TCDD-Induced Degradation of Ah Receptor by the Ubiquitin-Proteasome Pathway

Details

• Personal Author:
  Baldwin KT ; Ma Q
• Description:
  The aryl hydrocarbon receptor (AhA), a ligand-activated Bhlh/PAS transcription factor, mediates a broad range of biological responses to halogenated aromatic hydrocarbons. TCDD, a potent agonist for AhA, induces a rapid reduction of the steady state AhA. In this study, we analyzed the mechanism of the agonist-induced down regulation of AhA. We show that TCDD shortens the half life of AhA, as measured by pulse-chase experiment. The TCDD-induced degradation of both unlabeled and pulse-labeled AhA is blocked by lactacystin and MG132, potent inhibitors of the 26S proteasome. Treatment with TCDD induces formation of ubiquitinated AhA. Furthermore, analyses of AhA degradation in cells bearing a temperature-sensitive mutation in the ubiquitin-activating enzyme (E1) reveal that degradation of AhA in both untreated and TCDD-treated cells requires functional E1. Collectively, these studies demonstrate that TCDD induces degradation of AhA via a ubiquitin-proteasome pathway. Lastly, we show that treatment with proteasome inhibitors enhances the induction of CYP1A1 gene expression by TCDD, suggesting that the ubiquitinproteasome mediated degradation of AhA serves as a mechanism for controlling the activity of ligand-activated AhA. [Description provided by NIOSH]
• Subjects:
  Genetics Hydrocarbons Occupational Health Safety
• Keywords:
  Aromatic Hydrocarbons Aryls Biological Effects Genes Genetic Factors Halogenated Compounds Halogenated Hydrocarbons
• Document Type:
  Text
• Genre:
  Abstract or Summary ; Proceedings
• 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:
  82
• NIOSHTIC Number:
  nn:20020997
• Citation:
  Nuclear Receptors 2000 Mar; :82
• CAS Registry Number:
  2,3,7,8-Tetrachlorodibenzo-p-dioxin (CAS RN 1746-01-6)
• Federal Fiscal Year:
  2000
• Peer Reviewed:
  False
• Source Full Name:
  Nuclear Receptors
• Collection(s):
  National Institute for Occupational Safety and Health
• Main Document Checksum:
  urn:sha-512:ac8f0ea7154995fe402fa57450e2fa9a39a002fa440977fd680d34102af89242bef6b3ebae463416f0e78e6a09346d4e4ef11293ed34649d09210e64b6944a36
• Download URL:
  https://stacks.cdc.gov/view/cdc/198597/cdc_198597_DS1.pdf
• File Type:
  [PDF - 75.19 KB ]