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J.Health Sci., 54(3), 261-266, 2008
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Molecular Basis of the Intracellular Localization of the Constitutive Androstane Receptor (CAR)
Yuichiro Kanno* Yoshio Inouye
Department of Environmental Hygiene, Faculty of Pharmaceutical Sciences, Toho University, 2-2-1 Miyama, Funabashi, Chiba 274-8510, Japan
Control of the intracellular localization of the constitutive androstane receptor (CAR, NR1I3) has more impact on the transcriptional activation of target genes by CAR ligands/activators, including medicines, environmental contaminants and endogenous metabolites, than the conformational change induced by ligand binding, because CAR, unlike other members of nuclear receptor superfamily, is constitutively active. Human CAR (hCAR) and rat CAR (rCAR) were comparatively studied, in primary hepatocytes and in immortal cells, to assess the functional domains controlling nucleo-cytoplasmic shuttling and/or intracellular localization. There are two nuclear localization signals (NLSs) and two nuclear export signals (NESs) in rCAR as well as a cytoplasmic retention region (CRR), whereas hCAR has a single NLS and two NESs. A xenochemical response signal (XRS) controls the neighboring NLS, in a phenobarbital-responsive manner, in both rCAR and hCAR in vivo, but not in immortal cells.
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