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J. Biol. Chem., Vol. 281, Issue 52, 39776-39784, December 29, 2006

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p53 Suppresses the Nrf2-dependent Transcription of Antioxidant Response Genes^*

Raffaella Faraonio, Paola Vergara, Domenico Di Marzo, Maria Giovanna Pierantoni, Maria Napolitano^¶, Tommaso Russo¹, and Filiberto Cimino

From the Dipartimento di Biochimica e Biotecnologie Mediche, Università di Napoli Federico II, CEINGE Biotecnologie avanzate, 80131 Napoli, Dipartimento di Biologia e Patologia Cellulare e Molecolare, Università di Napoli Federico II, 80131 Napoli, and the ^¶Istituto Nazionale dei Tumori Fondazione Pascale, 80131 Napoli, Italy

Cells respond to the shift of intracellular environment toward pro-oxidant conditions by activating the transcription of numerous "antioxidant" genes. This response is based on the activation of the Nrf2 transcription factor, which transactivates the genes containing in their promoters the antioxidant response cis-elements (AREs). If the oxidative stress provokes DNA damage, a second response of the cell takes place, based on the activation of p53, which induces cell cycle arrest and/or apoptosis. Here we have explored the cross-talk between these two regulatory mechanisms. The results show that p53 counteracts the Nrf2-induced transcription of three ARE-containing promoters of the x-CT, NQO1, and GST-1 genes. Endogenous transcripts of these antioxidant genes accumulate as a consequence of Nrf2 overexpression or exposure to electrophile diethylmaleate, but these effects are again blocked by p53 overexpression or endogenous p53 activation. Chromatin immunoprecipitation experiments support the hypothesis that this p53-dependent trans-repression is due to the direct interaction of p53 with the ARE-containing promoters. Considering that p53-induced apoptosis requires an accumulation of reactive oxygen species, this negative control on the Nrf2 transactivation appears to be aimed to prevent the generation of a strong anti-oxidant intracellular environment that could hinder the induction of apoptosis.

Received for publication, June 14, 2006 , and in revised form, October 31, 2006.

^* This work was supported by MIUR-PRIN and L.5 Regione Campania (to F. C.), by the NOGEC Oncogenomic Centre at CEINGE supported by Associazione Italiana Ricerca sul Cancro, and by VI FP EC Grant LSHM-CT-2003-503330 and MIUR-PRIN2005 (to T. R.). 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.

¹ To whom correspondence should be addressed: Dipartimento di Biochimica e Biotecnologie Mediche, via S. Pansini 5, 80131 Napoli, Italy or Tommaso Russo, CEINGE Biotecnologie avanzate, via Comunale Margherita 482, 80134 Napoli, Italy. Tel.: 39-0813737863; Fax: +39-0813737808; E-mail: russot{at}dbbm.unina.it.

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