Document Detail


Effect of an experimental proteasome inhibitor on the cytoskeleton, cytosolic protein turnover, and induction in the neuronal cells in vitro.
MedLine Citation:
PMID:  18155769     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
GT-1 murine neuronal cells exposed to an experimental proteasome inhibitor (EPI) for 24h showed increased cell death via a non-apoptotic mechanism, as assessed by TUNEL and DNA fragmentation assays. Immunofluorescence staining demonstrated that EPI induced reorganization and relocation of non-ubiquinated actin microfilaments and microtubules to the perinuclear region in EPI treated cells. Immunohistochemistry analysis also demonstrated that other non-cytoskeletal proteins became ubiquitinated and/or upregulated including ubiquitin and other stress proteins. Perinuclear-centrosomal accumulation of gamma-tubulin and vimentin, key components of aggresomes, was observed in the EPI treated cells. Biochemical analysis indicated that EPI-induced accumulation of ubiquitinated protein aggregates in GT-1 cells was detergent - and mechanical - disruption resistant, a feature of aggresomes. Similar results were observed in GT-1 cells treated with lactacystin, a prototypical proteasome inhibitor, which is structurally dissimilar to EPI indicating a pharmacologic effect. In conclusion, EPI causes cytoskeletal reorganization and accumulation of diverse ubiquitinated and non-ubiquitinated proteins in the perinuclear region and potentially overloads the endoplasmic reticulum-dependent quality control mechanism. These processes acting alone, or in combination, are hypothesized to affect axonal transport or other aspects of cellular homeostasis and thus, represent events potentially relevant to the development of peripheral neuropathy associated with administration of proteasome inhibitors in nonclinical studies.
Authors:
Vilmos Csizmadia; Arek Raczynski; Eva Csizmadia; Eric R Fedyk; James Rottman; Carl L Alden
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Publication Detail:
Type:  Journal Article     Date:  2007-11-19
Journal Detail:
Title:  Neurotoxicology     Volume:  29     ISSN:  0161-813X     ISO Abbreviation:  Neurotoxicology     Publication Date:  2008 Mar 
Date Detail:
Created Date:  2008-03-04     Completed Date:  2008-06-05     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  7905589     Medline TA:  Neurotoxicology     Country:  Netherlands    
Other Details:
Languages:  eng     Pagination:  232-43     Citation Subset:  IM    
Affiliation:
Department of Drug Safety Evaluation, Millennium Pharmaceuticals, Inc., Cambridge, MA 02139, USA. vcsizmad@mpi.com
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MeSH Terms
Descriptor/Qualifier:
Acetylcysteine / analogs & derivatives*,  toxicity
Actins / metabolism
Animals
Blotting, Western
Cell Death / drug effects
Cell Line
Cell Survival / drug effects
Cysteine Proteinase Inhibitors / toxicity*
Cytoskeleton / drug effects*,  metabolism
Cytosol / drug effects,  metabolism
DNA Fragmentation
Dose-Response Relationship, Drug
Heat-Shock Proteins / metabolism
Immunohistochemistry
In Situ Nick-End Labeling
Mice
Microscopy, Fluorescence
Nerve Tissue Proteins / metabolism*
Neurons / drug effects*,  enzymology,  metabolism,  pathology
Proteasome Endopeptidase Complex / antagonists & inhibitors*,  metabolism
Time Factors
Tubulin / metabolism
Ubiquitin / metabolism
Chemical
Reg. No./Substance:
0/Actins; 0/Cysteine Proteinase Inhibitors; 0/Heat-Shock Proteins; 0/Nerve Tissue Proteins; 0/Tubulin; 0/Ubiquitin; 133343-34-7/lactacystin; 616-91-1/Acetylcysteine; EC 3.4.25.1/Proteasome Endopeptidase Complex

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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