title: PMA-induced dissociation of Ku86 from the promoter causes transcriptional up-regulation of histamine H(1) receptor.
abstract: Histamine H(1) receptor (H1R) gene is up-regulated in patients with allergic rhinitis, and its expression level strongly correlates with the severity of symptoms. However, the mechanism underlying this remains unknown. Here we report the mechanism of H1R gene up-regulation. The luciferase assay revealed the existence of two promoter regions, A and B1. Two AP-1 and one Ets-1 bound to region A, while Ku86, Ku70, and PARP-1 bound to region B1. Ku86 was responsible for DNA binding and poly(ADP-ribosyl)ated in response to phorbol-12-myristate-13-acetate stimulation, inducing its dissociation from region B1 that is crucial for promoter activity. Knockdown of Ku86 gene enhanced up-regulation of H1R gene expression. Experiments using inhibitors for MEK and PARP-1 indicate that regions A and B1 are downstream regulatory elements of the PKCδ/ERK/PARP-1 signaling pathway. Data suggest a novel mechanism for the up-regulation of H1R gene expression.
authors.affiliation: Department of Molecular Pharmacology, Institute of Health Biosciences, The University of Tokushima Graduate School, Tokushima 770-8505, Japan.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Mizuguchi
authors.forename: Kohei
authors.initials: K
authors.lastname: Miyagi
authors.forename: Takuma
authors.initials: T
authors.lastname: Terao
authors.forename: Noriko
authors.initials: N
authors.lastname: Sakamoto
authors.forename: Yosuke
authors.initials: Y
authors.lastname: Yamawaki
authors.forename: Tsubasa
authors.initials: T
authors.lastname: Adachi
authors.forename: Shohei
authors.initials: S
authors.lastname: Ono
authors.forename: Yohei
authors.initials: Y
authors.lastname: Sasaki
authors.forename: Yoshiyuki
authors.initials: Y
authors.lastname: Yoshimura
authors.forename: Yoshiaki
authors.initials: Y
authors.lastname: Kitamura
authors.forename: Noriaki
authors.initials: N
authors.lastname: Takeda
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Fukui
mesh_terms: D000818:Animals; D034961:Antigens, Nuclear / Q000378:metabolism*; D001483:Base Sequence; D001665:Binding Sites; D002460:Cell Line; D004268:DNA-Binding Proteins / Q000378:metabolism*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects; D023061:Gene Order; D006801:Humans; D000072200:Ku Autoantigen; D008297:Male; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D011401:Promoter Regions, Genetic; D011485:Protein Binding / Q000187:drug effects; D051745:Protein Kinase C-delta / Q000378:metabolism; D051381:Rats; D011969:Receptors, Histamine H1 / Q000235:genetics* / Q000378:metabolism; D020218:Response Elements; D015398:Signal Transduction; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology*; D014157:Transcription Factors / Q000378:metabolism; D014158:Transcription, Genetic; D015533:Transcriptional Activation / Q000187:drug effects
chemical_list: D034961:Antigens, Nuclear; D004268:DNA-Binding Proteins; D011969:Receptors, Histamine H1; D014157:Transcription Factors; D011065:Poly(ADP-ribose) Polymerases; D051745:Protein Kinase C-delta; D048049:Extracellular Signal-Regulated MAP Kinases; C000606509:Xrcc6 protein, human; C000606511:Xrcc6 protein, rat; D000072200:Ku Autoantigen; D013755:Tetradecanoylphorbol Acetate