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- W4376127580 endingPage "251" @default.
- W4376127580 startingPage "243" @default.
- W4376127580 abstract "The redox sensitive transcription factor NRF2 is a central regulator of the transcriptional response to reactive oxygen species (ROS). NRF2 is widely recognized for its ROS-responsive upregulation of antioxidant genes that are essential for mitigating the damaging effects of oxidative stress. However, multiple genome-wide approaches have suggested that NRF2's regulatory reach extends well beyond the canonical antioxidant genes, with the potential to regulate many noncanonical target genes. Recent work from our lab and others suggests HIF1A, which encodes the hypoxia-responsive transcription factor HIF1α, is one such noncanonical NRF2 target. These studies found that NRF2 activity is associated with high HIF1A expression in multiple cellular contexts, HIF1A expression is partially dependent on NRF2, and there is a putative NRF2 binding site (antioxidant response element, or ARE) approximately 30 kilobases upstream of HIF1A. These findings all support a model in which HIF1A is a direct target of NRF2, but did not confirm the functional importance of the upstream ARE in HIF1A expression. Here we use CRISPR/Cas9 genome editing to mutate this ARE in its genomic context and test the impact on HIF1A expression. We find that mutation of this ARE in a breast cancer cell line (MDA-MB-231) eliminates NRF2 binding and decreases HIF1A expression at the transcript and protein levels, and disrupts HIF1α target genes as well as phenotypes driven by these HIF1α targets. Taken together, these results indicate that this NRF2 targeted ARE plays an important role in the expression of HIF1A and activity of the HIF1α axis in MDA-MB-231 cells." @default.
- W4376127580 created "2023-05-12" @default.
- W4376127580 creator A5021343649 @default.
- W4376127580 creator A5035692441 @default.
- W4376127580 creator A5051456943 @default.
- W4376127580 creator A5064427220 @default.
- W4376127580 creator A5066162680 @default.
- W4376127580 date "2023-08-01" @default.
- W4376127580 modified "2023-09-29" @default.
- W4376127580 title "An antioxidant response element regulates the HIF1α axis in breast cancer cells" @default.
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