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Review
. 2012 Nov;3(11):1272-83.
doi: 10.18632/oncotarget.754.

NRF2 and p53: Januses in cancer?

Barak Rotblat  1 , Gerry Melino, Richard A Knight
Affiliations
Review

NRF2 and p53: Januses in cancer?

Barak Rotblat et al. Oncotarget. 2012 Nov.

Abstract

The transcription factor nuclear factor (erythroid-derived 2)-like 2, also known as NFE2L2 or NRF2, is a master regulator of the anti-oxidative stress response and positively controls the expression of a battery of anti-oxidative stress response proteins and enzymes implicated in detoxification and glutathione generation. Although its detoxifying activity is important in cancer prevention, it has recently been shown that cancer cells also exploit its protective functions to thrive and resist chemotherapy. NRF2 was also shown to the pentose phosphate pathway and glutaminolysis, which promotes purine synthesis for supporting rapid proliferation and glutathione for providing anti-oxidative stress protection. Evidence obtained from cancer patients and cell lines suggest that NRF2 is highly active in a variety of human cancers and is associated with aggressiveness. p53 is a tumor suppressor that also promotes an anti-oxidative stress metabolic program and glutaminolysis. Here we will discuss the similarities between NRF2 and p53 and review evidence that p53 might be exploited by cancer cells to gain protection against oxidative stress, as is the case for NRF2. We discuss findings of co-regulation between these transcription factors and propose possible therapeutic strategies that can be used for treatment of cancers that harbor WT p53 and express high levels of NRF2.

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Figures

Figure 1
Figure 1. NRF2 and p53 regulate the expression of proteins involved in protection ageist oxidative stress
NRF2 and p53 target genes (red and blue) that are contributing to protection against oxidative stress directly or by promoting glutathione synthesis by facilitating glutaminolysis, through direct synthesis or by facilitating NADPH production. NRF2, nuclear factor (erythroid-derived 2)-like 2; HMOX1, Heme Oxygenase 1; GCL, γ-glutamylcysteine ligase; GPX, glutathione peroxidase; NQO1, NAD(P)H quinine dehydrogenase; SENS, sestrins; GLS 1/2, glutaminase 1/2; GLH, reduced glutathione; NAPDH, Nicotinamide adenine dinucleotide phosphate.
Figure 2
Figure 2. Positive and negative (up or down) co-regulation between p53 and NRF2
Top to bottom. KEAP1 interacts with NRF2 and forms a complex with the E3 ligase CUL3 that results in NRF2 ubiquitylation and degradation by the proteasome (depicted as a blue X). The p53 target gene, p21, interacts with KEAP1 and inhibits NRF2 ubiquitylation and degradation. p53 is degraded by the proteasome in a ubiquitin n dependent manner. The NFR2 target, NQO1, interacts with p53 and protects it from degradation. NRF2 target gene, MDM2, promotes p53 ubiquitylation and degradation by the proteasome. P53 is a transcriptional repressor of NRF2. NRF2, nuclear factor (erythroid-derived 2)-like 2NQO1, NAD(P)H quinine dehydrogenase; mdm2, mouse double minute 2.
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