Mechanisms of 4-Hydroxy-2-nonenal Induced Pro- and Anti-Apoptotic Signaling
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- 作者：Pankaj Chaudhary ; Rajendra Sharma ; Abha Sharma ; Rit Vatsyayan ; Sushma Yadav ; Sharad S. Singhal ; Navin Rauniyar ; Laszlo Prokai ; Sanjay Awasthi ; Yogesh C. Awasthi
- 刊名：Biochemistry
- 出版年：2010
- 出版时间：July 27, 2010
- 年：2010
- 卷：49
- 期：29
- 页码：6263-6275
- 全文大小：1277K
- 年卷期：v.49,no.29(July 27, 2010)
- ISSN：1520-4995
文摘
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.