The Keap1-Nrf2 pathway: Mechanisms of activation and dysregulation in cancer

Kansanen, Emilia; Kuosmanen, Suvi M.; Leinonen, Hanna; Levonen, Anna–Liisa

doi:10.1016/j.redox.2012.10.001

Cited by 1,087 publications

(848 citation statements)

References 15 publications

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“…The Nrf2 transcriptional activity proceeds with the aid of other co-transcription factors in complex with the former. The stress conditions lead to the suspension of Keap1-Nrf2 interactions and causes transcription of cytoprotective genes like NQO1, GSTs and GCL, which in turn, scavenges the cellular oxidative stress (Kansanen et al 2013) (Fig. 1).…”

Section: Molecular Mechanism Of the Keap1-nrf2 Pathwaymentioning

confidence: 99%

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

et al. 2016

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The overproduction of reactive oxygen species (ROS) generates oxidative stress in cells. Oxidative stress results in various pathophysiological conditions, especially cancers and neurodegenerative diseases (NDD). The Keap1-Nrf2 [Kelch-like ECH-associated protein 1-nuclear factor (erythroid-derived 2)-like 2] regulatory pathway plays a central role in protecting cells against oxidative and xenobiotic stresses. The Nrf2 transcription factor activates the transcription of several cytoprotective genes that have been implicated in protection from cancer and NDD. The Keap1-Nrf2 system acts as a double-edged sword: Nrf2 activity protects cells and makes the cell resistant to oxidative and electrophilic stresses, whereas elevated Nrf2 activity helps in cancer cell survival and proliferation. Several groups in the recent past, from both academics and industry, have reported the potential role of Nrf2-mediated transcription to protect from cancer and NDD, resulting from mechanisms involving xenobiotic and oxidative stress. It suggests that the Keap1-Nrf2 system is a potential therapeutic target to combat cancer and NDD by designing and developing modulators (inhibitors/activators) for Nrf2 activation. Herein, we review and discuss the recent advancement in the regulation of the Keap1-Nrf2 system, its role under physiological and pathophysiological conditions including cancer and NDD, and modulators design strategies for Nrf2 activation.

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Section: Molecular Mechanism Of the Keap1-nrf2 Pathwaymentioning

confidence: 99%

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

et al. 2016

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“…The KEAP1/NRF2 pathway is a key pathway for sensing and responding to oxidative stress (Kansanen et al ., 2013). To sustain Nrf2 at the nucleus, GSK3β inhibition by Akt‐mediated phosphorylation at Ser9 is required (Leinonen et al ., 2014).…”

Section: Resultsmentioning

confidence: 99%

MicroRNA‐661 modulates redox and metabolic homeostasis in colon cancer

et al. 2017

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Cancer cell survival and metastasis are dependent on metabolic reprogramming that is capable of increasing resistance to oxidative and energetic stress. Targeting these two processes can be crucial for cancer progression. Herein, we describe the role of microRNA‐661 (miR661) as epigenetic regulator of colon cancer (CC) cell metabolism. MicroR661 induces a global increase in reactive oxygen species, specifically in mitochondrial superoxide anions, which appears to be mediated by decreased carbohydrate metabolism and pentose phosphate pathway, and by a higher dependency on mitochondrial respiration. MicroR661 overexpression in non‐metastatic human CC cells induces an epithelial‐to‐mesenchymal transition phenotype, and a reduced tolerance to metabolic stress. This seems to be a general effect of miR661 in CC, since metastatic CC cell metabolism is also compromised upon miR661 overexpression. We propose hexose‐6‐phosphate dehydrogenase and pyruvate kinase M2 as two key players related to the observed metabolic reprogramming. Finally, the clinical relevance of miR661 expression levels in stage‐II and III CC patients is discussed. In conclusion, we propose miR661 as a potential modulator of redox and metabolic homeostasis in CC.

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“…In response to endogenous and exogenous stresses caused by ROS and electrophiles, NRF2 translocates from the cytoplasm into the nucleus and binds together with small Maf proteins to the Antioxidant Response Element in the regulatory regions of target genes and transactivates expression of genes with antioxidant activity [50]. Small Maf (MafG, MafK and MafF) proteins are b-Zip proteins that lack a transcriptional activation domain.…”

Section: The Transcription Factor Nrf2mentioning

confidence: 99%

Role of the Transcription Factor Nrf2 in Parkinson’s Disease: New Insights

Lastres‐Becker¹

2017

J Alzheimers Dis Parkinsonism

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The Keap1-Nrf2 pathway: Mechanisms of activation and dysregulation in cancer

Cited by 1,087 publications

References 15 publications

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

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

MicroRNA‐661 modulates redox and metabolic homeostasis in colon cancer

Role of the Transcription Factor Nrf2 in Parkinson’s Disease: New Insights

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