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

被引:79
作者
Ma, Q
Renzelli, AJ
Baldwin, KT
Antonini, JM
机构
[1] Ctr Dis Control & Prevent, NIOSH, Pathol & Physiol Res Branch,Hlth Effects Lab Div,, NIH, Morgantown, WV 26505 USA
[2] Ctr Dis Control & Prevent, NIOSH, Mol Toxicol lab,Toxicol & Mol Biol Branch, NIH, Morgantown, WV 26505 USA
关键词
D O I
10.1074/jbc.275.17.12676
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
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 downregulation 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 Amt 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 (A) under bar hR (d) under bar egradation (p) under bar romoting (f) under bar actor, or ADPF) in controlling the removal of agonist-activated AhR in nucleus.
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页码:12676 / 12683
页数:8
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