Hairless Modulates Ligand-Dependent Activation of the Vitamin D Receptor-Retinoid X Receptor Heterodimer
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概要
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The active form of vitamin D, 1α,25-dihydroxyvitamin D3 [1,25(OH)2D3], binds to the vitamin D receptor (VDR) and regulates various physiological and pharmacological processes. Secondary bile acids, such as lithocholic acid (LCA), also act as endogenous VDR ligands. The molecular basis of ligand-selective VDR action remains largely unknown. Hairless (HR) acts as a coregulator of VDR through a direct interaction. HR mutations confer an alopecia phenotype similar to VDR mutations in mice and humans, but the underlying molecular mechanisms have not been elucidated. We examined the effect of HR on VDR activation induced by 1,25(OH)2D3 and LCA. HR repressed VDR transactivation induced by both 1,25(OH)2D3 and LCA. HR also repressed transactivation of VDR E269A and R391A mutants, but less effectively than that of wild-type VDR. These residues are involved in retinoid X receptor (RXR) heterodimer allosteric communication, through which information from ligands is transmitted to dimer and coactivator interfaces. In the presence of HR cotransfection, LCA activated these VDR mutants more effectively than wild-type VDR. In mammalian two-hybrid assays, HR enhanced the association of VDR with a corepressor, nuclear receptor corepressor. These findings indicate that HR affects VDR-RXR heterodimer allosteric communication and corepressor complex formation. Interestingly, HR knockdown in keratinocyte-derived HaCaT cells increased ligand-induced cytochrome P450, family 24, subfamily A, polypeptide 1 (CYP24A1) expression but suppressed expression of cathelicidin antimicrobial peptide, indicating that HR acts not only as a corepressor but also as a coactivator. HR may be a VDR modulator that affects the RXR allosteric communication network in order to regulate transcription in a gene-selective manner.
著者
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Shimba Shigeki
Department Of Health Science College Of Pharmacy Nihon University
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Yamada Sachiko
Division of Biochemistry, Department of Biomedical Sciences, School of Medicine, Nihon University
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Chuma Masayuki
Division of Biochemistry, Department of Biomedical Sciences, School of Medicine, Nihon University
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Endo-Umeda Kaori
Division of Biochemistry, Department of Biomedical Sciences, School of Medicine, Nihon University
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Makishima Makoto
Division of Biochemistry, Department of Biomedical Sciences, School of Medicine, Nihon University
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Makishima Makoto
Division of Biochemistry, Department of Biomedical Sciences, Nihon University School of Medicine
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Shimba Shigeki
Department of Health Sciences, Graduate School of Pharmacy, Nihon University
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