A cycloheximide-sensitive factor regulates TCDD-induced degradation of the aryl hydrocarbon receptor
A cycloheximide-sensitive factor regulates TCDD-induced degradation of the aryl hydrocarbon receptor
复制标题
DOI：
10.1016/s0045-6535(01)00270-3
复制
发表时间：
2002-03-01
期刊：
影响因子：
8.8
通讯作者：
Baldwin, KT
中科院分区：
文献类型：
--
作者：
Ma, Q;Baldwin, KT
2,3,7,8-四氯二苯并-对二恶英 (TCDD) 是环境卤代芳香烃的原型，可诱导稳态芳烃受体 (AhR) 快速减少。在这里，我们分析了下调的生化途径和功能。我们的结果表明，TCDD 通过缩短 AhR 的半衰期来下调 AhR 蛋白。 TCDD 诱导的 AhR 降解被 26S 蛋白酶体的有效抑制剂 MG132 抑制，表明泛素 26S 蛋白酶体介导的蛋白水解是 AhR 降解的机制。此外，放线菌酮对蛋白质合成的抑制会阻止TCDD对AhR的降解，这表明控制配体激活的AhR稳定性的不稳定因素（因此，称为AhR降解促进因子，或ADPF）。对核 AhR 的分析表明，放线菌酮可增加核 AhR 蛋白和功能性 AhR/Arnt DNA 结合复合物，从而导致 CYP1A1 的超诱导。最后，使用 AhR 或 Arnt 缺陷型变异细胞进行的遗传分析表明，放线菌酮的超诱导需要 AhR 的转录激活 (TA) 结构域，这表明 TA 结构域通过 ADPF 控制 AhR 转换。这些发现为 TCDD 激活的 AhR 通过 26S 蛋白酶体蛋白降解途径在细胞核中调节的机制提供了新的见解。 (C) 2002 Elsevier Science Ltd. 保留所有权利。
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. (C) 2002 Elsevier Science Ltd. All rights reserved.