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Superinduction of CYP1A1 gene expression. Regulation of 2,3,7,8-tetrachlorodibenzo-p-dioxin-induced degradation of Ah receptor by cycloheximide.

Authors
Ma-Q; Renzelli-AJ; Baldwin-KT; Antonini-JM
Source
J Biol Chem 2000 Apr; 275(17):12676-12683
NIOSHTIC No.
20020743
Abstract
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.
Keywords
Genes; Protein-synthesis; Proteins; Aryls; Arylamines; Hydrocarbons; Dioxins
Contact
CDC/NIOSH/HELD/TMBB, Mailstop 3014, 1095 Willowdale Road, Morgantown, WV 26505
CODEN
JBCHA3
CAS No.
66-81-9; 1746-01-6
Publication Date
20000426
Document Type
Journal Article
Fiscal Year
2000
NTIS Accession No.
NTIS Price
Issue of Publication
17
ISSN
0021-9258
NIOSH Division
HELD
Source Name
Journal of Biological Chemistry
State
WV
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