A Cycloheximide-Sensitive Factor Regulates TCDD-Induced Degradation of the Aryl Hydrocarbon Receptor

Details

• Personal Author:
  Baldwin KT ; Ma Q
• Description:
  2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD), a prototype of environmental halogenated aromatic hydrocarbons, induces a rapid reduction in steady state aryl hydrocarbon receptor (AhR). Here, we analyzed the biochemical pathway and function of the downregulation. Our results reveal that TCDD downregulates the AhR protein by shortening the halflife of AhR. The TCDD-induced degradation of AhR is inhibited by MG132, a potent inhibitor of the 26S proteasome, indicating the ubiquitin-26S proteasome mediated proteolysis as a mechanism for the degradation of AhR. Furthermore, inhibition of protein synthesis by cycloheximide blocks the degradation of AhR by TCDD, suggesting a labile factor in controlling the stability of ligand-activated AhR (hence, designated as AhR degradation promoting factor, or ADPF). Analyses of nuclear AhR demonstrated that cycloheximide increases nuclear AhR protein and functional AhR/Arnt DNA-binding complex, resulting in superinduction of CYP1A1. Lastly, genetic analyses by using AhR- or Arnt-defective variant cells demonstrate that superinduction by cycloheximide requires the transcription activation (TA) domain of AhR, implicating the TA domain in the control of AhR turnover by ADPF. These findings provide new insights into the mechanism by which TCDD-activated AhR is regulated in nucleus through the 26S proteasome protein degradation pathway. [Description provided by NIOSH]
• Subjects:
  Animals Chlorine Compounds Genetics Hydrocarbons Laboratories Occupational Health Polycyclic Aromatic Hydrocarbons Safety
• Keywords:
  2,3,7,8-Tetrachlorodibenzo-p-dioxin 26S Proteasome Animal-studies Aromatic-hydrocarbons Author Keywords: Ah Receptor Chlorine-compounds Combustion-products Degradation Laboratory-animals Superinduction
• ISSN:
  0045-6535
• 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
• Volume:
  46
• Issue:
  9
• NIOSHTIC Number:
  nn:20022946
• Citation:
  Chemosphere 2002 Mar; 46(9-10):1491-1500
• Contact Point Address:
  Molecular Toxicology Laboratory, Toxicology and Molecular Biology Branch, Health Effects Laboratory Division, National Institute for Occupational Safety and Health, 1095 Willowdale Road, Morgantown, WV 26505, USA
• Email:
  qam1@cdc.gov
• CAS Registry Number:
  (-)-Cycloheximide (CAS RN 66-81-9) ; 2,3,7,8-Tetrachlorodibenzo-p-dioxin (CAS RN 1746-01-6)
• Federal Fiscal Year:
  2002
• Peer Reviewed:
  True
• Source Full Name:
  Chemosphere
• Collection(s):
  National Institute for Occupational Safety and Health
• Main Document Checksum:
  urn:sha-512:d7cc508832ce09fde289caf0c116a5986df474234dd3dca683c1c080ecccecf58ffce601634129b8a0eeb255589f2ccd0823864e823ea2461aedab678941725d
• Download URL:
  https://stacks.cdc.gov/view/cdc/199550/cdc_199550_DS1.pdf
• File Type:
  [PDF - 261.08 KB ]