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KEAP1

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KEAP1
Available structures
PDBOrtholog search: PDBe RCSB
Identifiers
AliasesKEAP1, INrf2, KLHL19, kelch like ECH associated protein 1
External IDsOMIM: 606016; MGI: 1858732; HomoloGene: 8184; GeneCards: KEAP1; OMA:KEAP1 - orthologs
Orthologs
SpeciesHumanMouse
Entrez

9817

50868

Ensembl

ENSG00000079999

ENSMUSG00000003308

UniProt

Q14145

Q9Z2X8

RefSeq (mRNA)

NM_012289
NM_203500

NM_001110305
NM_001110306
NM_001110307
NM_016679

RefSeq (protein)

NP_036421
NP_987096

NP_001103775
NP_001103776
NP_001103777
NP_057888

Location (UCSC)Chr 19: 10.49 – 10.5 MbChr 9: 21.14 – 21.15 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/Edit Mouse

Kelch-like ECH-associated protein 1 is a protein that in humans is encoded by the Keap1 gene.[5]

Structure

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See also: Kelch protein and Kelch motif

Keap1 has four discrete protein domains. The N-terminal Broad complex, Tramtrack and Bric-à-Brac (BTB) domain contains the Cys151 residue, which is one of the important cysteines in stress sensing. The intervening region (IVR) domain contains two critical cysteine residues, Cys273 and Cys288, which are a second group of cysteines important for stress sensing. A double glycine repeat (DGR) and C-terminal region domains collaborate to form a βべーた-propeller structure, which is where Keap1 interacts with Nrf2.

Interactions

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The KEAP1/NRF2 pathway modulates the body's antitumor response

Keap1 has been shown to interact with Nrf2, a master regulator of the antioxidant response, which is important for the amelioration of oxidative stress.[6][7][8]

Under quiescent conditions, Nrf2 is anchored in the cytoplasm through binding to Keap1, which, in turn, facilitates the ubiquitination and subsequent proteolysis of Nrf2. Such sequestration and further degradation of Nrf2 in the cytoplasm are mechanisms for the repressive effects of Keap1 on Nrf2. Keap1 is not only a 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

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Because Nrf2 activation leads to a coordinated antioxidant and anti-inflammatory response, and Keap1 represses Nrf2 activation, Keap1 has become a very attractive drug target.[13][14][15][16]

A series of synthetic oleane triterpenoid compounds, known as antioxidant inflammation modulators (AIMs), are being developed by Reata Pharmaceuticals, Inc. and are potent inducers of the Keap1-Nrf2 pathway, blocking Keap1-dependent Nrf2 ubiquitination and leading to the stabilization and nuclear translocation of Nrf2 and subsequent induction of Nrf2 target genes.[citation needed] The lead compound in this series, bardoxolone methyl (also known as CDDO-Me or RTA 402), was in late-stage clinical trials for the treatment of chronic kidney disease (CKD) in patients with type 2 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

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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]

[edit]
  • (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]
    (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]
    The relationship of the NRF2/KEAP1 pathway with cellular metabolism[17]

References

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  1. ^ a b c GRCh38: Ensembl release 89: ENSG00000079999 – Ensembl, May 2017
  2. ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000003308 – Ensembl, May 2017
  3. ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. ^ "Entrez Gene: KEAP1 kelch-like ECH-associated protein 1".
  6. ^ 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. doi:10.1128/mcb.23.20.7198-7209.2003. PMC 230321. PMID 14517290.
  7. ^ Shibata T, Ohta T, Tong KI, Kokubu A, Odogawa R, Tsuta K, et al. (September 2008). "Cancer related mutations in NRF2 impair its recognition by Keap1-Cul3 E3 ligase and promote malignancy". Proceedings of the National Academy of Sciences of the United States of America. 105 (36): 13568–73. Bibcode:2008PNAS..10513568S. doi:10.1073/pnas.0806268105. PMC 2533230. PMID 18757741.
  8. ^ Wang XJ, Sun Z, Chen W, Li Y, Villeneuve NF, Zhang DD (August 2008). "Activation of Nrf2 by arsenite and monomethylarsonous acid is independent of Keap1-C151: enhanced Keap1-Cul3 interaction". Toxicology and Applied Pharmacology. 230 (3): 383–9. doi:10.1016/j.taap.2008.03.003. PMC 2610481. PMID 18417180.
  9. ^ Lignitto L, LeBoeuf SE, Homer H, Jiang S, Askenazi M, Karakousi TR, et al. (July 2019). "Nrf2 Activation Promotes Lung Cancer Metastasis by Inhibiting the Degradation of Bach1". Cell. 178 (2): 316–329.e18. doi:10.1016/j.cell.2019.06.003. PMC 6625921. PMID 31257023.
  10. ^ Lee OH, Jain AK, Papusha V, Jaiswal AK (December 2007). "An auto-regulatory loop between stress sensors INrf2 and Nrf2 controls their cellular abundance". The Journal of Biological Chemistry. 282 (50): 36412–20. doi:10.1074/jbc.M706517200. PMID 17925401.
  11. ^ Chorley BN, Campbell MR, Wang X, Karaca M, Sambandan D, Bangura F, et al. (August 2012). "Identification of novel NRF2-regulated genes by ChIP-Seq: influence on retinoid X receptor alpha". Nucleic Acids Research. 40 (15): 7416–29. doi:10.1093/nar/gks409. PMC 3424561. PMID 22581777.
  12. ^ Tian Y, Liu Q, Yu S, Chu Q, Chen Y, Wu K, Wang L (October 2020). "NRF2-Driven KEAP1 Transcription in Human Lung Cancer". Molecular Cancer Research. 18 (10): 1465–1476. doi:10.1158/1541-7786.MCR-20-0108. PMID 32571982. S2CID 219989242.
  13. ^ Abed DA, Goldstein M, Albanyan H, Jin H, Hu L (July 2015). "Discovery of direct inhibitors of Keap1-Nrf2 protein-protein interaction as potential therapeutic and preventive agents". Acta Pharmaceutica Sinica B. 5 (4): 285–99. doi:10.1016/j.apsb.2015.05.008. PMC 4629420. PMID 26579458.
  14. ^ Lu MC, Ji JA, Jiang ZY, You QD (September 2016). "The Keap1-Nrf2-ARE Pathway As a Potential Preventive and Therapeutic Target: An Update". Medicinal Research Reviews. 36 (5): 924–63. doi:10.1002/med.21396. PMID 27192495. S2CID 30047975.
  15. ^ Deshmukh P, Unni S, Krishnappa G, Padmanabhan B (February 2017). "The Keap1-Nrf2 pathway: promising therapeutic target to counteract ROS-mediated damage in cancers and neurodegenerative diseases". Biophysical Reviews. 9 (1): 41–56. doi:10.1007/s12551-016-0244-4. PMC 5425799. PMID 28510041.
  16. ^ Kerr F, Sofola-Adesakin O, Ivanov DK, Gatliff J, Gomez Perez-Nievas B, Bertrand HC, et al. (March 2017). "Direct Keap1-Nrf2 disruption as a potential therapeutic target for Alzheimer's disease". PLOS Genetics. 13 (3): e1006593. doi:10.1371/journal.pgen.1006593. PMC 5333801. PMID 28253260.
  17. ^ a b c Wu WL, Papagiannakopoulos T (2020-03-09). "The Pleiotropic Role of the KEAP1/NRF2 Pathway in Cancer". Annual Review of Cancer Biology. 4 (1): 413–435. doi:10.1146/annurev-cancerbio-030518-055627. ISSN 2472-3428.

Further reading

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