A critical role for MAP kinases in the control of Ah receptor complex activity.
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.
Center for Environmental Genetics and Department of Environmental Health, University of Cincinnati Medical Center, 123 E. Shields Street, Cincinnati, OH 45267-0056, USA.
Zongqing
Z
Tan
Mingya
M
Huang
Alvaro
A
Puga
Ying
Y
Xia
D000818:Animals; D051784:Aryl Hydrocarbon Receptor Nuclear Translocator; D045744:Cell Line, Tumor; D002522:Chlorocebus aethiops; D019363:Cytochrome P-450 CYP1A1 / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000096:biosynthesis* / Q000187:drug effects / Q000235:genetics; D004785:Environmental Pollutants / Q000633:toxicity; D048049:Extracellular Signal-Regulated MAP Kinases / Q000037:antagonists & inhibitors / Q000096:biosynthesis*; D005260:Female; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D008099:Liver / Q000187:drug effects / Q000201:enzymology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D048056:Mitogen-Activated Protein Kinase 9 / Q000096:biosynthesis* / Q000235:genetics; D000072317:Polychlorinated Dibenzodioxins / Q000633:toxicity; D018336:Receptors, Aryl Hydrocarbon / Q000096:biosynthesis* / Q000187:drug effects / Q000235:genetics; D013737:Testis / Q000187:drug effects / Q000201:enzymology; D013950:Thymus Gland / Q000187:drug effects / Q000201:enzymology; D014157:Transcription Factors / Q000096:biosynthesis* / Q000187:drug effects / Q000235:genetics
C497397:Arnt protein, mouse; D004268:DNA-Binding Proteins; D004785:Environmental Pollutants; D000072317:Polychlorinated Dibenzodioxins; D018336:Receptors, Aryl Hydrocarbon; D014157:Transcription Factors; D051784:Aryl Hydrocarbon Receptor Nuclear Translocator; D019363:Cytochrome P-450 CYP1A1; D048056:Mitogen-Activated Protein Kinase 9; D048049:Extracellular Signal-Regulated MAP Kinases