title: Hairless modulates ligand-dependent activation of the vitamin D receptor-retinoid X receptor heterodimer.
abstract: The active form of vitamin D, 1α,25-dihydroxyvitamin D(3) [1,25(OH)(2)D(3)], 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)(2)D(3) and LCA. HR repressed VDR transactivation induced by both 1,25(OH)(2)D(3) 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.
authors.affiliation: Division of Biochemistry, Department of Biomedical Sciences, School of Medicine, Nihon University, Tokyo, Japan.
authors.forename: Masayuki
authors.initials: M
authors.lastname: Chuma
authors.forename: Kaori
authors.initials: K
authors.lastname: Endo-Umeda
authors.forename: Shigeki
authors.initials: S
authors.lastname: Shimba
authors.forename: Sachiko
authors.initials: S
authors.lastname: Yamada
authors.forename: Makoto
authors.initials: M
authors.lastname: Makishima
mesh_terms: D002117:Calcitriol / Q000494:pharmacology*; D002460:Cell Line; D056970:Co-Repressor Proteins / Q000378:metabolism; D000242:Cyclic AMP / Q000235:genetics; D057809:HEK293 Cells; D006801:Humans; D008024:Ligands; D008095:Lithocholic Acid / Q000494:pharmacology*; D012333:RNA, Messenger / Q000378:metabolism; D018167:Receptors, Calcitriol / Q000235:genetics / Q000378:metabolism*; D047488:Retinoid X Receptors / Q000378:metabolism*; D013250:Steroid Hydroxylases / Q000235:genetics; D014157:Transcription Factors / Q000378:metabolism*; D015533:Transcriptional Activation / Q000187:drug effects; D065668:Vitamin D3 24-Hydroxylase
chemical_list: D056970:Co-Repressor Proteins; C490267:HR protein, human; D008024:Ligands; D012333:RNA, Messenger; D018167:Receptors, Calcitriol; D047488:Retinoid X Receptors; D014157:Transcription Factors; D008095:Lithocholic Acid; D000242:Cyclic AMP; D013250:Steroid Hydroxylases; C585549:CYP24A1 protein, human; C585550:Cyp24a1 protein, mouse; D065668:Vitamin D3 24-Hydroxylase; D002117:Calcitriol