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

Details

• Personal Author:
  Bi Y ; He X ; Ma Q ; Rojanasakul Y ; Szklarz GD ; Wang L
• 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. [Description provided by NIOSH]
• Subjects:
  Animals Carcinogens Energy Metabolism Environmental Exposure Environmental Pollution Enzymes Genetics Hazardous Substances Laboratories Occupational Health Pathology Risk Assessment Risk Factors Safety Toxicology

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• Keywords:
  ARE Author Keywords: Ah Receptor Cross-interaction Environmental-contamination Environmental-hazards Enzymatic-disorders Enzymatic-effects Exposure-levels Genes Hazards Laboratory-animals Metabolism NQO1 Nrf2 Proteins Risk-factors TCDD Toxins

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• ISSN:
  0003-9861
• Document Type:
  Text
• Genre:
  Journal Article
• Place as Subject:
  OSHA Region 3 ; West Virginia
• CIO:
  National Institute for Occupational Safety and Health (NIOSH)
• Division:
  HELD - Health Effects Laboratory Division
• Topic:
  Workplace Safety & Health
• Location:
  North America
• Pages in Document:
  31-38
• Volume:
  537
• Issue:
  1
• NIOSHTIC Number:
  nn:20042963
• Citation:
  Arch Biochem Biophys 2013 Sep; 537(1):31-38
• Contact Point Address:
  Liping Wang, 185 Donghu Road, Wuhan, Hubei 430071, China
• Email:
  may21thwlp@163.com
• Federal Fiscal Year:
  2013
• NORA Priority Area:
  Manufacturing
• Peer Reviewed:
  True
• Source Full Name:
  Archives of Biochemistry and Biophysics
• Collection(s):
  National Institute for Occupational Safety and Health
• Main Document Checksum:
  urn:sha-512:f85ea965708d6d67d3893432420e1093de6d4c42e1da1b8cebf19975b98a1f0265fbc3f9563e344273d463df9f2db1655dc1dd7addaafaa22c8e34ea4a705bed
• Download URL:
  https://stacks.cdc.gov/view/cdc/195010/cdc_195010_DS1.pdf
• File Type:
  [PDF - 940.80 KB ]