Review article| Volume 21, P88-91, April 2018

The putative interplay between DJ-1/NRF2 and Dimethyl Fumarate: A potentially important pharmacological target

Published:February 26, 2018DOI:


      • Dimethyl Fumarate (DMF) is an immunomodulating treatment in multiple sclerosis.
      • DMF and its active metabolite, Monomethyl Fumarate (MMF) exert their activities at least in part through the KEAP1/NRF2 pathway.
      • The PARK7/DJ-1 protein that acts effector of the NRF2/KEAP1 pathway.
      • The introduction of DMF / MMF in an organism would inadvertedly influence the DJ-1/NRF2 axis.
      • IThe DMF/MMF - DJ-1/NRF2 interaction has not been explored in the setting of MS.
      • In this review, the relevant literature on this putative interaction is summarized in detail.


      Recent research has outlined that Dimethyl Fumarate (DMF) functions as a gene regulator via multiple pathways, critical among which is the NRF2 cytoprotective cascade. PARK7/DJ-1 is a multifunctional protein that acts as a redox sensor and effector of multiple cytoprotective pathways, including NRF2. Specifically, it prevents the association of NRF2 with its inhibitor KEAP1, allowing NRF2 to enter the nucleus and mediate cytoprotective and antioxidant cascades. It is our hypothesis that while the NRF2-KEAP1 inhibitory complex is reported the main pharmacological target for DMF's NRF dependent functions, no study to date has explored the effects of DMF on DJ-1's expression, and vice-versa, the possibility of a regulatory inadequacy in the upstream, oxidant-responsive DJ-1 activator of the NRF2 cascade.


      NRF2 (transcription factor nuclear factor (erythroid derived 2)-like2 (NRF2)), KEAP1 (Kelch-like erythroid cell-derived (ECH) associated protein-1), MMF (monomethyl fumarate), DMF (Dimethyl Fumarate), ARE (antioxidant response element), ROS (reactive oxygen species)


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        • Akaike N.
        • Sato M.
        Role of anions and cations in frog taste cell stimulation.
        Comp. Biochem. Physiol. A Comp. Physiol. 1976; 55 (Epub 1976/01/01): 383-391
        • Al-Jaderi Z.
        • Maghazachi A.A.
        Utilization of dimethyl fumarate and related molecules for treatment of multiple sclerosis, cancer, and other diseases.
        Front. Immunol. 2016; 7 (Epub 2016/08/09): 278
        • Bahmed K.
        • Messier E.M.
        • Zhou W.
        • et al.
        DJ-1 modulates nuclear erythroid 2-related factor-2-mediated protection in human primary alveolar type II cells in smokers.
        Am. J. Respir. Cell Mol. Biol. 2016; 55 (Epub 2016/04/20): 439-449
        • Bande M.F.
        • Santiago M.
        • Blanco M.J.
        • et al.
        Serum DJ-1/park 7 is a potential biomarker of choroidal nevi transformation.
        Investig. Ophthalmol. Vis. Sci. 2012; 53 (Epub 2011/11/30): 62-67
        • Booth L.
        • Cruickshanks N.
        • Tavallai S.
        • et al.
        Regulation of dimethyl-fumarate toxicity by proteasome inhibitors.
        Cancer Biol. Ther. 2014; 15 (Epub 2014/12/09): 1646-1657
        • Brennan M.S.
        • Matos M.F.
        • Li B.
        • et al.
        Dimethyl fumarate and monoethyl fumarate exhibit differential effects on KEAP1, NRF2 activation, and glutathione depletion in vitro.
        PLoS One. 2015; 10 (Epub2015/03/21): e0120254
        • Brennan M.S.
        • Patel H.
        • Allaire N.
        • et al.
        Pharmacodynamics of dimethyl fumarate are tissue specific and involve NRF2-dependent and -independent mechanisms.
        Antioxid. Redox Signal. 2016; 24 (Epub 2016/03/17): 1058-1071
        • Cao J.
        • Lou S.
        • Ying M.
        • Yang B.
        DJ-1 as a human oncogene and potential therapeutic target.
        Biochem. Pharmacol. 2015; 93 (Epub 2014/12/17): 241-250
        • Chen L.L.
        • Tian J.J.
        • Su L.
        • et al.
        DJ-1: a promising marker in metastatic uveal melanoma.
        J. Cancer Res. Clin. Oncol. 2015; 141 (Epub 2014/08/19): 315-321
        • Clements C.M.
        • McNally R.S.
        • Conti B.J.
        • Mak T.W.
        • Ting J.P.
        DJ-1, a cancer- and Parkinson's disease-associated protein, stabilizes the antioxidant transcriptional master regulator Nrf2.
        Proc. Natl. Acad. Sci. USA. 2006; 103 (Epub 2006/10/04): 15091-15096
        • Duan X.
        • Kelsen S.G.
        • Merali S.
        Proteomic analysis of oxidative stress-responsive proteins in human pneumocytes: insight into the regulation of DJ-1 expression.
        J. Proteome Res. 2008; 7 (Epub 2008/09/27): 4955-4961
        • Enesa K.
        • Zakkar M.
        • Chaudhury H.
        • et al.
        NF-kappaB suppression by the deubiquitinating enzyme Cezanne: a novel negative feedback loop in pro-inflammatory signaling.
        J. Biol. Chem. 2008; 283 (Epub 2008/01/08): 7036-7045
        • Enesa K.
        • Zakkar M.
        • Chaudhury H.
        • et al.
        NF-kappaB suppression by the deubiquitinating enzyme Cezanne: a novel negative feedback loop in pro-inflammatory signaling.
        J. Biol. Chem. 2008; 283 (Epub 2008/01/08): 7036-7045
        • Gilgun-Sherki Y.
        • Melamed E.
        • Offen D.
        The role of oxidative stress in the pathogenesis of multiple sclerosis: the need for effective antioxidant therapy.
        J. Neurol. 2004; 251 (Epub 2004/03/12): 261-268
        • Gill A.J.
        • Kolson D.L.
        Dimethyl fumarate modulation of immune and antioxidant responses: application to HIV therapy.
        Crit. Rev. Immunol. 2013; 33 (Epub 2013/08/27): 307-359
        • de Jong R.
        • Bezemer A.C.
        • Zomerdijk T.P.
        • van de Pouw-Kraan T.
        • Ottenhoff T.H.
        • Nibbering P.H.
        Selective stimulation of T helper 2 cytokine responses by the anti-psoriasis agent monomethylfumarate.
        Eur. J. Immunol. 1996; 26 (Epub 1996/09/01): 2067-2074
        • Jung S.H.
        • Won K.J.
        • Lee K.P.
        • et al.
        DJ-1 protein regulates CD3+ T cell migration via overexpression of CXCR4 receptor.
        Atherosclerosis. 2014; 235 (Epub 2014/06/24): 503-509
        • Kobayashi K.
        • Tomiki H.
        • Inaba Y.
        • Ichikawa M.
        • Kim B.S.
        • Koh C.S.
        Dimethyl fumarate suppresses Theiler's murine encephalomyelitis virus-induced demyelinating disease by modifying the Nrf2-Keap1 pathway.
        Int. Immunol. 2015; 27 (Epub 2015/02/28): 333-344
        • Lev N.
        • Ickowicz D.
        • Melamed E.
        • Offen D.
        Oxidative insults induce DJ-1 upregulation and redistribution: implications for neuroprotection.
        Neurotoxicology. 2008; 29 (Epub 2008/04/02): 397-405
        • Linker R.A.
        • Haghikia A.
        Dimethyl fumarate in multiple sclerosis: latest developments, evidence and place in therapy.
        Ther. Adv. Chronic Dis. 2016; 7 (Epub 2016/07/20): 198-207
        • Liu H.
        • Wang M.
        • Li M.
        • et al.
        Expression and role of DJ-1 in leukemia.
        Biochem. Biophys. Res. Commun. 2008; 375 (Epub 2008/08/30): 477-483
        • Loewe R.
        • Valero T.
        • Kremling S.
        • et al.
        Dimethylfumarate impairs melanoma growth and metastasis.
        Cancer Res. 2006; 66 (Epub 2006/12/21): 11888-11896
        • McNally R.S.
        • Davis B.K.
        • Clements C.M.
        • Accavitti-Loper M.A.
        • Mak T.W.
        • Ting J.P.
        DJ-1 enhances cell survival through the binding of Cezanne, a negative regulator of NF-kappaB.
        J. Biol. Chem. 2011; 286 (Epub 2010/11/26): 4098-4106
        • Metz I.
        • Traffehn S.
        • Strassburger-Krogias K.
        • et al.
        Glial cells express nuclear nrf2 after fumarate treatment for multiple sclerosis and psoriasis.
        Neurol. Neuroimmunol. Neuroinflamm. 2015; 2 (Epub2015/04/14): e99
        • Mirshafiey A.
        • Mohsenzadegan M.
        Antioxidant therapy in multiple sclerosis.
        Immunopharmacol. Immunotoxicol. 2009; 31 (Epub 2008/09/03): 13-29
        • Mo J.S.
        • Jung J.
        • Yoon J.H.
        • et al.
        DJ-1 modulates the p38 mitogen-activated protein kinase pathway through physical interaction with apoptosis signal-regulating kinase 1.
        J. Cell. Biochem. 2010; 110 (Epub2010/03/10): 229-237
        • Moscovitz O.
        • Ben-Nissan G.
        • Fainer I.
        • Pollack D.
        • Mizrachi L.
        • Sharon M.
        The Parkinson's-associated protein DJ-1 regulates the 20S proteasome.
        Nat. Commun. 2015; 6 (Epub 2015/04/04): 6609
        • Muralidharan P.
        • Hayes Jr., D.
        • Black S.M.
        • Mansour H.M.
        Microparticulate/nanoparticulate powders of a novel Nrf2 activator and an aerosol performance enhancer for pulmonary delivery targeting the lung Nrf2/Keap-1 pathway.
        Mol. Syst. Des. Eng. 2016; 1 (Epub 2016/10/25): 48-65
        • Pitarokoili K.
        • Ambrosius B.
        • Meyer D.
        • Schrewe L.
        • Gold R.
        Dimethyl fumarate ameliorates lewis rat experimental autoimmune neuritis and mediates axonal protection.
        PLoS One. 2015; 10 (Epub2015/12/01): e0143416
        • Rockwell C.E.
        • Zhang M.
        • Fields P.E.
        • Klaassen C.D.
        Th2 skewing by activation of Nrf2 in CD4(+) T cells.
        J. Immunol. 2012; 188 (Epub 2012/01/18): 1630-1637
        • Saidu N.E.
        • Noé G.
        • Cerles O.
        • et al.
        Dimethyl fumarate controls the NRF2/DJ-1 axis in cancer cells: therapeutic applications.
        Mol. Cancer Ther. 2017; 16: 529-539
        • Seidel P.
        • Merfort I.
        • Hughes J.M.
        • Oliver B.G.
        • Tamm M.
        • Roth M.
        Dimethylfumarate inhibits NF-{kappa}B function at multiple levels to limit airway smooth muscle cell cytokine secretion.
        Am. J. Physiol. Lung Cell Mol. Physiol. 2009; 297 (Epub 2009/05/26): L326-L339
        • Singh Y.
        • Chen H.
        • Zhou Y.
        • et al.
        Differential effect of DJ-1/PARK7 on development of natural and induced regulatory T cells.
        Sci. Rep. 2015; 5 (Epub 2015/12/05): 17723
        • Takaya K.
        • Suzuki T.
        • Motohashi H.
        • et al.
        Validation of the multiple sensor mechanism of the Keap1-Nrf2 system.
        Free Radic. Biol. Med. 2012; 53 (Epub 2012/06/27): 817-827
        • van Horssen J.
        • Drexhage J.A.
        • Flor T.
        • Gerritsen W.
        • van der Valk P.
        • de Vries H.E.
        Nrf2 and DJ1 are consistently upregulated in inflammatory multiple sclerosis lesions.
        Free Radic. Biol. Med. 2010; 49 (Epub 2010/08/03): 1283-1289
        • Xie X.
        • Zhao Y.
        • Ma C.Y.
        • et al.
        Dimethyl fumarate induces necroptosis in colon cancer cells through GSH depletion/ROS increase/MAPKs activation pathway.
        Br. J. Pharmacol. 2015; 172 (Epub 2015/05/09): 3929-3943
        • Xu Z.
        • Zhang F.
        • Sun F.
        • Gu K.
        • Dong S.
        • He D.
        Dimethyl fumarate for multiple sclerosis.
        Cochrane Database Syst. Rev. 2015; (Epub 2015/04/23): CD011076
        • Yamazoe Y.
        • Tsubaki M.
        • Matsuoka H.
        • et al.
        Dimethylfumarate inhibits tumor cell invasion and metastasis by suppressing the expression and activities of matrix metalloproteinases in melanoma cells.
        Cell Biol. Int. 2009; 33 (Epub 2009/07/15): 1087-1094
        • Zhu Z.M.
        • Li Z.R.
        • Huang Y.
        • et al.
        DJ-1 is involved in the peritoneal metastasis of gastric cancer through activation of the Akt signaling pathway.
        Oncol. Rep. 2014; 31 (Epub 2014/01/09): 1489-1497