Document Detail


Mechanisms of 4-hydroxy-2-nonenal induced pro- and anti-apoptotic signaling.
MedLine Citation:
PMID:  20565132     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
In recent years, 4-hydroxy-2-nonenal (4-HNE) has emerged as an important second messenger in cell cycle signaling. Here, we demonstrate that 4-HNE induces signaling for apoptosis via both the Fas-mediated extrinsic and the p53-mediated intrinsic pathways in HepG2 cells. 4-HNE induces a Fas-mediated DISC independent apoptosis pathway by activating ASK1, JNK, and caspase-3. Parallel treatment of 4-HNE to HepG2 cells also induces apoptosis by the p53 pathway through activation of Bax, p21, JNK, and caspase-3. Exposure of HepG2 cells to 4-HNE leads to the activation of both Fas and Daxx, promotes the export of Daxx from the nucleus to cytoplasm, and facilitates Fas-Daxx binding. Depletion of Daxx by siRNA results in the potentiation of apoptosis, indicating that Fas-Daxx binding in fact is inhibitory to Fas-mediated apoptosis in cells. 4-HNE-induced translocation of Daxx is also accompanied by the activation and nuclear accumulation of HSF1 and up-regulation of heat shock protein Hsp70. All these effects of 4-HNE in cells can be attenuated by ectopic expression of hGSTA4-4, the isozyme of glutathione S-transferase with high activity for 4-HNE. Through immunoprecipitation and liquid chromatography-tandem mass spectrometry, we have demonstrated the covalent binding of 4-HNE to Daxx. We also demonstrate that 4-HNE modification induces phosphorylation of Daxx at Ser668 and Ser671 to facilitate its cytoplasmic export. These results indicate that while 4-HNE exhibits toxicity through several mechanisms, in parallel it evokes signaling for defense mechanisms to self-regulate its toxicity and can simultaneously affect multiple signaling pathways through its interactions with membrane receptors and transcription factors/repressors.
Authors:
Pankaj Chaudhary; Rajendra Sharma; Abha Sharma; Rit Vatsyayan; Sushma Yadav; Sharad S Singhal; Navin Rauniyar; Laszlo Prokai; Sanjay Awasthi; Yogesh C Awasthi
Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  Biochemistry     Volume:  49     ISSN:  1520-4995     ISO Abbreviation:  Biochemistry     Publication Date:  2010 Jul 
Date Detail:
Created Date:  2010-07-29     Completed Date:  2010-08-23     Revised Date:  2013-05-29    
Medline Journal Info:
Nlm Unique ID:  0370623     Medline TA:  Biochemistry     Country:  United States    
Other Details:
Languages:  eng     Pagination:  6263-75     Citation Subset:  IM    
Affiliation:
Department of Molecular Biology and Immunology, University of North Texas Health Science Center, Fort Worth, Texas 76107, USA.
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MeSH Terms
Descriptor/Qualifier:
Adaptor Proteins, Signal Transducing / genetics,  metabolism
Aldehydes / pharmacology*
Antigens, CD95 / agonists,  metabolism*
Apoptosis / drug effects*
Caspase 3 / metabolism
Cell Line, Tumor
Death Domain Receptor Signaling Adaptor Proteins / metabolism*
Enzyme Activation
Humans
MAP Kinase Kinase 4 / metabolism
MAP Kinase Kinase Kinase 5 / metabolism
Nuclear Proteins / genetics,  metabolism
Phosphorylation
RNA, Small Interfering / genetics
Signal Transduction / drug effects
Grant Support
ID/Acronym/Agency:
AG025384/AG/NIA NIH HHS; CA77495/CA/NCI NIH HHS; ES012171/ES/NIEHS NIH HHS; EY04396/EY/NEI NIH HHS; R01 ES012171-06A2/ES/NIEHS NIH HHS; R01 EY004396-26/EY/NEI NIH HHS
Chemical
Reg. No./Substance:
0/Adaptor Proteins, Signal Transducing; 0/Aldehydes; 0/Antigens, CD95; 0/DAXX protein, human; 0/Death Domain Receptor Signaling Adaptor Proteins; 0/FAS protein, human; 0/Nuclear Proteins; 0/RNA, Small Interfering; 29343-52-0/4-hydroxy-2-nonenal; EC 2.7.11.25/MAP Kinase Kinase Kinase 5; EC 2.7.12.2/MAP Kinase Kinase 4; EC 3.4.22.-/Caspase 3
Comments/Corrections

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