PMA-induced dissociation of Ku86 from the promoter causes transcriptional up-regulation of histamine H(1) receptor

• Published in: Scientific reports 2012, Vol.2, p.916
• Main Authors: Mizuguchi, Hiroyuki, Miyagi, Kohei, Terao, Takuma, Sakamoto, Noriko, Yamawaki, Yosuke, Adachi, Tsubasa, Ono, Shohei, Sasaki, Yohei, Yoshimura, Yoshiyuki, Kitamura, Yoshiaki, Takeda, Noriaki, Fukui, Hiroyuki
• Format: Article
• Language: English
• Subjects: Animals; Antigens, Nuclear - metabolism; Base Sequence; Binding Sites; Cell Line; DNA-Binding Proteins - metabolism; Extracellular Signal-Regulated MAP Kinases - metabolism; Gene Expression Regulation - drug effects; Gene Order; Humans; Ku Autoantigen; Male; Poly(ADP-ribose) Polymerases - metabolism; Promoter Regions, Genetic; Protein Binding - drug effects; Protein Kinase C-delta - metabolism; Rats; Receptors, Histamine H1 - genetics; Receptors, Histamine H1 - metabolism; Response Elements; Signal Transduction; Tetradecanoylphorbol Acetate - pharmacology; Transcription Factors - metabolism; Transcription, Genetic; Transcriptional Activation - drug effects
• ISSN: 2045-2322
• DOI: 10.1038/srep00916

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.