The NRF2-KEAP1 Pathway Is an Early Responsive Gene Network in Arsenic Exposed Lymphoblastoid Cells

Abstract

Inorganic arsenic (iAs), a major environmental contaminant, has risen as an important health problem worldwide. More detailed identification of the molecular mechanisms associated with iAs exposure would help to establish better strategies for prevention and treatment. Although chronic iAs exposures have been previously studied there is little to no information regarding the early events of exposure to iAs. To better characterize the early mechanisms of iAs exposure we conducted gene expression studies using sublethal doses of iAs at two different time-points. The major transcripts differentially regulated at 2 hrs of iAs exposure included antioxidants, detoxificants and chaperones. Moreover, after 12 hrs of exposure many of the down-regulated genes were associated with DNA replication and S phase cell cycle progression. Interestingly, the most affected biological pathway by both 2 or 12 hrs of iAs exposure were the Nrf2-Keap1 pathway, represented by the highly up-regulated HMOX1 transcript, which is transcriptionally regulated by the transcription factor Nrf2. Additional Nrf2 targets included SQSTM1 and ABCB6, which were not previously associated with acute iAs exposure. Signalling pathways such as interferon, B cell receptor and AhR route were also responsive to acute iAs exposure. Since HMOX1 expression increased early (20 min) and was responsive to low iAs concentrations (0.1 µM), this gene could be a suitable early biomarker for iAs exposure. In addition, the novel Nrf2 targets SQSTM1 and ABCB6 could play an important and previously unrecognized role in cellular protection against iAs.

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

“…Consistent with previous results [14], As treatment greatly induced Nrf2 protein content in MEL cells, and subsequentially increased the luciferase reporter activity of pGL3/ARE (an established construct to assay the transcriptional activity of Nrf2 [55]) in MEL cells ( Fig. 3E, Po 0.05).…”

“…The important role of Nrf2 in anti-stress responses has also been documented in erythroid cells [14,71]. Although evidence suggested that ATF4 could interact with Nrf2 to regulate the expression of antioxidant enzymes (e.g.…”

“…residues of Keap1 protein, resulting in the disruption of the contact between Keap1 and Nrf2 [11,[14][15][16]. Meanwhile, burgeoning evidence suggests that Nrf2 also targets mircroRNAs (miRNAs) that are involved in cell metabolism, adhesion, tumorigenesis and so on [17,18].…”

An Integrated Network Approach to Identifying Biological Pathways and Environmental Exposure Interactions in Complex Diseases

“…Indeed, arsenic occurred most frequently in conjunction with “signaling by GPCR” and “GPCR downstream signaling”, with a combined 225 co-occurrences and an approximate 1.4% chance co-occurrence, and less than 2.3% chance respectively. Arsenic exposure also had a high number of co-occurrences with more specific signaling transduction pathways such as T-cell receptor signaling (28 co-occurrences, 1% probability) 19 and B-cell receptor signaling (36 co-occurrences, 1.2% probability), 20 both of which have been supported by scientific literature.…”

Skin Metabolite, Farnesyl Pyrophosphate, Regulates Epidermal Response to Inflammation, Oxidative Stress, and Migration

“…In addition, the Ectodermal‐Neural Cortex 1 (ENC1) gene, a negative regulator of NRF2 (Wang and Zhang, ), was also found down‐regulated by ZGA (Supplementary Materials S1 and 2). The Nrf2‐mediated oxidative stress response pathway has been shown to play an important role in protecting cells against oxidative damage and promoting detoxification (Cordova et al, ). Nrf2 has been shown to aid in the acute wound healing process by regulating inflammation and promoting survival of keratinocytes under stress conditions (Braun et al, ).…”