Yang Yusong, Sharma Rajendra, Sharma Abha, Awasthi Sanjay, Awasthi Yogesh C
Department of Human Biological Chemistry and Genetics, University of Texas Medical Branch, Galveston, TX 77550, USA.
Acta Biochim Pol. 2003;50(2):319-36.
Role of lipid peroxidation products, particularly 4-hydroxynonenal (4-HNE) in cell cycle signaling is becoming increasingly clear. In this article, recent studies suggesting an important role of 4-HNE in stress mediated signaling for apoptosis are critically evaluated. Evidence demonstrating the modulation of UV, oxidative stress, and chemical stress mediated apoptosis by blocking lipid peroxidation by the alpha-class glutathione S-transferases (GSTs) is presented which suggest an important role of these enzymes in protection against oxidative stress and a role of lipid peroxidation products in stress mediated signaling. Overexpression of 4-HNE metabolizing GSTs (mGSTA4-4, hGSTA4-4, or hGST5.8) protects cells against 4-HNE, oxidative stress (H(2)O(2) or xanthine/xanthine oxidase), and UV-A mediated apoptosis by blocking JNK and caspase activation suggesting a role of 4-HNE in the mechanisms of apoptosis caused by these stress factors. The intracellular concentration of 4-HNE appears to be crucial for the nature of cell cycle signaling and may be a determinant for the signaling for differentiation, proliferation, transformation, or apoptosis. The intracellular concentrations of 4-HNE are regulated through a coordinated action of GSTs (GSTA4-4 and hGST5.8) which conjugate 4-HNE to GSH to form the conjugate (GS-HNE) and the transporter 76 kDa Ral-binding GTPase activating protein (RLIP76), which catalyze ATP-dependent transport of GS-HNE. A mild stress caused by heat, UV-A, or H(2)O(2)with no apparent effect on the cells in culture causes a rapid, transient induction of hGST5.8 and RLIP76. These stress preconditioned cells acquire ability to metabolize and exclude 4-HNE at an accelerated pace and acquire relative resistance to apoptosis by UV and oxidative stress as compared to unconditioned control cells. This resistance of stress preconditioned cells can be abrogated by coating the cells with anti-RLIP76 antibodies which block the transport of GS-HNE. These studies and previous reports discussed in this article strongly suggest a key role of 4-HNE in stress mediated signaling.
脂质过氧化产物，尤其是4-羟基壬烯醛（4-HNE）在细胞周期信号传导中的作用正变得越来越清晰。在本文中，对近期表明4-HNE在应激介导的细胞凋亡信号传导中起重要作用的研究进行了批判性评估。文中展示了通过α类谷胱甘肽S-转移酶（GSTs）阻断脂质过氧化来调节紫外线、氧化应激和化学应激介导的细胞凋亡的证据，这表明这些酶在抵御氧化应激中起重要作用，且脂质过氧化产物在应激介导的信号传导中起作用。4-HNE代谢型GSTs（mGSTA4-4、hGSTA4-4或hGST5.8）的过表达通过阻断JNK和半胱天冬酶激活来保护细胞免受4-HNE、氧化应激（H₂O₂或黄嘌呤/黄嘌呤氧化酶）和UV-A介导的细胞凋亡，这表明4-HNE在这些应激因素引起的细胞凋亡机制中起作用。4-HNE的细胞内浓度似乎对细胞周期信号传导的性质至关重要，并且可能是分化、增殖、转化或细胞凋亡信号传导的决定因素。4-HNE的细胞内浓度通过GSTs（GSTA4-4和hGST5.8）的协同作用来调节，GSTs将4-HNE与谷胱甘肽（GSH）结合形成共轭物（GS-HNE），以及转运蛋白76 kDa Ral结合GTP酶激活蛋白（RLIP76），其催化GS-HNE的ATP依赖性转运。由热、UV-A或H₂O₂引起的轻度应激对培养中的细胞无明显影响，但会导致hGST5.8和RLIP76的快速、短暂诱导。与未预处理的对照细胞相比，这些应激预处理的细胞获得了以加速速度代谢和排除4-HNE的能力，并获得了对紫外线和氧化应激诱导的细胞凋亡的相对抗性。通过用抗RLIP76抗体包被细胞来阻断GS-HNE的转运，可以消除应激预处理细胞的这种抗性。本文讨论的这些研究和先前的报告强烈表明4-HNE在应激介导的信号传导中起关键作用。
