KEAP1
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| Location (UCSC) | Chr 19: 10.49 – 10.5 Mb | Chr 9: 21.14 – 21.15 Mb | |||||||
| PubMed search | [3] | [4] | |||||||
| View/Edit Human | View/Edit Mouse |
Kelch-like ECH-associated protein 1 is a protein that in humans is encoded by the Keap1 gene.[5]
Structure
Keap1 has four discrete protein domains. The
Nrf2
.
Interactions
Keap1 has been shown to
Nrf2, a master regulator of the antioxidant response, which is important for the amelioration of oxidative stress.[6][7][8]
Under quiescent conditions,
tumor suppressor gene, but also a metastasis suppressor gene.[9]
Recently, several interesting studies have also identified a hidden circuit in NRF2 regulations. In the mouse Keap1 (INrf2) gene, Lee and colleagues [10] found that an AREs located on a negative strand can subtly connect Nrf2 activation to Keap1 transcription. When examining NRF2 occupancies in human lymphocytes, Chorley and colleagues identified an approximately 700 bp locus within the KEAP1 promoter region was consistently top rank enriched, even at the whole-genome scale.[11] These basic findings have depicted a mutually influenced pattern between NRF2 and KEAP1. NRF2-driven KEAP1 expression characterized in human cancer contexts, especially in human squamous cell cancers,[12] depicted a new perspective in understanding NRF2 signaling regulation.
As a drug target
Because Nrf2 activation leads to a coordinated
A series of synthetic oleane
diabetes mellitus and showed an ability to improve markers of renal function in these patients.[citation needed
] However, the Phase 3 trial was halted due to safety concerns.
Human health
Mutations in KEAP1 that result in loss-of-function are not linked to familial cancers, though they do predispose individuals to
multinodular goiters. The proposed mechanism leading to goiter formation is that the redox stress experienced when the thyroid produces hormones selects for loss of heterozygosity of KEAP1, leading to the goiters.[17]
Gallery
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![(a) NRF2 and KEAP1 protein domains; (b) KEAP1 homodimerizes through the BTB domain, and through the Kelch domains KEAP1 interacts with NRF2 at the ETGE and DLG motifs[17]](//upload.wikimedia.org/wikipedia/commons/thumb/2/28/KEAP1_NRF2_signaling_pathway.jpg/370px-KEAP1_NRF2_signaling_pathway.jpg)
(a) NRF2 and KEAP1 protein domains; (b) KEAP1 homodimerizes through the BTB domain, and through the Kelch domains KEAP1 interacts with NRF2 at the ETGE and DLG motifs[17] -
![The relationship of the NRF2/KEAP1 pathway with cellular metabolism[17]](//upload.wikimedia.org/wikipedia/commons/thumb/e/e0/KEAP1_and_NRF2_interacting_with_cellular_metabolism.jpg/355px-KEAP1_and_NRF2_interacting_with_cellular_metabolism.jpg)
The relationship of the NRF2/KEAP1 pathway with cellular metabolism[17]
![(a) NRF2 and KEAP1 protein domains; (b) KEAP1 homodimerizes through the BTB domain, and through the Kelch domains KEAP1 interacts with NRF2 at the ETGE and DLG motifs[17]](/File:KEAP1_NRF2_signaling_pathway.jpg)
![The relationship of the NRF2/KEAP1 pathway with cellular metabolism[17]](/File:KEAP1_and_NRF2_interacting_with_cellular_metabolism.jpg)
References
- ^ a b c GRCh38: Ensembl release 89: ENSG00000079999 – Ensembl, May 2017
- ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000003308 – Ensembl, May 2017
- ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- ^ "Entrez Gene: KEAP1 kelch-like ECH-associated protein 1".
- PMID 14517290.
- PMID 18757741.
- PMID 18417180.
- PMID 31257023.
- PMID 17925401.
- PMID 22581777.
- S2CID 219989242.
- PMID 26579458.
- S2CID 30047975.
- PMID 28510041.
- PMID 28253260.
- ^ ISSN 2472-3428.
Further reading
- Zhang DD (2007). "Mechanistic studies of the Nrf2-Keap1 signaling pathway". Drug Metabolism Reviews. 38 (4): 769–89. S2CID 7627379.
- Nagase T, Seki N, Tanaka A, Ishikawa K, Nomura N (August 1995). "Prediction of the coding sequences of unidentified human genes. IV. The coding sequences of 40 new genes (KIAA0121-KIAA0160) deduced by analysis of cDNA clones from human cell line KG-1". DNA Research. 2 (4): 167–74, 199–210. PMID 8590280.
- Itoh K, Wakabayashi N, Katoh Y, Ishii T, Igarashi K, Engel JD, Yamamoto M (January 1999). "Keap1 represses nuclear activation of antioxidant responsive elements by Nrf2 through binding to the amino-terminal Neh2 domain". Genes & Development. 13 (1): 76–86. PMID 9887101.
- Dhakshinamoorthy S, Jaiswal AK (June 2001). "Functional characterization and role of INrf2 in antioxidant response element-mediated expression and antioxidant induction of NAD(P)H:quinone oxidoreductase1 gene". Oncogene. 20 (29): 3906–17. PMID 11439354.
- Sekhar KR, Spitz DR, Harris S, Nguyen TT, Meredith MJ, Holt JT, et al. (April 2002). "Redox-sensitive interaction between KIAA0132 and Nrf2 mediates indomethacin-induced expression of gamma-glutamylcysteine synthetase". Free Radical Biology & Medicine. 32 (7): 650–62. PMID 11909699.
- Velichkova M, Guttman J, Warren C, Eng L, Kline K, Vogl AW, Hasson T (March 2002). "A human homologue of Drosophila kelch associates with myosin-VIIa in specialized adhesion junctions". Cell Motility and the Cytoskeleton. 51 (3): 147–64. PMID 11921171.
- Zipper LM, Mulcahy RT (September 2002). "The Keap1 BTB/POZ dimerization function is required to sequester Nrf2 in cytoplasm". The Journal of Biological Chemistry. 277 (39): 36544–52. PMID 12145307.
- Sekhar KR, Yan XX, Freeman ML (October 2002). "Nrf2 degradation by the ubiquitin proteasome pathway is inhibited by KIAA0132, the human homolog to INrf2". Oncogene. 21 (44): 6829–34. PMID 12360409.
- Bloom DA, Jaiswal AK (November 2003). "Phosphorylation of Nrf2 at Ser40 by protein kinase C in response to antioxidants leads to the release of Nrf2 from INrf2, but is not required for Nrf2 stabilization/accumulation in the nucleus and transcriptional activation of antioxidant response element-mediated NAD(P)H:quinone oxidoreductase-1 gene expression". The Journal of Biological Chemistry. 278 (45): 44675–82. PMID 12947090.
- Cullinan SB, Zhang D, Hannink M, Arvisais E, Kaufman RJ, Diehl JA (October 2003). "Nrf2 is a direct PERK substrate and effector of PERK-dependent cell survival". Molecular and Cellular Biology. 23 (20): 7198–209. PMID 14517290.
- Colland F, Jacq X, Trouplin V, Mougin C, Groizeleau C, Hamburger A, et al. (July 2004). "Functional proteomics mapping of a human signaling pathway". Genome Research. 14 (7): 1324–32. PMID 15231748.
- Kobayashi A, Kang MI, Okawa H, Ohtsuji M, Zenke Y, Chiba T, et al. (August 2004). "Oxidative stress sensor Keap1 functions as an adaptor for Cul3-based E3 ligase to regulate proteasomal degradation of Nrf2". Molecular and Cellular Biology. 24 (16): 7130–9. PMID 15282312.
- Strachan GD, Morgan KL, Otis LL, Caltagarone J, Gittis A, Bowser R, Jordan-Sciutto KL (September 2004). "Fetal Alz-50 clone 1 interacts with the human orthologue of the Kelch-like Ech-associated protein". Biochemistry. 43 (38): 12113–22. PMID 15379550.
- Li X, Zhang D, Hannink M, Beamer LJ (December 2004). "Crystal structure of the Kelch domain of human Keap1". The Journal of Biological Chemistry. 279 (52): 54750–8. PMID 15475350.
- Zhang DD, Lo SC, Cross JV, Templeton DJ, Hannink M (December 2004). "Keap1 is a redox-regulated substrate adaptor protein for a Cul3-dependent ubiquitin ligase complex". Molecular and Cellular Biology. 24 (24): 10941–53. PMID 15572695.
- Li X, Zhang D, Hannink M, Beamer LJ (December 2004). "Crystallization and initial crystallographic analysis of the Kelch domain from human Keap1". Acta Crystallographica. Section D, Biological Crystallography. 60 (Pt 12 Pt 2): 2346–8. PMID 15583386.
- Furukawa M, Xiong Y (January 2005). "BTB protein Keap1 targets antioxidant transcription factor Nrf2 for ubiquitination by the Cullin 3-Roc1 ligase". Molecular and Cellular Biology. 25 (1): 162–71. PMID 15601839.
- Hosoya T, Maruyama A, Kang MI, Kawatani Y, Shibata T, Uchida K, et al. (July 2005). "Differential responses of the Nrf2-Keap1 system to laminar and oscillatory shear stresses in endothelial cells". The Journal of Biological Chemistry. 280 (29): 27244–50. PMID 15917255.
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