Antioxidant response elements: Discovery, classes, regulation and potential applications

Abstract

Exposure to antioxidants and xenobiotics triggers the expression of a myriad of genes encoding antioxidant proteins, detoxifying enzymes, and xenobiotic transporters to offer protection against oxidative stress. This articulated universal mechanism is regulated through the cis-acting elements in an array of Nrf2 target genes called antioxidant response elements (AREs), which play a critical role in redox homeostasis. Though the Keap1/Nrf2/ARE system involves many players, AREs hold the key in transcriptional regulation of cytoprotective genes. ARE-mediated reporter constructs have been widely used, including xenobiotics profiling and Nrf2 activator screening. The complexity of AREs is brought by the presence of other regulatory elements within the AREs. The diversity in the ARE sequences not only bring regulatory selectivity of diverse transcription factors, but also confer functional complexity in the Keap1/Nrf2/ARE pathway. The different transcription factors either homodimerize or heterodimerize to bind the AREs. Depending on the nature of partners, they may activate or suppress the transcription. Attention is required for deeper mechanistic understanding of ARE-mediated gene regulation. The computational methods of identification and analysis of AREs are still in their infancy. Investigations are required to know whether epigenetics mechanism plays a role in the regulation of genes mediated through AREs. The polymorphisms in the AREs leading to oxidative stress related diseases are warranted. A thorough understanding of AREs will pave the way for the development of therapeutic agents against cancer, neurodegenerative, cardiovascular, metabolic and other diseases with oxidative stress.

Identification of compounds that inhibit the binding of Keap1a/Keap1b Kelch DGR domain with Nrf2 ETGE/DLG motifs in zebrafish

“…These identified inhibitors corroborate with the principle that DLG and ETGE motifs of Nrf2 are obstructed to interact with Keap1a/Keap1b Kelch domains as demonstrated from structural and functional studies . Yet another complexity in Keap1/Nrf2/ARE pathway is that different groups of compounds elicit this cytoprotective pathway via different mechanisms of activation . This is due to the structural diversity in the compounds.…”

“…55 Yet another complexity in Keap1/Nrf2/ARE pathway is that different groups of compounds elicit this cytoprotective pathway via different mechanisms of activation. [56][57][58] This is due to the structural diversity in the compounds. Neurodegenerative diseases are one among the oxidative stress-mediated disorders, and most of the best compounds identified to disrupt Keap1a/b interaction with Nrf2 have the potential to cross the blood-brain barrier.…”

Nrf2 promotes breast cancer cell migration via up‐regulation of G6PD/HIF‐1α/Notch1 axis

“…4 The antioxidant response is principally mediated by the transcription factor Nrf2, which induces the transcriptional activation of several genes involved in glutathione (GSH) synthesis, chemoresistance and cytoprotection. 5 Despite the recent progress in the characterization of Nrf2 transcription factors, biological functions of Nrf2 remain to be explored. 5 Despite the recent progress in the characterization of Nrf2 transcription factors, biological functions of Nrf2 remain to be explored.…”

Epigenetic treatment of dermatologic disorders

“…Representing the outermost surface of the body, skin is uniquely vulnerable to a plethora of environmental insults. Exposure to harmful chemicals, xenobiotics, oxidative stress, and solar UV‐radiation is mitigated by various protective mechanisms that rely on signaling networks and the expression of proteins involved in the detoxification of compounds or reactive oxygen species (Dinkova‐Kostova et al, ; Dodson et al, ; Hiebert et al, ; Jadkauskaite et al, ; Raghunath et al, ; Siegenthaler et al, ; Sivandzade, Prasad, Bhalerao, & Cucullo, ; Tonelli, Chio, & Tuveson, ; Vega, Krajisnik, Zhang, & Wondrak, ; Yamamoto, Kensler, & Motohashi, ).…”