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Hoffmann, R. A wiki for the life sciences where authorship matters. Nature Genetics (2008)

Protein kinase C activates human lipocalin-type prostaglandin D synthase gene expression through de-repression of notch-HES signaling and enhancement of AP-2 beta function in brain-derived TE671 cells.

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 approximately 10% of normal. The AP-2 element was bound by AP-2beta 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 Calpha expression vector induced phosphorylation of Hes-1, inhibition of DNA binding of Hes-1 to the N-box, and activation of the AP-2beta 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.[1]


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