RPA1 binding to NRF2 switches ARE-dependent transcriptional activation to ARE-NRE–dependent repression

Liu, Pengfei; Vega, Montserrat Rojo de la; Sammani, Saad; Mascarenhas, Joseph B.; Kerins, Michael; Dodson, Matthew; Sun, Xiaoguang; Wang, Ting; Ooi, Aikseng; Garcia, Joe G.N.; Zhang, Donna D.

doi:10.1073/pnas.1812125115

Cited by 46 publications

(53 citation statements)

References 50 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Additionally, the total protein concentration and the levels of IL-6 and TNF-α in each sample were detected with the Pierce BCA Protein Assay Kit (Thermo Fisher Scientific), IL-6 ELISA Kit ELISA kit (Invitrogen) and TNF-α ELISA Kit (Invitrogen) according to the manufacturer's instructions. Lung tissues in different groups were collected for qPCR and western blot detection, and part of lung tissues was fixed using 10% buffered formalin, then the tissues were embedded in paraffin for histological analyses as the references [25,[30][31][32]. Herein, a scoring system of 0-4 was used for the evaluation of lung injury as the reference [33].…”

Section: Animal Experimentsmentioning

confidence: 99%

Ferrostatin-1 alleviates lipopolysaccharide-induced acute lung injury via inhibiting ferroptosis

et al. 2020

Self Cite

View full text Add to dashboard Cite

Background: Ferroptosis is a newly recognized type of cell death, which is different from traditional necrosis, apoptosis or autophagic cell death. However, the position of ferroptosis in lipopolysaccharide (LPS)-induced acute lung injury (ALI) has not been explored intensively so far. In this study, we mainly analyzed the relationship between ferroptosis and LPS-induced ALI. Methods: In this study, a human bronchial epithelial cell line, BEAS-2B, was treated with LPS and ferrostatin-1 (Fer-1, ferroptosis inhibitor). The cell viability was measured using CCK-8. Additionally, the levels of malondialdehyde (MDA), 4-hydroxynonenal (4-HNE), and iron, as well as the protein level of SLC7A11 and GPX4, were measured in different groups. To further confirm the in vitro results, an ALI model was induced by LPS in mice, and the therapeutic action of Fer-1 and ferroptosis level in lung tissues were evaluated. Results: The cell viability of BEAS-2B was down-regulated by LPS treatment, together with the ferroptosis markers SLC7A11 and GPX4, while the levels of MDA, 4-HNE and total iron were increased by LPS treatment in a dose-dependent manner, which could be rescued by Fer-1. The results of the in vivo experiment also indicated that Fer-1 exerted therapeutic action against LPS-induced ALI, and down-regulated the ferroptosis level in lung tissues. Conclusions: Our study indicated that ferroptosis has an important role in the progression of LPS-induced ALI, and ferroptosis may become a novel target in the treatment of ALI patients.

show abstract

Section: Animal Experimentsmentioning

confidence: 99%

Ferrostatin-1 alleviates lipopolysaccharide-induced acute lung injury via inhibiting ferroptosis

et al. 2020

Self Cite

View full text Add to dashboard Cite

show abstract

“…In this model, RPA1 becomes a novel NRF2-binding partner which competes with sMAF for NRF2 binding. The in silico and RNAseq data sets indicates that the NRF2-RPA1-ARE complex may also transcriptionally inhibit other genes, including cancer related gene, FOCAD [ 22 ].…”

Section: Introductionmentioning

confidence: 99%

NRF2 regulates the sensitivity of human NSCLC cells to cystine deprivation-induced ferroptosis via FOCAD-FAK signaling pathway

Liu

Duan

et al. 2020

Redox Biology

Self Cite

View full text Add to dashboard Cite

Transcription factor nuclear factor-erythroid 2-like 2 (NRF2) mainly regulates cellular antioxidant response, redox homeostasis and metabolic balance. Our previous study illustrated the translational significance of NRF2-mediated transcriptional repression, and the transcription of FOCAD gene might be negatively regulated by NRF2. However, the detailed mechanism and the related significance remain unclear. In this study, we mainly explored the effect of NRF2-FOCAD signaling pathway on ferroptosis regulation in human non-small-cell lung carcinoma (NSCLC) model. Our results confirmed the negative regulation relationship between NRF2 and FOCAD, which was dependent on NRF2-Replication Protein A1 (RPA1)-Antioxidant Response Elements (ARE) complex. In addition, FOCAD promoted the activity of focal adhesion kinase (FAK), which further enhanced the sensitivity of NSCLC cells to cysteine deprivation-induced ferroptosis via promoting the tricarboxylic acid (TCA) cycle and the activity of Complex I in mitochondrial electron transport chain (ETC). However, FOCAD didn't affect GPX4 inhibition-induced ferroptosis. Moreover, the treatment with the combination of NRF2 inhibitor (brusatol) and erastin showed better therapeutic action against NSCLC in vitro and in vivo than single treatment, and the improved therapeutic function partially depended on the activation of FOCAD-FAK signal. Taken together, our study indicates the close association of NRF2-FOCAD-FAK signaling pathway with cysteine deprivation-induced ferroptosis, and elucidates a novel insight into the ferroptosis-based therapeutic approach for the patients with NSCLC.

show abstract

“…Ahrr and tiparp are an integral part of AHR signaling and both have been shown to negatively regulate AHR activity by distinct mechanisms (MacPherson et al 2014). In addition, recent studies demonstrated that nrf2b, a homolog of mammalian nuclear factor, erythroid 2-like 2 (NFE2L2) also act as a repressor of gene expression (Bahn et al 2019;Liu et al 2018;Thangasamy et al 2011;Timme-Laragy et al 2012). The expression of these transcripts was upregulated in response to PCB126 exposure.…”

Section: Discussionmentioning

confidence: 99%

PCB126 exposure revealed alterations in m6A RNA modifications in transcripts associated with AHR activation

Aluru

Karchner

2020

Preprint

View full text Add to dashboard Cite

AbstractChemical modifications of proteins, DNA and RNA moieties play critical roles in regulating gene expression. Emerging evidence suggests these RNA modifications (epitranscriptomics) have substantive roles in basic biological processes. One of the most common modifications in mRNA and noncoding RNAs is N6-methyladenosine (m6A). In a subset of mRNAs, m6A sites are preferentially enriched near stop codons, in 3’ UTRs, and within exons, suggesting an important role in the regulation of mRNA processing and function including alternative splicing and gene expression. Very little is known about the effect of environmental chemical exposure on m6A modifications. As many of the commonly occurring environmental contaminants alter gene expression profiles and have detrimental effects on physiological processes, it is important to understand the effects of exposure on this important layer of gene regulation. Hence, the objective of this study was to characterize the acute effects of developmental exposure to PCB126, an environmentally relevant dioxin-like PCB, on m6A methylation patterns. We exposed zebrafish embryos to PCB126 for 6 hours starting from 72 hours post-fertilization and profiled m6A RNA using methylated RNA immunoprecipitation followed by sequencing (MeRIP-seq). Our analysis revealed 117 and 217 m6A peaks in the DMSO and PCB126 samples (FDR 5%), respectively. The majority of the peaks were preferentially located around the 3’UTR and stop codons. Statistical analysis revealed 15 m6A marked transcripts to be differentially methylated by PCB126 exposure. These include transcripts that are known to be activated by AHR agonists (e.g., ahrra, tiparp, nfe2l2b) as well as others that are important for normal development (vgf, cebpd, foxi1). These results suggest that environmental chemicals such as dioxin-like PCBs could affect developmental gene expression patterns by altering m6A levels. Further studies are necessary to understand the functional consequences of exposure-associated alterations in m6A levels.

show abstract

RPA1 binding to NRF2 switches ARE-dependent transcriptional activation to ARE-NRE–dependent repression

Cited by 46 publications

References 50 publications

Ferrostatin-1 alleviates lipopolysaccharide-induced acute lung injury via inhibiting ferroptosis

Ferrostatin-1 alleviates lipopolysaccharide-induced acute lung injury via inhibiting ferroptosis

NRF2 regulates the sensitivity of human NSCLC cells to cystine deprivation-induced ferroptosis via FOCAD-FAK signaling pathway

PCB126 exposure revealed alterations in m6A RNA modifications in transcripts associated with AHR activation

Contact Info

Product

Resources

About