molecular Chaperones/metabolism ; Phosphorylation ; Protein Biosynthesis/drug effects ; Protein Folding/drug effects ; Protein Phosphatase 1/*antagonists & inhibitors/metabolism ; Protein Subunits/drug effects/metabolism ; Proteins/metabolism ; Stress, Physiological ; Tunicamycin
    Print ISSN: 0036-8075
    Electronic ISSN: 1095-9203
    Topics: Biology , Chemistry and Pharmacology , Computer Science , Medicine , Natural Sciences in General , Physics
    Published by American Association for the Advancement of Science (AAAS)
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  • 2
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    A selective inhibitor of eIF2alpha dephosphorylation protects cells from ER stress (2005)
    American Association for the Advancement of Science (AAAS)
    Details
    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
    Published by American Association for the Advancement of Science (AAAS)
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  • 3
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    Stress-induced phosphorylation and activation of the transcription factor CHOP (GADD153) by p38 MAP Kinase (1996)
    American Association for the Advancement of Science (AAAS)
    Details
    Publication Date: 1996-05-31
    Description: CHOP, a member of the C/EBP family of transcription factors, mediates effects of cellular stress on growth and differentiation. It accumulates under conditions of stress and undergoes inducible phosphorylation on two adjacent serine residues (78 and 81). In vitro, CHOP is phosphorylated on these residues by p38 mitogen-activated protein kinase (MAP kinase). A specific inhibitor of p38 MAP kinase, SB203580, abolished the stress-inducible in vivo phosphorylation of CHOP. Phosphorylation of CHOP on these residues enhanced its ability to function as a transcriptional activator and was also required for the full inhibitory effect of CHOP on adipose cell differentiation. CHOP thus serves as a link between a specific stress-activated protein kinase, p38, and cellular growth and differentiation.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Wang, X Z -- Ron, D -- New York, N.Y. -- Science. 1996 May 31;272(5266):1347-9.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Medicine, Skirball Institute of Biomolecular Medicine, New York University Medical Center, 10016, NY, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/8650547" target="_blank"〉PubMed〈/a〉
    Keywords: 3T3 Cells ; Adipocytes/cytology ; Amino Acid Sequence ; Animals ; *CCAAT-Enhancer-Binding Proteins ; Calcium-Calmodulin-Dependent Protein Kinases/*metabolism ; Cell Differentiation ; Cell Division ; Culture Media ; DNA-Binding Proteins/chemistry/genetics/*metabolism ; Enzyme Inhibitors/pharmacology ; Imidazoles/pharmacology ; Methyl Methanesulfonate/pharmacology ; Mice ; *Mitogen-Activated Protein Kinases ; Molecular Sequence Data ; Phosphorylation ; Pyridines/pharmacology ; Recombinant Fusion Proteins/metabolism ; Signal Transduction ; Transcription Factor CHOP ; Transcription Factors/chemistry/genetics/*metabolism ; Transcriptional Activation ; p38 Mitogen-Activated Protein Kinases
    Print ISSN: 0036-8075
    Electronic ISSN: 1095-9203
    Topics: Biology , Chemistry and Pharmacology , Computer Science , Medicine , Natural Sciences in General , Physics
    Published by American Association for the Advancement of Science (AAAS)
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