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J. Biol. Chem., Vol. 280, Issue 18, 18452-18461, May 6, 2005

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Protein Kinase C Activates Human Lipocalin-type Prostaglandin D Synthase Gene Expression through De-repression of Notch-HES Signaling and Enhancement of AP-2 Function in Brain-derived TE671 Cells^*

Ko Fujimori, Keiichi Kadoyama, and Yoshihiro Urade

From the Department of Molecular Behavioral Biology, Osaka Bioscience Institute, 6-2-4 Furuedai, Suita, Osaka 565-0874, Japan

Here we investigated the regulatory mechanism of lipocalin-type prostaglandin D synthase (L-PGDS) gene expression in human TE671 (medulloblastoma of cerebellum) cells. Reporter analysis of the promoter region from -730 to +75 of the human L-PGDS gene demonstrated that deletion or mutation of the N-box at -337 increased the promoter activity 220-300%. The N-box was bound by Hes-1, a mammalian homologue of Drosophila Hairy and enhancer of split, as examined by electrophoretic mobility shift assay and chromatin immunoprecipitation assay. Functional expression of the Notch intracellular domain significantly increased Hes-1 expression and decreased L-PGDS expression level in TE671 cells. Moreover, knock-down of Hes-1 mRNA by RNA interference significantly enhanced the L-PGDS mRNA level, indicating that the L-PGDS gene expression is repressed by the Notch-Hes signaling. When the AP-2 element at -98 of the promoter region was deleted or mutated, the promoter activity was drastically decreased to 10% of normal. The AP-2 element was bound by AP-2 dominantly expressed in TE671 cells, according to the results of electrophoretic mobility shift assay and chromatin immunoprecipitation assay. L-PGDS expression was induced by 12-O-tetradecanoylphorbol-13-acetate in TE671 cells, and this induction was inhibited by a protein kinase C inhibitor. Stimulation of TE671 cells with 12-O-tetradecanoylphorbol-13-acetate or transfection with protein kinase C expression vector induced phosphorylation of Hes-1, inhibition of DNA binding of Hes-1 to the N-box, and activation of the AP-2 function to up-regulate L-PGDS gene expression. These results reveal a novel transcriptional regulatory mechanism responsible for the high level expression of the human L-PGDS gene in TE671 cells.

Received for publication, October 15, 2004 , and in revised form, February 14, 2005.

^* This work was supported by grants-in-aid for scientific research from the Ministry of Education, Culture, Sports, Science and Technology of Japan (to Y. U.) and by grants from the Takeda Science Foundation (to K. F. and Y. U.), the Mitsubishi Foundation (to Y. U.), the program for Promotion of Basic Research Activities for Innovative Biosciences (PROBRAIN) (to Y. U.), and Osaka City. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

To whom correspondence should be addressed: Dept. of Molecular Behavioral Biology, Osaka Bioscience Institute, 6-2-4 Furuedai, Suita, Osaka 565-0874, Japan. Tel.: 81-6-6872-4851; Fax: 81-6-6872-2841; E-mail: uradey{at}obi.or.jp.

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