4-hydroxynonenal (HNE), an aldehyde product of membrane lipid peroxidation, has been suggested to mediate a number of oxidative stress-linked pathological events in humans, including cellular growth inhibition and apoptosis induction. Because HNE is potentially reactive to a number of both cell surface and intracellular proteins bearing sulfhydryl, amino and imidazole groups, it seems that there are multiple signal transduction cascades. Here we briefly review the HNE-triggered signal transduction cascades that lead to suppression of cellular functions and to cell death, based mainly on our own recent study results. We first showed that formation of HNE-cell surface protein adducts, which mimicked ligand-cell surface receptor binding, induced activation of receptor-type protein tyrosine kinases such as epithelial growth factor receptor (EGFR) and that this caused growth inhibition through a cascade of activation of EGFR, Shc and ERK. Next, we showed that HNE-mediated scavenging of cellular glutathione led to activation of caspases and to DNA fragmentation through a Fas-independent and mitochondria-linked pro-apoptotic signal pathway. More recently, we have obtained evidence that the HNE-triggered signal cascade for caspase activation encounters complex positive feedback regulatory mechanisms that are linked to the inhibition of anti-apoptotic signals and are dependent on caspase activity. Underlying multiple regulatory mechanisms, including mechanisms of activation of Akt-dephosphorylating PP2A activity, activities of protein tyrosine kinases have been shown to be biphasically controlled by HNE. In addition, we have obtained results suggesting that HNE inhibits phosphorylation of IkappaB, possibly by targeting some elements upstream of IkappaB, which might downregulate the NF-kappaB-mediated cellular responses, including serum deprivation-induced iNOS expression and generation of anti-apoptotic signals. These results suggest that HNE reacts with multiple cell surface and intracellular sites for triggering a network of signal transduction that is ultimately focused on suppression of cellular functions.

中文翻译：

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4-羟基壬醛触发多步信号转导级联反应，以抑制细胞功能。

有人提出4-羟基壬烯醛（HNE）是膜脂质过氧化的醛产物，可介导人类许多与氧化应激相关的病理事件，包括细胞生长抑制和凋亡诱导。由于HNE可能对许多带有巯基，氨基和咪唑基团的细胞表面和细胞内蛋白发生反应，因此似乎存在多个信号转导级联。在这里，我们主要根据我们自己最近的研究结果，简要回顾一下HNE触发的信号转导级联反应，该反应导致细胞功能受到抑制并导致细胞死亡。我们首先表明，HNE细胞表面蛋白加合物的形成类似于配体与细胞表面受体的结合，诱导受体型蛋白酪氨酸激酶如上皮生长因子受体（EGFR）的激活，并通过EGFR，Shc和ERK的激活级联引起生长抑制。接下来，我们表明，HNE介导的细胞内谷胱甘肽清除作用导致胱天蛋白酶激活，并通过独立于Fas和线粒体相关的促凋亡信号通路使DNA断裂。最近，我们已经获得证据表明，HNE触发的Caspase激活信号级联遇到复杂的正反馈调节机制，该机制与抗凋亡信号的抑制有关，并且依赖Caspase活性。多种调节机制的基础，包括激活Akt磷酸化PP2A活性的机制，酪氨酸蛋白激酶的活性已显示受HNE双重控制。此外，我们已经获得的结果表明，HNE可能通过靶向IkappaB上游的某些元素来抑制IkappaB的磷酸化，这可能下调NF-kappaB介导的细胞反应，包括血清剥夺诱导的iNOS表达和抗凋亡信号的产生。 。这些结果表明，HNE与多个细胞表面和细胞内部位发生反应，以触发信号转导网络，该网络最终集中于抑制细胞功能。包括血清剥夺诱导的iNOS表达和抗凋亡信号的产生。这些结果表明，HNE与多个细胞表面和细胞内部位发生反应，以触发信号转导网络，该网络最终集中于抑制细胞功能。包括血清剥夺诱导的iNOS表达和抗凋亡信号的产生。这些结果表明，HNE与多个细胞表面和细胞内部位发生反应，以触发信号转导网络，该网络最终集中于抑制细胞功能。