|Effect of an experimental proteasome inhibitor on the cytoskeleton, cytosolic protein turnover, and induction in the neuronal cells in vitro.|
|PMID: 18155769 Owner: NLM Status: MEDLINE|
|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.|
|Vilmos Csizmadia; Arek Raczynski; Eva Csizmadia; Eric R Fedyk; James Rottman; Carl L Alden|
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|Type: Journal Article Date: 2007-11-19|
|Title: Neurotoxicology Volume: 29 ISSN: 0161-813X ISO Abbreviation: Neurotoxicology Publication Date: 2008 Mar|
|Created Date: 2008-03-04 Completed Date: 2008-06-05 Revised Date: -|
Medline Journal Info:
|Nlm Unique ID: 7905589 Medline TA: Neurotoxicology Country: Netherlands|
|Languages: eng Pagination: 232-43 Citation Subset: IM|
|Department of Drug Safety Evaluation, Millennium Pharmaceuticals, Inc., Cambridge, MA 02139, USA. firstname.lastname@example.org|
|APA/MLA Format Download EndNote Download BibTex|
analogs & derivatives*,
Actins / metabolism
Cell Death / drug effects
Cell Survival / drug effects
Cysteine Proteinase Inhibitors / toxicity*
Cytoskeleton / drug effects*, metabolism
Cytosol / drug effects, metabolism
Dose-Response Relationship, Drug
Heat-Shock Proteins / metabolism
In Situ Nick-End Labeling
Nerve Tissue Proteins / metabolism*
Neurons / drug effects*, enzymology, metabolism, pathology
Proteasome Endopeptidase Complex / antagonists & inhibitors*, metabolism
Tubulin / metabolism
Ubiquitin / metabolism
|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 18.104.22.168/Proteasome Endopeptidase Complex|
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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