The aryl hydrocarbon receptor interacts with nuclear factor erythroid 2-related factor 2 to mediate induction of NAD(P)H: quinoneoxidoreductase 1 by 2,3,7,8-tetrachlorodibenzo-p-dioxin

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• Alternative Title:
  Arch Biochem Biophys
• Personal Author:
  Wang, Liping ; He, Xiaoqing ; Szklarz, Grazyna D. ; Bi, Yongyi ; Rojanasakul, Yon ; Ma, Qiang
• Description:
  NAD(P)H:quinoneoxidoreductase 1 (NQO1) belongs to a group of the aryl hydrocarbon receptor (AhR) battery of drug-metabolizing enzymes that are characteristically induced by both AhR agonists and nuclear factor erythroid 2-related factor 2 (Nrf2) activators. We have previously reported that induction of Nqo1 by the AhR agonist 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) in hepa1c1c7 cells involves Nrf2 (Ma et al., Biochem J 377, 205-213, 2004). Here we analyzed the molecular mechanism of induction. Induction required AhR and its DNA-binding partner Arnt because induction was not observed in AhR or Arnt-defective cells, but induction was restored upon reconstitution of the variant cells with functional AhR or Arnt. Induction also required Nrf2, as induction by benzo[a]pyrene was lost in the liver of Nrf2 knockout mice similarly to induction by butyl hydroxyanisol, demonstrating a cross-interaction between the AhR and Nrf2 pathways for induction in vivo. TCDD increased the protein level and induced the nuclear accumulation of Nrf2 with a delayed kinetics compared with activation of AhR. Chromatin immunoprecipitation revealed that TCDD recruited both AhR and Nrf2 to the Nqo1 promoter enhancer region containing a DRE and an ARE in time-dependent manners. Co-immunoprecipitation experiments revealed that, in addition to AhR-Arnt binding, TCDD induced an interaction between AhR and Nrf2 as well as Keap1. The findings reveal that TCDD induces multi protein complexes to mediate cross-interaction between the AhR and Nrf2 pathways, uncovering a novel mechanistic aspect of gene regulation by environmental chemicals through AhR and Nrf2.
• Subjects:
  Ah Receptor Animals ARE Article Cell Line Cross-interaction Hepatocytes Liver Mice Mice, Inbred C57BL Mice, Knockout NAD(P)H Dehydrogenase (Quinone) NF-E2-Related Factor 2 NQO1 Nrf2 Receptors, Aryl Hydrocarbon Signal Transduction TCDD Tetrachlorodibenzodioxin

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• Source:
  Arch Biochem Biophys. 537(1):31-38.
• Pubmed ID:
  23800876
• Pubmed Central ID:
  PMC4597779
• Document Type:
  Journal Article
• Funding:
  CC999999/Intramural CDC HHS/United States
• Volume:
  537
• Issue:
  1
• Collection(s):
  CDC Public Access
• Main Document Checksum:
  urn:sha256:ab9f44b8c5b34ca2924af1fec02eefe6262b5b233e6b60679e3e86a5797ac13b
• Download URL:
  https://stacks.cdc.gov/view/cdc/34851/cdc_34851_DS1.pdf
• File Type:
  [PDF - 1.57 MB ]