KEAP1-NFE2L2 pathway

Stable Identifier
Homo sapiens
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The KEAP1:NFE2L2 (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 multiple homeostatic responses including adaptation to oxidative, inflammatory, metabolic, proteotoxic and xenobiotic stresses. The NFE2L2 transcriptome has been implicated in protection against many chronic diseases including cardiovascular, metabolic, neurodgenerative and respiratory diseases (reviewed in Cuadrado et al, 2018; Baird and Yamamoto, 2020). In cancer, NFE2L2 plays a critical role in the metabolic reprogramming, directing metabolic intermediates into the Warburg and pentose phosphate pathways to support proliferative growth and redox homeostasis (reviewed in He et al, 2020; Ge et al, 2020; Hayes et al, 2020; Kitamura and Hotomashi, 2018)

KEAP1 is a redox sensor that together with CUL3/RBX1 forms part of an E3 ubiquitin ligase, which tightly regulates the activity of the transcription factor NFE2L2 by targeting it for ubiquitination and proteasome-dependent degradation. Oxidative modifications or electrophile adduct formation with redox-sensitive cysteines within KEAP1 renders this protein unable to target bound NFE2L2 for ubiquitination and allows newly translated NFE2L2 to accumulate within the cell and translocate to the nucleus where it can promote its transcriptional program (reviewed in Cuadrado et al, 2019; Baird and Yamamoto, 2020).
Literature References
PubMed ID Title Journal Year
30610225 Therapeutic targeting of the NRF2 and KEAP1 partnership in chronic diseases

Wells, G, Cousin, SP, Franklin, S, Cuadrado, A, Rojo, AI, Hayes, JD, Rumsey, WL, Levonen, AL, Dinkova-Kostova, AT, Kensler, TW, Attucks, OC

Nat Rev Drug Discov 2019
32640524 NRF2, a Transcription Factor for Stress Response and Beyond

He, F, Wen, T, Ru, X

Int J Mol Sci 2020
32582032 The Role of the Pentose Phosphate Pathway in Diabetes and Cancer

Ge, T, Yang, J, Tong, X, Wang, Y, Zhou, S, Li, Y

Front Endocrinol (Lausanne) 2020
32284348 The Molecular Mechanisms Regulating the KEAP1-NRF2 Pathway

Yamamoto, M, Baird, L

Mol Cell Biol 2020
29507103 Transcription Factor NRF2 as a Therapeutic Target for Chronic Diseases: A Systems Medicine Approach

Alcaraz, MJ, Pajares, M, León, R, Robledinos-Antón, N, Valverde, AM, López, MG, Manda, G, Guney, E, Oliva, B, Cuadrado, A, Schmidt, HHHW, Ghezzi, P, Rojo, AI, Hassan, A, Barbas, C, Daiber, A

Pharmacol Rev 2018
29450944 NRF2 addiction in cancer cells

Motohashi, H, Kitamura, H

Cancer Sci 2018
32649885 Oxidative Stress in Cancer

Hayes, JD, Tew, KD, Dinkova-Kostova, AT

Cancer Cell 2020
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