logo logo
Nitric oxide as a modulator of apoptosis. Li Chun-Qi,Wogan Gerald N Cancer letters Unphysiologically high levels of nitric oxide (NO*) are mutagenic and may contribute to carcinogenesis. Proapoptotic and anitiapoptotic functions of NO* have been reported in various in vivo and in vitro experimental models. The complexity of biological responses induced is a consequence of the multiple chemical pathways through which NO* causes damage to critical cellular macromolecules. The extent and kinetics of apoptotic and other responses are highly dependent on steady-state NO* levels, cumulative total dose and cell type. Steady-state and total dose thresholds have been defined, both of which must be exceeded for the induction of apoptosis and other responses in human lymphoblastoid cells. DNA damage, protein modifications, p53 activation and mitochondrial respiratory inhibition contribute to NO*-mediated apoptosis via mitochondrial and Fas receptor pathways. Multifaceted cellular defense systems including glutathione, antioxidant enzymes and Nrf2-Keap1 signaling participate in protective responses to mitigate damage by toxic levels of NO*. 10.1016/j.canlet.2004.10.021
The cytoprotective role of the Keap1-Nrf2 pathway. Baird Liam,Dinkova-Kostova Albena T Archives of toxicology An elaborate network of highly inducible proteins protects aerobic cells against the cumulative damaging effects of reactive oxygen intermediates and toxic electrophiles, which are the major causes of neoplastic and chronic degenerative diseases. These cytoprotective proteins share common transcriptional regulation, through the Keap1-Nrf2 pathway, which can be activated by various exogenous and endogenous small molecules (inducers). Inducers chemically react with critical cysteine residues of the sensor protein Keap1, leading to stabilisation and nuclear translocation of transcription factor Nrf2, and ultimately to coordinate enhanced expression of genes coding for cytoprotective proteins. In addition, inducers inhibit pro-inflammatory responses, and there is a linear correlation spanning more than six orders of magnitude of concentrations between inducer and anti-inflammatory activity. Genetic deletion of transcription factor Nrf2 renders cells and animals much more sensitive to the damaging effects of electrophiles, oxidants and inflammatory agents in comparison with their wild-type counterparts. Conversely, activation of the Keap1-Nrf2 pathway allows survival and adaptation under various conditions of stress and has protective effects in many animal models. Cross-talks with other signalling pathways broadens the role of the Keap1-Nrf2 pathway in determining the fate of the cell, impacting fundamental biological processes such as proliferation, apoptosis, angiogenesis and metastasis. 10.1007/s00204-011-0674-5
Molecular Mechanism of Cellular Oxidative Stress Sensing by Keap1. Suzuki Takafumi,Muramatsu Aki,Saito Ryota,Iso Tatsuro,Shibata Takahiro,Kuwata Keiko,Kawaguchi Shin-Ichi,Iwawaki Takao,Adachi Saki,Suda Hiromi,Morita Masanobu,Uchida Koji,Baird Liam,Yamamoto Masayuki Cell reports The Keap1-Nrf2 system plays a central role in the oxidative stress response; however, the identity of the reactive oxygen species sensor within Keap1 remains poorly understood. Here, we show that a Keap1 mutant lacking 11 cysteine residues retains the ability to target Nrf2 for degradation, but it is unable to respond to cysteine-reactive Nrf2 inducers. Of the 11 mutated cysteine residues, we find that 4 (Cys226/613/622/624) are important for sensing hydrogen peroxide. Our analyses of multiple mutant mice lines, complemented by MEFs expressing a series of Keap1 mutants, reveal that Keap1 uses the cysteine residues redundantly to set up an elaborate fail-safe mechanism in which specific combinations of these four cysteine residues can form a disulfide bond to sense hydrogen peroxide. This sensing mechanism is distinct from that used for electrophilic Nrf2 inducers, demonstrating that Keap1 is equipped with multiple cysteine-based sensors to detect various endogenous and exogenous stresses. 10.1016/j.celrep.2019.06.047
Beyond repression of Nrf2: An update on Keap1. Free radical biology & medicine Nrf2 (NFE2L2 - nuclear factor (erythroid-derived 2)-like 2) is a transcription factor, which is repressed by interaction with a redox-sensitive protein Keap1 (Kelch-like ECH-associated protein 1). Deregulation of Nrf2 transcriptional activity has been described in the pathogenesis of multiple diseases, and the Nrf2/Keap1 axis has emerged as a crucial modulator of cellular homeostasis. Whereas the significance of Nrf2 in the modulation of biological processes has been well established and broadly discussed in detail, the focus on Keap1 rarely goes beyond the regulation of Nrf2 activity and redox sensing. However, recent studies and scrutinized analysis of available data point to Keap1 as an intriguing and potent regulator of cellular function. This review aims to shed more light on Keap1 structure, interactome, regulation and non-canonical functions, thereby enhancing its significance in cell biology. We also intend to highlight the impact of balance between Keap1 and Nrf2 in the maintenance of cellular homeostasis. 10.1016/j.freeradbiomed.2020.03.023
Stress-induced peroxiredoxins. Ishii Tetsuro,Yanagawa Toru Sub-cellular biochemistry Some members of the Prx family are up-regulated in cells under stress conditions. Prx I is the major cytoplasmic Prx and is known as a stress-inducible antioxidant enzyme. Various stress agents or conditions activate Prx I gene expression in vitro and in vivo. The transcription factor Nrf2 and its inhibitor Keap1 play an essential role in the regulation of the stress-induced Prx I gene activation through the ARE/EpRE (antioxidant/electrophile response element). The expression levels of Prx II and III are also up-regulated under stress conditions, although the molecular mechanisms of their up-regulation have not yet been thoroughly studied. Gene expression of both Prx I and II is activated by X-ray irradiation of the testis. Mitochondrial Prx III is up-regulated by stress agents in both cultured cells and experimental animals. The up-regulation of the Prxs in cells and tissues under oxidative stress conditions is one of the cellular recovery responses after oxidative damage. 10.1007/978-1-4020-6051-9_18
Epigenetic regulation of Keap1-Nrf2 signaling. Guo Yue,Yu Siwang,Zhang Chengyue,Kong Ah-Ng Tony Free radical biology & medicine The kelch-like ECH-associated protein 1 (Keap1)-nuclear factor erythroid 2-related factor 2 (Nrf2) signaling axis serves as a "master regulator" in response to oxidative/electrophilic stresses and chemical insults through the coordinated induction of a wide array of cytoprotective genes. Therefore, activation of Nrf2 is considered to be an important approach for preventing chronic diseases triggered by stresses and toxins, including cancer. Despite extensive studies suggested that the Keap1-Nrf2 signaling pathway is subject to multiple layers of regulation at the transcriptional, translational, and post-translational levels, the potential epigenetic regulation of Nrf2 and Keap1 has begun to be recognized only in recent years. Epigenetic modifications, heritable alterations in gene expression that occur without changes in the primary DNA sequence, have been reported to be profoundly involved in oxidative stress responses. In this review, we discuss the latest findings regarding the epigenetic regulation of Keap1-Nrf2 signaling by DNA methylation, histone modification, and microRNAs. The crosstalk among these epigenetic modifications in the regulation of Keap1-Nrf2 signaling pathways is also discussed. Studies of the epigenetic modification of Nrf2 and Keap1 have not only enhanced our understanding of this complex cellular defense system but have also provided potential new therapeutic targets for the prevention of certain diseases. 10.1016/j.freeradbiomed.2015.06.013
Discovery of the negative regulator of Nrf2, Keap1: a historical overview. Itoh Ken,Mimura Junsei,Yamamoto Masayuki Antioxidants & redox signaling An antioxidant response element (ARE) or an electrophile responsive element (EpRE) regulate the transcriptional induction of a battery of drug-detoxifying enzymes that are protective against electrophiles. Based on the high similarity of the ARE consensus sequence to an erythroid gene regulatory element NF-E2 binding site, we have found that the transcription factor Nrf2 is indispensable for the ARE-mediated induction of drug-metabolizing enzymes. Recent genome-wide analysis demonstrated that Nrf2 regulates hundreds of genes that are involved in the cytoprotective response against oxidative stress. In-depth analysis of Nrf2 regulatory mechanisms has led us to the discovery of a novel protein, which we have named Keap1. Keap1 suppresses Nrf2 activity by specifically binding to its evolutionarily conserved N-terminal Neh2 regulatory domain. In this review article, we summarize the findings and observations that have lead to the discovery of the Nrf2-Keap1 system. Furthermore, we briefly discuss the function of the Nrf2-Keap1 system under the regulation of the endogenous electrophilic compound 15-deoxy-Δ¹²(,)¹⁴-prostaglandin J₂. We propose that Nrf2-Keap1 plays a significant physiological role in the response to endogenous, environmental, and pharmacological electrophiles. 10.1089/ars.2010.3222