Regulation of lipocalin-type prostaglandin D synthase gene expression by Hes-1 through E-box and interleukin-1 beta via two NF-kappa B elements in rat leptomeningeal cells.
The promoter function of the rat lipocalin-type prostaglandin D synthase (L-PGDS) gene was characterized in primary cultures of leptomeningeal cells prepared from the neonatal rat brain. Luciferase reporter assays with deletion and site-directed mutation of the promoter region (-1250 to +77) showed that an AP-2 element at -109 was required for activation and an E-box at +57, for repression. Binding of nuclear factors to each of these cis-elements was demonstrated by an electrophoretic mobility shift assay. Several components of the Notch-Hes signaling pathway, Jagged, Notch1, Notch3, and Hes-1, were expressed in the leptomeningeal cells. Human Hes-1 co-expressed in the leptomeningeal cells bound to the E-box of the rat L-PGDS gene, and repressed the promoter activity of the rat L-PGDS gene in a dose-dependent manner. The L-PGDS gene expression was up-regulated slowly by interleukin-1 beta to the maximum level at 24 h. The reporter assay with deletion and mutation revealed that two NF-kappa B elements at -1106 and -291 were essential for this up-regulation. Binding of two NF-kappa B subunits, p65 and c-Rel, to these two NF-kappa B elements occurred after the interleukin-1 beta treatment. Therefore, the L-PGDS gene is the first gene identified as the target for the Notch-Hes signal through the E-box among a variety of genes involved in the prostanoid biosynthesis, classified to the lipocalin family, and expressed in the leptomeninges. Moreover, the L-PGDS gene is a unique gene that is activated slowly by the NF-kappa B system.
Fujimori
Ko
K
Core Research for Evolutional Science and Technology, Japan Science and Technology Corporation and the Department of Molecular Behavioral Biology, Osaka Bioscience Institute, 6-2-4 Furuedai, Suita, Osaka 565-0874, Japan.
Fujitani
Yasushi
Y
Kadoyama
Keiichi
K
Kumanogoh
Haruko
H
Ishikawa
Koichi
K
Urade
Yoshihiro
Y
D000818:Animals; D001483:Base Sequence; D051792:Basic Helix-Loop-Helix Proteins; D002540:Cerebral Cortex / Q000201:enzymology; D017931:DNA Primers; D015971:Gene Expression Regulation, Enzymologic; D018398:Homeodomain Proteins / Q000378:metabolism*; D006801:Humans; D007375:Interleukin-1 / Q000502:physiology*; D019746:Intramolecular Oxidoreductases / Q000235:genetics*; D054834:Lipocalins; D008578:Meninges / Q000201:enzymology*; D008969:Molecular Sequence Data; D016328:NF-kappa B / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics; D051381:Rats; D012097:Repressor Proteins / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D016415:Sequence Alignment; D012689:Sequence Homology, Nucleic Acid; D000072056:Transcription Factor HES-1; D014158:Transcription, Genetic
D051792:Basic Helix-Loop-Helix Proteins; D017931:DNA Primers; D018398:Homeodomain Proteins; D007375:Interleukin-1; D019746:Intramolecular Oxidoreductases; D054834:Lipocalins; D016328:NF-kappa B; D012333:RNA, Messenger; D012097:Repressor Proteins; D000072056:Transcription Factor HES-1; C489735:Hes1 protein, rat; C078493:HES1 protein, human; C022466:prostaglandin R2 D-isomerase