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

The Keap1–Nrf2 pathway: promising therapeutic target to counteract ROS-mediated damage in cancers and neurodegenerative diseases

“…As mentioned before, under oxidative stress, p62 dissociates Nrf2 from Keap1 by direct competition, which subsequently activates Nrf2 and mediates the autophagic degradation of Keap1 (Faraonio et al 2006). The cross-talk between p62 and the Keap1-Nrf2 pathway in the regulation of autophagy may play an important role in the removal of ROS, prevention of oxidative damage and alleviation of ER stress during cerebral IR injury .…”

“…Conversely, DNA methylation by DNA methyltransferases (DNMTs) appears to downregulate the Nrf2 expression indirectly (Khor et al 2014;Yu et al 2010;Rajabi et al 2016;Tagde et al 2016b). (c) Accumulation of p21 and p62 disrupts the Nrf2-Keap1 complex: it has been demonstrated that p53 negatively regulates Nrf2 and specifically suppresses the transcription of target genes of Nrf2 (Faraonio et al 2006). p21 (a direct downstream target of p53) associates with the DLG motif of Nrf2, which leads to the disruption of Keap1 binding with Nrf2.…”

Dose-dependent deleterious and salutary actions of the Nrf2 inducer dh404 in chronic kidney disease

“…In fact, our CKD animals treated with high dose of dh404 exhibited increased phosphorylated IKB and activation of NF k B pathway. Activation of NF k B, in turn, suppresses Nrf2 activity by preventing dissociation of Nrf2 from keap1 in the cytoplasm and by blocking Nrf2 binding to the antioxidant response elements of its target genes in the nucleus [56,57]. Thus excessive oxidative or covalent modification of keap1 leads to activation of inflammatory system and paradoxical inhibition of Nrf2, a scenario which is consistent with the divergent dose response to BARD analogs observed in CKD rats employed in the present study and in ApoE deficient mice with streptozotocin-induced diabetes.…”

p38MAPK and ERK1/2 dictate cell death/survival response to different pro-oxidant stimuli via p53 and Nrf2 in neuroblastoma cells SH-SY5Y

“…regulation of Nrf2 mediated by Kelch-like ECH-Associated Protein 1 (Keap1), recent pieces of evidence indicate that Nrf2 and p53 are functional competitors for the same DNA promoter regions [15], thereby identifying a new sophisticated level of control of Nrf2 trans-activation. In particular, it has been indicated that p53 binds to the antioxidant response elements (ARE), inhibiting, in such a way, Nrf2 transcriptional activity of the battery of genes involved in the antioxidant defense.…”