| Mechanisms of 4-hydroxy-2-nonenal induced pro- and anti-apoptotic signaling. | |
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MedLine Citation:
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PMID: 20565132 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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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. |
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Authors:
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Pankaj Chaudhary; Rajendra Sharma; Abha Sharma; Rit Vatsyayan; Sushma Yadav; Sharad S Singhal; Navin Rauniyar; Laszlo Prokai; Sanjay Awasthi; Yogesh C Awasthi |
Publication Detail:
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Type: Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't |
Journal Detail:
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Title: Biochemistry Volume: 49 ISSN: 1520-4995 ISO Abbreviation: Biochemistry Publication Date: 2010 Jul |
Date Detail:
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Created Date: 2010-07-29 Completed Date: 2010-08-23 Revised Date: 2011-09-26 |
Medline Journal Info:
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Nlm Unique ID: 0370623 Medline TA: Biochemistry Country: United States |
Other Details:
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Languages: eng Pagination: 6263-75 Citation Subset: IM |
Affiliation:
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Department of Molecular Biology and Immunology, University of North Texas Health Science Center, Fort Worth, Texas 76107, USA. |
Export Citation:
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APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
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Adaptor Proteins, Signal Transducing
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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:
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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:
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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 | |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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