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ToxSci Advance Access published online on July 22, 2004
Toxicological Sciences, doi:10.1093/toxsci/kfh228
Toxicological Sciences © Society of Toxicology 2004; all rights reserved
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Received May 20, 2004
Accepted July 14, 2004

Environmental Toxicology

A Critical Role for MAP Kinases in the Control of Ah Receptor Complex Activity

Zongqing Tan 1, Mingya Huang 1, Alvaro Puga 1, Ying Xia 1*

1 Center for Environmental Genetics, Department of Environmental Health, University of Cincinnati Medical Center, Cincinnati, OH 45267-0056

* To whom correspondence should be addressed. E-mail: xiay{at}email.uc.edu.


  Abstract

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 knock-out 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.

Keywords: Jun N-terminal kinase (JNK); extracellular signal-regulated kinase (ERK); aromatic hydrocarbon receptor (AHR); Ah receptor nuclear translocator (ARNT); 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD); cytochrome p450 (CYP).
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