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J. Biol. Chem., Vol. 276, Issue 39, 36303-36310, September 28, 2001

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p53 Phosphorylation at Serine 15 Is Required for Transcriptional Induction of the Plasminogen Activator Inhibitor-1 (PAI-1) Gene by the Alkylating Agent N-Methyl-N'-nitro-N-nitrosoguanidine^*

Maribel Parra^§, Mercè Jardí^§, Magdalena Koziczak^¶, Yoshikuni Nagamine^¶, and Pura Muñoz-Cánoves

From the  Institut de Recerca Oncologica, Center d'Oncologia Molecular, Aut. Castelldefels, km 2.7, L'Hospitalet Ll., E-08907 Barcelona, Spain, and the ^¶ Friedrich Miescher Institute, CH-4002 Basel, Switzerland

The alkylating agent N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) is a widely spread environmental carcinogen that causes DNA lesions leading to cell killing. MNNG can also induce a cell-protective response by inducing the expression of DNA repair/transcription-related genes. We recently demonstrated that urokinase-type plasminogen activator, an extracellular protease to which no DNA repair functions have been assigned, was induced by MNNG. Here, we show that the physiological inhibitor of urokinase-type plasminogen activator, PAI-1, is also induced by MNNG in a p53-dependent fashion, because MNNG induced PAI-1 in p53-expressing cells but not in p53/ cells. MNNG induced p53 phosphorylation at serine 15, resulting in stabilization of the p53 protein, and this phosphorylation event was central for p53-dependent PAI-1 transcription. Finally, we showed that PAI-1 transcriptional induction by MNNG required a p53-responsive element located at 136 base pairs in the PAI-1 promoter, because specific mutation of this site abrogated the induction. Because PAI-1 is a prognostic factor in many metastatic cancers, being involved in the control of tumor invasiveness, our finding that a genotoxic agent induces the PAI-1 gene via p53 adds a new feature to the role of the tumor-suppressor p53 protein. Our results also suggest the possibility that genotoxic agents contribute to tumor metastasis by inducing PAI-1 without involving genetic modification.

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