Superinduction of CYP1A1 Gene Expression. Regulation of 2,3, 7,8-Tetrachlorodibenzo-P-Dioxin-Induced Degradation of Ah Receptor by Cycloheximide

Details

• Personal Author:
  Antonini JM ; Baldwin KT ; Ma Q ; Renzelli AJ
• Description:
  Cycloheximide superinduces the transcription of CYP1A1 in the presence of an agonist for the Ah receptor (AhR). To investigate the molecular target for "superinduction," we analyzed the agonist-induced degradation of AhR. Whereas 2,3,7, 8-tetrachlorodibenzo-p-dioxin (TCDD), a potent agonist of AhR, induces a rapid reduction of the AhR protein, cycloheximide blocks the down-regulation of steady state AhR. Analyses of the turnover of AhR reveal that cycloheximide blocks the shortening of the half-life of AhR by TCDD. Blocking of the TCDD-induced AhR degradation requires inhibition of protein synthesis, because (a) cycloheximide inhibits protein synthesis at the concentration at which it causes superinduction and inhibition of AhR degradation; and (b) puromycin, an inhibitor of protein synthesis by mimicking aminoacyl-tRNA, also blocks the TCDD-induced AhR degradation. The blocking of the TCDD-induced AhR degradation correlates with the superinduction of CYP1A1 gene expression in a time- and dose-dependent manner. Furthermore, cycloheximide is shown to increase the accumulation of the TCDD-activated AhR and the functional AhR x Arnt complex in nucleus. Collectively, our results reveal a mechanism of superinduction by cycloheximide by enhancing the stability of agonist-activated AhR. The finding that inhibition of protein synthesis blocks the TCDD-induced AhR turnover implicates a cycloheximide-sensitive, labile factor (designated as AhR degradation promoting factor, or ADPF) in controlling the removal of agonist-activated AhR in nucleus. [Description provided by NIOSH]
• Subjects:
  Dioxins Genetics Hydrocarbons Occupational Health Safety
• Keywords:
  Arylamines Aryls Genes Proteins Protein Synthesis
• ISSN:
  0021-9258
• 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:
  275
• Issue:
  17
• NIOSHTIC Number:
  nn:20020743
• Citation:
  J Biol Chem 2000 Apr; 275(17):12676-12683
• Contact Point Address:
  CDC/NIOSH/HELD/TMBB, Mailstop 3014, 1095 Willowdale Road, Morgantown, WV 26505
• CAS Registry Number:
  (-)-Cycloheximide (CAS RN 66-81-9) ; 2,3,7,8-Tetrachlorodibenzo-p-dioxin (CAS RN 1746-01-6)
• Federal Fiscal Year:
  2000
• Peer Reviewed:
  True
• Source Full Name:
  Journal of Biological Chemistry
• Collection(s):
  National Institute for Occupational Safety and Health
• Main Document Checksum:
  urn:sha-512:424c3e79ed45c0cd4eefa39576bb4003041c6faa87fe451903c24752ea4fd46a6cd8f31424f6cbb58838aedae23ee2231b2249efc63d2db281b1b4b3f0f7be4f
• Download URL:
  https://stacks.cdc.gov/view/cdc/198413/cdc_198413_DS1.pdf
• File Type:
  [PDF - 391.74 KB ]