Transcriptional activation by NRF2 in response to phytochemicals (Homo sapiens)

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1Phase II enzymesNucleusERKC/EBP-betaMAFPI3KGCLCJNKP38NRF2PPPKCKEAP1NRF2PP2HO-1SLC7A11NQO1CurcuminGSTA2GCLMKEAP1Caffeic acid phenethyl esterC/EBP-betaSulforaphane6-HITCNRF2KEAP1NRF2PP2


Based on Surh, 2003, figure 4. NRF2 is a transcription factor that regulates expression of many detoxification or antioxidant enzymes. The Kelch-like-ECH-associated protein 1 (KEAP1) is a cytoplasmic repressor of NRF2 that inhibits its ability to translocate to the nucleus. These two proteins interact with each other through the double glycine-rich domains of KEAP1 and a hydrophilic region in the NEH2 domain of NRF2. KEAP1 contains many cysteine residues. Phase II enzyme inducers and/or prooxidants can cause oxidation or covalent modification (R) of these cysteine residues. As a result, NRF2 is released from KEAP1. In addition, phosphorylation of NRF2 at serine (S) and threonine (T) residues by kinases such as phosphatidylinositol 3-kinase (PI3K), protein kinase C (PKC), c-Jun NH2-terminal kinase (JNK) and extracellular-signal-regulated kinase (ERK) is assumed to facilitate the dissociation of NRF2 from KEAP1 and subsequent translocation to the nucleus. p38 can both stimulate and inhibit the NRF2 nuclear translocation. In the nucleus, NRF2 associates with small MAF (the term is derived from musculoaponeurotic-fibrosarcoma virus), forming a heterodimer that binds to the antioxidant-responsive element (ARE) to stimulate gene expression. NRF2/MAF target genes encode phase II detoxification or antioxidant enzymes such as glutathione S-transferase alpha2 (GSTA2), NAD(P)H:quinone oxidoreductase (NQO1), gamma-glutamate cysteine ligase (gamma -GCLC and gamma -GCLM) and heme oxygenase-1 (HO-1). PI3K also phosphorylates the CCAAT/enhancer binding protein-beta (C/EBPbeta), inducing its translocation to the nucleus and binding to the CCAAT sequence of C/EBP-beta response element within the xenobiotic response element (XRE), in conjunction with NRF2 binding to ARE. Transfection of human neuroblastoma cells with PI3K activates ARE, which is attenuated by a pharmacological inhibitor of PI3K or dominant-negative NRF2. Curcumin and caffeic acid phenethyl ester (CAPE) disrupt the NRF2–KEAP1 complex, leading to increased NRF2 binding to ARE. Sulphoraphane directly interacts with KEAP1 by covalent binding to its thiol groups. 6-(Methylsulfinyl)hexyl isothiocyanate (6-HITC) — a sulphoraphane analogue from Japanese horseradish wasabi — stimulates nuclear translocation of NRF2, which subsequently activates ARE.

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  1. Surh YJ; ''Cancer chemoprevention with dietary phytochemicals.''; Nat Rev Cancer, 2003 PubMed Europe PMC Scholia
  2. Niture SK, Khatri R, Jaiswal AK; ''Regulation of Nrf2-an update.''; Free Radic Biol Med, 2014 PubMed Europe PMC Scholia


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120028view22:58, 15 October 2021Khanspersupdated phospho sites
116707view09:35, 11 May 2021EweitzModified title
106155view12:05, 16 August 2019MaintBotHMDB identifier normalization
98703view18:19, 28 September 2018KhanspersModified title
94689view22:49, 4 October 2017KhanspersModified description
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79527view10:22, 24 March 2015Zariadded ID for GSTA2
74850view02:48, 1 May 2014NsalomonisAdded SLC7A11
73388view16:42, 25 January 2014EgonwAdded another missing metabolite identifier.
73387view16:39, 25 January 2014EgonwAdded a missing metabolite identifier.
68891view17:28, 8 July 2013MaintBotUpdated to 2013 gpml schema
67421view10:59, 26 June 2013DdiglesOntology Term : 'nuclear factor, erythroid derived 2, like 2 signaling pathway' added !
66318view17:34, 17 June 2013MaintBotModified title
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46085view02:20, 15 December 2011AllanKuchinskyupdated HGNC IDs
44881view10:08, 6 October 2011MartijnVanIerselOntology Term : 'oxidative stress response pathways' added !
44880view10:08, 6 October 2011MartijnVanIerselModified description
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28163view09:42, 29 January 2009Thomasextended pathway
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External references


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NameTypeDatabase referenceComment
6-HITCMetabolite7991398 (Chemspider) Full name: 6-(Methylsulfinyl)hexylisothiocyanate, or Japanese horseradish wasabi
C/EBP-betaGeneProduct1051 (Entrez Gene)
Caffeic acid phenethyl esterMetaboliteCHEBI:8062 (ChEBI)
CurcuminMetaboliteHMDB0002269 (HMDB)
ERKGeneProduct2048 (Entrez Gene)
GCLCGeneProduct2729 (Entrez Gene)
GCLMGeneProduct2730 (Entrez Gene)
GSTA2GeneProduct2939 (Entrez Gene)
HO-1GeneProduct3162 (Entrez Gene)
JNKGeneProduct5599 (Entrez Gene)
KEAP1GeneProduct9817 (Entrez Gene)
MAFGeneProduct4094 (Entrez Gene)
NQO1GeneProduct1728 (Entrez Gene)
NRF2GeneProduct4780 (Entrez Gene)
P38GeneProduct7965 (Entrez Gene)
PI3KGeneProduct5290 (Entrez Gene)
PKCGeneProduct5578 (Entrez Gene)
SLC7A11GeneProductENSG00000151012 (Ensembl)
SulforaphaneMetaboliteHMDB0005792 (HMDB)

Annotated Interactions

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