Author(s): Taguchi K, Motohashi H, Yamamoto M
The Keap1–Nrf2 regulatory pathway plays a central role in the protection of cells against oxidative and xenobiotic damage. Under unstressed conditions, Nrf2 is constantly ubiquitinated by the Cul3–Keap1 ubiquitin E3 ligase complex and rapidly degraded in proteasomes. Upon exposure to electrophilic and oxidative stresses, reactive cysteine residues of Keap1 become modified, leading to a decline in the E3 ligase activity, stabilization of Nrf2 and robust induction of a battery of cytoprotective genes. Biochemical and structural analyses have revealed that the intact Keap1 homodimer forms a cherry-bob structure in which one molecule of Nrf2 associates with two molecules of Keap1 by using two binding sites within the Neh2 domain of Nrf2. This two-site binding appears critical for Nrf2 ubiquitination. In many human cancers, missense mutations in KEAP1 and NRF2 genes have been identified. These mutations disrupt the Keap1–Nrf2 complex activity involved in ubiquitination and degradation of Nrf2 and result in constitutive activation of Nrf2. Elevated expression of Nrf2 target genes confers advantages in terms of stress resistance and cell proliferation in normal and cancer cells. Discovery and development of selective Nrf2 inhibitors should make a critical contribution to improved cancer therapy.
Referred From: https://www.ncbi.nlm.nih.gov/pubmed/21251164
Author(s): Zimmet P, Alberti KG, Shaw J
Author(s): Murarka S, Movahed MR
Author(s): Khavandi K, Khavandi A, Asghar O, Greenstein A, Withers S, et al.
Author(s): Francis GS
Author(s): Giacco F, Brownlee M
Author(s): Baynes JW, Thorpe SR
Author(s): Brownlee M
Author(s): Cai L, Kang YJ
Author(s): Cai L, Wang J, Li Y, Sun X, Wang L, et al.
Author(s): He X, Kan H, Cai L, Ma Q
Author(s): Kensler TW, Wakabayashi N, Biswal S
Author(s): Leung L, Kwong M, Hou S, Lee C, Chan JY
Author(s): Ma Q
Author(s): Talalay P, Dinkova-Kostova AT, Holtzclaw WD
Author(s): Kobayashi A, Ohta T, Yamamoto M
Author(s): Nguyen T, Sherratt PJ, Pickett CB
Author(s): Ma Q, Battelli L, Hubbs AF
Author(s): Hubbs AF, Benkovic SA, Miller DB, O'Callaghan JP, Battelli L, et al.
Author(s): Ramos-Gomez M, Kwak MK, Dolan PM, Itoh K, Yamamoto M, et al.
Author(s): He X, Lin GX, Chen MG, Zhang JX, Ma Q
Author(s): He X, Chen MG, Ma Q
Author(s): Hu X, Roberts JR, Apopa PL, Kan YW, Ma Q
Author(s): Cho HY, Reddy SP, Yamamoto M, Kleeberger SR
Author(s): He X, Chen MG, Lin GX, Ma Q
Author(s): He X, Ma Q
Author(s): He X, Ma Q
Author(s): Chan K, Lu R, Chang JC, Kan YW
Author(s): Ma Q, Kinneer K, Bi Y, Chan JY, Kan YW
Author(s): Kan H, Xie Z, Finkel MS
Author(s): Dobrin JS, Lebeche D
Author(s): Duncan JG
Author(s): Yates MS, Kwak MK, Egner PA, Groopman JD, Bodreddigari S, et al.
Author(s): Dinkova-Kostova AT, Liby KT, Stephenson KK, Holtzclaw WD, Gao X, et al.
Author(s): Liby K, Royce DB, Williams CR, Risingsong R, Yore MM, et al.
Author(s): Sussan TE, Rangasamy T, Blake DJ, Malhotra D, El-Haddad H, et al.