A critical role for MAP kinases in the control of Ah receptor complex activity.
A critical role for MAP kinases in the control of Ah receptor complex activity.
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DOI：
10.1093/toxsci/kfh228
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发表时间：
2004-11
期刊：
影响因子：
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通讯作者：
Zongqing Tan;Ming-ya Huang;A. Puga;Ying Xia
中科院分区：
文献类型：
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作者：
Zongqing Tan;Ming-ya Huang;A. Puga;Ying Xia
芳香烃受体（AHR）和Ah受体核转运子（ARNT）的异二聚体复合物在控制药物代谢基因的表达中起着关键作用，如细胞色素p450（Cyp）1a 1和1b 1，被认为是环境污染物2，3，7，8-四氯二苯并-p-二恶英（TCDD）的主要毒性作用。在这项研究中，我们表明，Jun N-末端激酶（JNK）和细胞外信号调节激酶（ERK）的激活调节ARNT的转录活性和增强AHR/ARNT复合物的转录活性。通过化合物抑制ERK和消融JNK导致TCDD对CYP 1A 1诱导的显著降低。与野生型相比，JNK 2消融显著降低了TCDD刺激的小鼠胸腺和睾丸中CYP 1A 1的表达，但在肝脏中没有。相比之下，CYP 1B 1表达在敲除小鼠的所有三种组织中均不受影响。这些数据表明，JNK和ERK调节ARNT活性和AHR/ARNT依赖的基因表达，有助于环境污染物的基因特异性和组织特异性毒性。
The heterodimeric complex of aromatic hydrocarbon receptor (AHR) and Ah receptor nuclear translocator (ARNT) plays a pivotal role in controlling the expression of drug metabolism genes, such as the cytochromes p450 (Cyp) 1a1 and 1b1, believed to be responsible for most toxic effects of the environmental contaminant 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). In this study, we show that activation of Jun N-terminal kinase (JNK) and extracellular signal-regulated kinase (ERK) modulates ARNT transcription activity and potentiates the transcriptional activity of AHR/ARNT complexes. Inhibition of ERK by chemical compounds and ablation of JNK caused significant decreases in CYP1A1 induction by TCDD. Compared to wild type, JNK2 ablation significantly reduced TCDD-stimulated CYP1A1 expression in mouse thymus and testis, but not in liver. In contrast, CYP1B1 expression was unaffected in all three tissues of the knockout mice. These data suggest that JNK and ERK modulate ARNT activity and AHR/ARNT-dependent gene expression, contributing to the gene-specific and tissue-specific toxicity of environmental contaminants.