Review Article
JNK signaling pathway is a key modulator in cell death mediated by reactive oxygen and nitrogen species

https://doi.org/10.1016/j.freeradbiomed.2005.10.056Get rights and content

Abstract

c-Jun N-terminal kinase (JNK), or stress-activated protein kinase, is an important member of the mitogen-activated protein kinase superfamily, the members of which are readily activated by many environmental stimuli. Reactive oxygen species (ROS) and reactive nitrogen species (RNS) are important groups of free radicals that are capable of eliciting direct damaging effects or acting as critical intermediate signaling molecules, leading to oxidative and nitrosative stress and a series of biological consequences. Recently there has been an increasing amount of research interest focusing on the regulatory role of JNK activation in ROS-and RNS–induced cellular responses. In this review we will first summarize and discuss some recent findings regarding the signaling mechanisms of ROS-or RNS-mediated JNK activation. Second, we will talk about the role of JNK in ROS-or RNS-mediated cell death (both apoptosis and necrosis). Finally, we will analyze the emerging evidence for the involvement of ROS and RNS as mediators in tumor necrosis factor α-induced apoptosis. Taken together, the accumulating knowledge about the ROS/RNS-induced JNK signaling pathway has greatly advanced our understanding of the complex processes deciding the cellular responses to environmental stress.

Section snippets

JNK activation induced by both exogenous and endogenous ROS

It has been well established that ROS are potent inducers of JNK. Most reports on ROS-induced JNK activation result from using exogenous ROS, mostly H2O2 [14]. Although H2O2 is a relatively weak oxidant compared to other ROS such as radical dotOH, it has emerged as a particularly important signaling molecule based on its unique biochemical properties: H2O2 is ubiquitously present in the biological system with a relatively long half-life; and more importantly H2O2 is soluble in both lipid and aqueous

JNK activation in oxidative stress-induced apoptosis

ROS and oxidative stress are known as apoptosis triggers and modulators [68], [69]. Exogenous ROS such as H2O2 at moderate levels induce apoptosis in many types of cells [19]. Endogenously produced ROS have also been found to be important in the apoptotic cell death process triggered by many other stimuli such as UV, ionizing radiation, cancer therapeutical drugs, and cytokines [9], [68], [69]. Because ROS themselves are not able to activate, but rather suppress redox-sensitive caspase

Involvement of ROS/RNS and JNK activation in TNF-α-induced apoptosis

Most of the studies we have discussed so far are based on systems in which oxidative stress or nitrosative stress is induced by exogenously applied ROS or RNS. It has been well studied that high levels of ROS or RNS produced endogenously are part of the mechanisms contributing to the cell death process induced by many stress factors, such as UV, ionizing radiation, cancer chemotherapeutics, and TNF-α [9], [68], [69]. TNF-α is a pleiotropic cytokine with critical regulatory roles in diverse

Summary and perspectives

The importance of JNK activation in cell death mediated by ROS and RNS has been gradually appreciated in recent years. It is believed that ROS/RNS-mediated JNK activation is a critical component deciding the fate of cells in response to various stress stimuli, including TNF-α. One important implication of such knowledge is related to our understanding of the link between chronic inflammation and carcinogenesis. The recent work by Karin and his colleagues, using an in vivo hepatocarcinogenesis

Acknowledgments

The authors thank Dr. Yong Lin for his valuable comments and Dr. Siyuan Zhang for preparing the illustrations. This work was in part supported by an Oncology Fellowship from the NCI, NIH (to H.M. Shen), and research grants from the NUS Academic Research Fund and the Biomedical Research Council, Singapore.

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