Activation of mitogen-activated protein kinases (MAPKs) by aromatic hydrocarbons: role in the regulation of aryl hydrocarbon receptor (AHR) function.
The aromatic hydrocarbon (Ah) receptor (AHR) is the only known cellular receptor of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and of many other widespread environmental contaminants that cause diverse toxic effects in animals and humans. Most, if not all, the biological effects of TCDD are mediated by the activation of AHR, which is a ligand-activated transcription factor required for ligand-induced expression of several detoxification genes, including those encoding for cytochrome P450 enzymes CYP1A1, CYP1A2, and CYP1B1. Environmental agents also activate several mitogen-activated protein kinase (MAPK) pathways, believed to modulate transcription factor function and to regulate gene expression. However, the contribution to TCDD toxicity resulting from cross-talk between AHR and MAPK pathways has yet to be determined. In this study, we show that TCDD and other AHR ligands induced the immediate activation of the extracellular signal-regulated kinases and the Jun N-terminal kinases, but not the p38 MAPKs. MAPK activation by TCDD did not require the AHR, since it occurred equally well in AHR-negative CV-1 cells and in Ahr (-/-) mouse embryonic fibroblasts as in AHR-positive cells. Distinct from serum factors and the tumor promoter TPA-induced MAPKs, which resulted in transcriptional activation of ELK or c-JUN, TCDD-stimulated MAPKs were critical for the induction of AHR-dependent gene transcription and CYP1A1 expression. These data indicate that AHR ligands elicit AHR-independent non-genomic events that are essential for AHR activation and function.
Tan
Zongqing
Z
Department of Environmental Health, Center for Environmental Genetics, University of Cincinnati Medical Center, Cincinnati, OH 45267-0056, USA.
Chang
Xiaoqing
X
Puga
Alvaro
A
Xia
Ying
Y
D000818:Animals; D001189:Aryl Hydrocarbon Hydroxylases; D019363:Cytochrome P-450 CYP1A1 / Q000096:biosynthesis; D065633:Cytochrome P-450 CYP1B1; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D006841:Hydrocarbons, Aromatic / Q000494:pharmacology*; D048031:JNK Mitogen-Activated Protein Kinases; D051379:Mice; D008810:Mice, Inbred C57BL; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000072317:Polychlorinated Dibenzodioxins / Q000031:analogs & derivatives / Q000494:pharmacology; D018336:Receptors, Aryl Hydrocarbon / Q000187:drug effects / Q000235:genetics / Q000378:metabolism* / Q000502:physiology; D014158:Transcription, Genetic / Q000187:drug effects; D014407:Tumor Cells, Cultured
D004791:Enzyme Inhibitors; D006841:Hydrocarbons, Aromatic; D000072317:Polychlorinated Dibenzodioxins; D018336:Receptors, Aryl Hydrocarbon; C445379:1,2,7,8-tetrachlorodibenzo-p-dioxin; D001189:Aryl Hydrocarbon Hydroxylases; C585496:CYP1B1 protein, human; C585498:Cyp1b1 protein, mouse; D019363:Cytochrome P-450 CYP1A1; D065633:Cytochrome P-450 CYP1B1; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases