Document Detail


Altered transcription factor trafficking in oxidatively-stressed neuronal cells.
MedLine Citation:
PMID:  22902725     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Age-related neurodegenerative diseases are associated with alterations in gene expression in affected neurons. One of the mechanisms that could account for this is altered subcellular localization of transcription factors, which has been observed in human post-mortem brains of each of the major neurodegenerative diseases, including Parkinson's disease (PD). The specific mechanisms are yet to be elucidated; however a potential mechanism involves alterations in nuclear transport. In this study, we examined the nucleocytoplasmic trafficking of select transcription factors in response to a PD-relevant oxidative injury, 6-hydroxydopamine (6OHDA). Utilizing a well-established model of ligand-regulated nucleocytoplasmic shuttling, the glucocorticoid receptor, we found that 6OHDA selectively impaired nuclear import through an oxidative mechanism without affecting nuclear export or nuclear retention. Interestingly, impaired nuclear import was selective as Nrf2 (nuclear factor E2-related factor 2) nuclear localization remained intact in 6OHDA-treated cells. Thus, oxidative stress specifically impacts the subcellular localization of some but not all transcription factors, which is consistent with observations in post-mortem PD brains. Our data further implicate a role for altered microtubule dependent trafficking in the differential effects of 6OHDA on transcription factor import. Oxidative disruption of microtubule-dependent nuclear transport may contribute to selective declines in transcriptional responses of aging or diseased dopaminergic cells.
Authors:
Vivek P Patel; Donald B Defranco; Charleen T Chu
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural     Date:  2012-08-08
Journal Detail:
Title:  Biochimica et biophysica acta     Volume:  1822     ISSN:  0006-3002     ISO Abbreviation:  Biochim. Biophys. Acta     Publication Date:  2012 Nov 
Date Detail:
Created Date:  2012-09-17     Completed Date:  2012-11-13     Revised Date:  2013-07-12    
Medline Journal Info:
Nlm Unique ID:  0217513     Medline TA:  Biochim Biophys Acta     Country:  Netherlands    
Other Details:
Languages:  eng     Pagination:  1773-82     Citation Subset:  IM    
Copyright Information:
Copyright © 2012 Elsevier B.V. All rights reserved.
Affiliation:
Department of Pathology, Division of Neuropathology, University of Pittsburgh, Pittsburgh, PA 15261, USA. vpp3@pitt.edu
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MeSH Terms
Descriptor/Qualifier:
Active Transport, Cell Nucleus / drug effects*
Cell Line, Tumor
Gene Expression / drug effects
Humans
NF-E2-Related Factor 2 / metabolism*
Neuroblastoma
Oxidative Stress
Oxidopamine / pharmacology*
Parkinson Disease / metabolism*
Receptors, Glucocorticoid / metabolism*
Tubulin / metabolism
Grant Support
ID/Acronym/Agency:
F31 NS076040/NS/NINDS NIH HHS; F31-NS076040/NS/NINDS NIH HHS; R01 AG026389/AG/NIA NIH HHS; R01 AG026389/AG/NIA NIH HHS; T32 NS007433/NS/NINDS NIH HHS; T32-NS007433/NS/NINDS NIH HHS
Chemical
Reg. No./Substance:
0/NF-E2-Related Factor 2; 0/NFE2L2 protein, human; 0/Receptors, Glucocorticoid; 0/Tubulin; 1199-18-4/Oxidopamine
Comments/Corrections

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