Document Detail


Paraquat exposure induces nuclear translocation of glyceraldehyde-3-phosphate dehydrogenase (GAPDH) and the activation of the nitric oxide-GAPDH-Siah cell death cascade.
MedLine Citation:
PMID:  20478973     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Paraquat (PQ) is a well-known herbicide that exerts its effects by elevating intracellular levels of superoxide. It has been previously demonstrated that oxidative and nitrosative stress participate to PQ-induced cell death. Here, we document that PQ increases the levels of nitric oxide (NO) in rat mesencephalic cells and causes nuclear translocation of glyceraldehyde-3-phosphate dehydrogenase (GAPDH) to activate the NO/GAPDH/Siah cell death cascade. PQ exposure increases expression of the p300/CREB-binding protein (p300/CBP) and phosphorylation of p53 at Ser 15, which stimulates p53-dependent transactivation through increased binding with p300. Although this cascade could be inhibited by preincubation with the monoamine oxidase B inhibitor deprenyl, cell death was not prevented. Pretreatment of cells with the neuronal nitric oxide synthase inhibitor 7-nitroindazole efficiently prevented the activation of the GAPDH/NO/Siah cell death cascade, thereby protecting cells against PQ-induced toxicity. The results suggest that PQ induces this novel cell death cascade in rat mesencephalic cells, but inhibition of the pathway does not impede cell death because of an oxidative burst generated by the pesticide.
Authors:
Miguel A Ortiz-Ortiz; José M Morán; Luz M Ruiz-Mesa; José M Bravo-San Pedro; José M Fuentes
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2010-05-17
Journal Detail:
Title:  Toxicological sciences : an official journal of the Society of Toxicology     Volume:  116     ISSN:  1096-0929     ISO Abbreviation:  Toxicol. Sci.     Publication Date:  2010 Aug 
Date Detail:
Created Date:  2010-07-19     Completed Date:  2010-10-28     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  9805461     Medline TA:  Toxicol Sci     Country:  United States    
Other Details:
Languages:  eng     Pagination:  614-22     Citation Subset:  IM    
Affiliation:
Departamento de Bioquímica y Biología Molecular y Genética, EU Enfermería y Terapia Ocupacional, Universidad de Extremadura, Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas, Cáceres, Spain.
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MeSH Terms
Descriptor/Qualifier:
1-Methyl-4-phenylpyridinium / toxicity
Active Transport, Cell Nucleus / drug effects
Animals
Cell Nucleus / metabolism*
Cell Survival / drug effects
Cells, Cultured
Glyceraldehyde-3-Phosphate Dehydrogenases / metabolism*
Herbicides / toxicity*
Nitric Oxide / physiology*
Nuclear Proteins / metabolism*
Paraquat / toxicity*
Phosphorylation
Rats
Tumor Suppressor Protein p53 / metabolism
Ubiquitin-Protein Ligases / metabolism*
p300-CBP Transcription Factors / metabolism
Chemical
Reg. No./Substance:
0/Herbicides; 0/Nuclear Proteins; 0/Tumor Suppressor Protein p53; 10102-43-9/Nitric Oxide; 4685-14-7/Paraquat; 48134-75-4/1-Methyl-4-phenylpyridinium; EC 1.2.1.-/Glyceraldehyde-3-Phosphate Dehydrogenases; EC 2.3.1.48/p300-CBP Transcription Factors; EC 6.3.2.19/Ubiquitin-Protein Ligases; EC 6.3.2.19/seven in absentia proteins

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