p53 suppresses the Nrf2-dependent transcription of antioxidant response genes

Raffaella Faraonio, Paola Vergara, Domenico Di Marzo, Maria Giovanna Pierantoni, Maria Napolitano, Tommaso Russo, Filiberto Cimino

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Abstract

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-α1 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 antioxidant intracellular environment that could hinder the induction of apoptosis.

Original languageEnglish
Pages (from-to)39776-39784
Number of pages9
JournalJournal of Biological Chemistry
Volume281
Issue number52
DOIs
Publication statusPublished - Dec 29 2006

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ASJC Scopus subject areas

  • Biochemistry

Cite this

Faraonio, R., Vergara, P., Di Marzo, D., Pierantoni, M. G., Napolitano, M., Russo, T., & Cimino, F. (2006). p53 suppresses the Nrf2-dependent transcription of antioxidant response genes. Journal of Biological Chemistry, 281(52), 39776-39784. https://doi.org/10.1074/jbc.M605707200