Blockade by SB203580 of Cyp1a1 induction by 2,3,7,8-tetrachlorodibenzo-p-dioxin, and the possible mechanism: possible involvement of the p38 mitogen-activated protein kinase pathway in shuttling of Ah receptor overexpressed in COS-7 cells.
A transiently overexpressed aryl hydrocarbon receptor (AhR) became translocated into the nucleus of COS-7 cells without treatment with any ligand, such as 2,3,7,8-tetrachlorodibenzo-p-dioxin. This spontaneous AhR translocation into the nucleus was reduced by pretreatment of the recipient cells with the p38 mitogen-activated protein (MAP) kinase inhibitor SB203580. Immunofluorescent microscopic analysis revealed that SB203580 treatment increased the fluorescence intensity of AhR within the cytoplasm. An analogue compound, SB202474, which does not inhibit p38 MAP kinase, did not reduce AhR translocation into the nucleus. Moreover, a reporter gene assay showed that the AhR spontaneously translocated into the nucleus activated reporter gene transcription and that SB203580 suppressed its transcriptional activity. From these data we conclude that the p38 MAP kinase pathway is involved in determining AhR cellular localization in COS-7 cells overexpressing AhR.
Shibazaki
Masahiko
M
Department of Molecular Genetics, Institute of Development, Aging, and Cancer, Tohoku University, Sendai, Japan.
Takeuchi
Takahashi
T
Ahmed
Sohel
S
Kikuchia
Hideaki
H
D000818:Animals; D019556:COS Cells; D002467:Cell Nucleus / Q000378:metabolism; D019363:Cytochrome P-450 CYP1A1 / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000235:genetics; D004790:Enzyme Induction; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D017930:Genes, Reporter; D007093:Imidazoles / Q000494:pharmacology*; D008856:Microscopy, Fluorescence; D000072317:Polychlorinated Dibenzodioxins / Q000494:pharmacology*; D021381:Protein Transport / Q000187:drug effects; D011725:Pyridines / Q000494:pharmacology*; D018336:Receptors, Aryl Hydrocarbon / Q000378:metabolism*; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*
D004791:Enzyme Inhibitors; D007093:Imidazoles; D000072317:Polychlorinated Dibenzodioxins; D011725:Pyridines; D018336:Receptors, Aryl Hydrocarbon; D019363:Cytochrome P-450 CYP1A1; D048051:p38 Mitogen-Activated Protein Kinases; C093642:SB 203580