Document Detail

Selective alterations of transcription factors in MPP+-induced neurotoxicity in PC12 cells.
MedLine Citation:
PMID:  16112330     Owner:  NLM     Status:  MEDLINE    
MPP(+) (1-methyl-4-phenylpyridinium; the active metabolite of the neurotoxin MPTP (1-methyl-4-phenyl-1,2,5,6-tetrahydropyridine)) depletes dopamine (DA) content and elicits cell death in PC12 cells. However, the mechanism of MPP(+)-induced neurotoxicity is still unclear. In this study, the dose response and time-course of MPP(+)-induced DA depletion and decreased cell viability were determined in nerve growth factor (NGF)-differentiated PC12 cells. The alteration of transcription factors (TFs) induced by MPP(+) from a selected dose level and time point was then evaluated using protein/DNA-binding arrays. K-means clustering analysis identified four patterns of protein/DNA-binding changes. Three of the 28 TFs identified in PC12 cells increased by 100% (p53, PRE, Smad SBE) and 2 decreased by 50% (HSE, RXR(DR1)) of control with MPP(+) treatment. In addition, three TFs decreased within the range of 33-50% (TFIID, E2F1, CREB) and two TFs increased within the range of 50-100% (PAX-5, Stat4). An electrophoretic mobility shift assay (EMSA) was used to confirm the changes of p53 and HSE. The observed changes in TFs correlated with the alterations of DA and cell viability. The data indicates that selective transcription factors are involved in MPP(+)-induced neurotoxicity and it provides mechanistic information that may be applicable to animal studies with MPTP and clinical studies of Parkinson's disease.
Z Xu; D Cawthon; K A McCastlain; H M Duhart; G D Newport; H Fang; T A Patterson; W Slikker; S F Ali
Publication Detail:
Type:  Journal Article; Research Support, U.S. Gov't, Non-P.H.S.    
Journal Detail:
Title:  Neurotoxicology     Volume:  26     ISSN:  0161-813X     ISO Abbreviation:  Neurotoxicology     Publication Date:  2005 Aug 
Date Detail:
Created Date:  2005-08-22     Completed Date:  2005-10-19     Revised Date:  2006-11-15    
Medline Journal Info:
Nlm Unique ID:  7905589     Medline TA:  Neurotoxicology     Country:  Netherlands    
Other Details:
Languages:  eng     Pagination:  729-37     Citation Subset:  IM    
Neurochemistry Laboratory, Division of Neurotoxicology, HFT-132, National Center for Toxicological Research, Food and Drug Administration, 3900 NCTR Road, Jefferson, AR 72079, USA.
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MeSH Terms
1-Methyl-4-phenylpyridinium / toxicity*
Cell Survival / drug effects
DNA / metabolism
Dopamine / metabolism
Dose-Response Relationship, Drug
Electrophoretic Mobility Shift Assay
Neurotoxicity Syndromes / metabolism*
Neurotransmitter Agents / metabolism
Oligonucleotide Array Sequence Analysis
PC12 Cells
Protein Binding
Transcription Factors / metabolism*
Reg. No./Substance:
0/Neurotransmitter Agents; 0/Transcription Factors; 48134-75-4/1-Methyl-4-phenylpyridinium; 9007-49-2/DNA

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

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