p53-Independent Activation of the gadd45 Promoter by Δ12-Prostaglandin J2

A p53-inducible gene, the growth arrest and DNA damage-inducible gene 45 (gadd45), is associated with cell growth inhibition, DNA damage response and DNA repair. Here we report that Δ12-prostaglandin J2(Δ12-PGJ2), anin vivometabolite of arachidonic acid, which inhibits cell proliferation, induces gadd45 mRNA in HeLa cells. Because the p53 protein in HeLa cells is inactivated by papilloma virus E6, this type of gadd45 induction appears to be p53-independent. The induction was dose-dependent, and the maximum induction was observed at a concentration of 7.5 μg/ml. In a time course study, gadd45 mRNA was induced 3 h after the addition of 7.5 μg/ml Δ12-PGJ2. To investigate the transcriptional mechanism of gadd45 mRNA induction, we cloned a human genomic DNA fragment containing the gadd45 promoter region, and investigated the effect of Δ12-PGJ2on the gadd45 promoter activity. In HeLa cells, 7.5 μg/ml Δ12-PGJ2markedly stimulated the gadd45 gene promoter about 20-fold or more. On the other hand, Δ12-PGJ2did not stimulate the promoter activity of a reporter plasmid containing only p53 binding sites in HeLa cells, indicating that the gadd45 promoter activation by Δ12-PGJ2was not mediated by p53. These results suggest that one of the mechanisms of cell growth arrest by Δ12-PGJ2is mediated through a p53-independent induction of gadd45.

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