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

J Biol Chem. 2003 Feb 21;278(8):6018-26. doi: 10.1074/jbc.M208288200. Epub 2002 Dec 17.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Base Sequence
  • Basic Helix-Loop-Helix Transcription Factors
  • Cerebral Cortex / enzymology
  • DNA Primers
  • Gene Expression Regulation, Enzymologic*
  • Homeodomain Proteins / metabolism*
  • Humans
  • Interleukin-1 / physiology*
  • Intramolecular Oxidoreductases / genetics*
  • Lipocalins
  • Meninges / enzymology*
  • Molecular Sequence Data
  • NF-kappa B / metabolism*
  • RNA, Messenger / genetics
  • Rats
  • Repressor Proteins / metabolism
  • Reverse Transcriptase Polymerase Chain Reaction
  • Sequence Alignment
  • Sequence Homology, Nucleic Acid
  • Transcription Factor HES-1
  • Transcription, Genetic*


  • Basic Helix-Loop-Helix Transcription Factors
  • DNA Primers
  • Hes1 protein, rat
  • Homeodomain Proteins
  • Interleukin-1
  • Lipocalins
  • NF-kappa B
  • RNA, Messenger
  • Repressor Proteins
  • Transcription Factor HES-1
  • HES1 protein, human
  • Intramolecular Oxidoreductases
  • prostaglandin R2 D-isomerase