Phytochemical activity on NRF2 transcriptional activation (Homo sapiens)

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2Phase II enzymesNucleusERKC/EBP-betaMAFPI3KGCLCJNKP38NRF2PPPKCNRF2KEAP1PPHO-11SLC7A11NQO1CurcuminGSTA2GCLMKEAP1Caffeic acid phenethyl esterC/EBP-betaSulforaphane6-HITCNRF2KEAP1NRF2PP1


Description

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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Bibliography

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

History

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CompareRevisionActionTimeUserComment
98703view18:19, 28 September 2018KhanspersModified title
94689view22:49, 4 October 2017KhanspersModified description
94688view22:49, 4 October 2017KhanspersModified description
94687view22:49, 4 October 2017KhanspersModified description
92783view21:24, 5 July 2017AlexanderPicoUpdated overall layout and state positions
92717view19:41, 29 June 2017Khanspersminor layout change
92716view19:40, 29 June 2017Khansperscorrected misplaced state
92714view19:35, 29 June 2017Khanspersoverhaul and update states
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
48217view05:28, 17 May 2012MaintBotAutomatic update of PubChem xrefs
46085view02:20, 15 December 2011AllanKuchinskyupdated HGNC IDs
44881view10:08, 6 October 2011MartijnVanIerselOntology Term : 'oxidative stress response pathways' added !
44880view10:08, 6 October 2011MartijnVanIerselModified description
41042view23:16, 1 March 2011MaintBotRemoved redundant pathway information and comments
39757view07:19, 17 January 2011AlexanderPicomore specific title
38881view18:56, 24 September 2010KhanspersChanged line types
38830view11:54, 24 September 2010Jildaunucleus
32036view13:27, 14 August 2009MaintBotFixed group labels
29720view21:20, 1 June 2009Khanspersadded ref for metabolite
28165view09:44, 29 January 2009ThomasModified categories
28164view09:44, 29 January 2009ThomasModified description
28163view09:42, 29 January 2009Thomasextended pathway
20675view11:29, 14 November 2008MaintBot[[Pathway:Homo sapiens:Keap1-Nrf2]] moved to [[Pathway:WP3]]: Moved to stable identifier
20254view08:19, 28 October 2008HubertPeriodical save, work in progress
19325view11:38, 2 October 2008HubertNew pathway

External references

DataNodes

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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)
CurcuminMetaboliteHMDB02269 (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)
SulforaphaneMetaboliteHMDB05792 (HMDB)

Annotated Interactions

No annotated interactions

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