Cell Survival Responses to Environmental Stresses Via the Keap1-Nrf2-ARE Pathway

Abstract

Keap1-Nrf2-ARE signaling plays a significant role in protecting cells from endogenous and exogenous stresses. The development of Nrf2 knockout mice has provided key insights into the toxicological importance of this pathway. These mice are more sensitive to the hepatic, pulmonary, ovarian, and neurotoxic consequences of acute exposures to environmental agents and drugs, inflammatory stresses, as well as chronic exposures to cigarette smoke and other carcinogens. Under quiescent conditions, the transcription factor Nrf2 interacts with the actin-anchored protein Keap1, largely localized in the cytoplasm. This quenching interaction maintains low basal expression of Nrf2-regulated genes. However, upon recognition of chemical signals imparted by oxidative and electrophilic molecules, Nrf2 is released from Keap1, escapes proteasomal degradation, translocates to the nucleus, and transactivates the expression of several dozen cytoprotective genes that enhance cell survival. This review highlights the key elements in this adaptive response to protection against acute and chronic cell injury provoked by environmental stresses.

miR-214 protects erythroid cells against oxidative stress by targeting ATF4 and EZH2

“…3A). The canonical ARE typically harbors a consensus sequence of 5′ TGAC-nnn-GC-3′ that could be specifically recognized by Nrf2, and the binding to ARE by Nrf2 is fundamentally involved in anti-oxidative stress responses [3,53]. To interrogate the binding of Nrf2 to the ARE within its promoter region, the ChIP assay in MEL cells was performed.…”

“…A considerable number of studies have demonstrated that Nrf2 signaling protects cells from many hazardous stimuli, such as radiation, invading pathogens and foreign chemicals (e.g. drugs through therapeutic interventions and environmental toxicants) [3][4][5]. Nrf2 directly targets a battery of roughly 250 genes responsible for a wide array of cellular antioxidant responses and detoxification processes, e.g.…”

“…Increased intracellular free radicals, such as reactive oxygen species (ROS), can trigger the dissociation of Keap1-Nrf2 complex, leading to nuclear translocation of Nrf2 and the transcriptional activation of its target genes through ARE in their promoter [9,10]. In fact, Keap1-Nrf2 complex is a most important cellular protection mechanism against a battery of toxic products including arsenic (As) [11][12][13], which could trigger oxidative stress and subsequently cause the modification changes of critical cysteine Abbreviations: ATF-4, activating transcription factor 4; Bim, BCL2-like 11; EZH2, enhancer of zeste 2 polycomb repressive complex 2 subunit; eIF2, eukaryotic initiation factor-2; Fe-NTA, ferric nitrilotriacetate; Hri, eukaryotic translation initiation factor 2 alpha kinase 1; Nrf2, nuclear factor erythroid 2-related factor 2; ROS, reactive oxygen species n Corresponding author at: 18 Shuangqing Road, Haidian, Beijing 100085, China.…”

Oxidative stress-inducible lentiviral vectors for gene therapy

“…Moreover, factors involved in ARE activation are highly homologous, thereby allowing cross-species activation of ARE-containing vectors. 35 It is therefore unlikely that AREs from the mouse gene would be functionally impaired in human cells thereby explaining the differences in activity. Conversely, vectors having ARE sequences derived from human genes are likely to be functional in cells derived form other species allowing the use of these in animal models of CVD.…”

The NRF2‐related interactome and regulome contain multifunctional proteins and fine‐tuned autoregulatory loops

“…Activation of NRF2 is a well-known adaptive response to environmental and endogenous stresses. Recent studies uncovered that NRF2 influences a wide range of physiologic and pathologic processes such as inflammation, carcinogenesis, chronic obstructive pulmonary disease, obesity, and neurodegeneration [9].…”