title: p53 suppresses the Nrf2-dependent transcription of antioxidant response genes.
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-alpha1 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.
authors.affiliation: Dipartimento di Biochimica e Biotecnologie Mediche, Università di Napoli Federico II, CEINGE Biotecnologie avanzate, 80131 Napoli, Italy.
authors.forename: Raffaella
authors.initials: R
authors.lastname: Faraonio
authors.forename: Paola
authors.initials: P
authors.lastname: Vergara
authors.forename: Domenico
authors.initials: D
authors.lastname: Di Marzo
authors.forename: Maria Giovanna
authors.initials: MG
authors.lastname: Pierantoni
authors.forename: Maria
authors.initials: M
authors.lastname: Napolitano
authors.forename: Tommaso
authors.initials: T
authors.lastname: Russo
authors.forename: Filiberto
authors.initials: F
authors.lastname: Cimino
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000378:metabolism / Q000502:physiology*; D017209:Apoptosis / Q000235:genetics; D002460:Cell Line; D045744:Cell Line, Tumor; D005982:Glutathione Transferase / Q000037:antagonists & inhibitors / Q000235:genetics; D045325:HCT116 Cells; D006801:Humans; D051379:Mice; D016660:NAD(P)H Dehydrogenase (Quinone) / Q000037:antagonists & inhibitors / Q000235:genetics; D051267:NF-E2-Related Factor 2 / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D041681:NIH 3T3 Cells; D011401:Promoter Regions, Genetic; D020218:Response Elements / Q000235:genetics*; D015533:Transcriptional Activation; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000502:physiology*
chemical_list: D000975:Antioxidants; D051267:NF-E2-Related Factor 2; D016159:Tumor Suppressor Protein p53; D016660:NAD(P)H Dehydrogenase (Quinone); C447479:NQO1 protein, human; C484555:GSTA1 protein, human; D005982:Glutathione Transferase