Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT1QHOS2)

• DOT Name: Endoplasmic reticulum membrane sensor NFE2L1 (NFE2L1)
• Synonyms: Locus control region-factor 1; LCR-F1; Nuclear factor erythroid 2-related factor 1; NF-E2-related factor 1; NFE2-related factor 1; Nuclear factor, erythroid derived 2, like 1; Protein NRF1, p120 form; Transcription factor 11; TCF-11
• Gene Name: NFE2L1
• Related Disease:
  Neuroblastoma
  Adult T-cell leukemia/lymphoma
  Alzheimer disease
  Autosomal dominant optic atrophy, classic form
  B-cell lymphoma
  B-cell neoplasm
  Breast cancer
  Breast carcinoma
  Cardiac failure
  Congestive heart failure
  Cytomegalovirus infection
  Fragile X syndrome
  Insulinoma
  Neoplasm
  Non-insulin dependent diabetes
  Obesity
  Retinoblastoma
  T-cell leukaemia
  Microphthalmia
  Nervous system inflammation
  Parkinson disease
• UniProt ID: NF2L1_HUMAN
• Pfam ID: PF03131
• Sequence:
  MLSLKKYLTEGLLQFTILLSLIGVRVDVDTYLTSQLPPLREIILGPSSAYTQTQFHNLRN
  TLDGYGIHPKSIDLDNYFTARRLLSQVRALDRFQVPTTEVNAWLVHRDPEGSVSGSQPNS
  GLALESSSGLQDVTGPDNGVRESETEQGFGEDLEDLGAVAPPVSGDLTKEDIDLIDILWR
  QDIDLGAGREVFDYSHRQKEQDVEKELRDGGEQDTWAGEGAEALARNLLVDGETGESFPA
  QVPSGEDQTALSLEECLRLLEATCPFGENAEFPADISSITEAVPSESEPPALQNNLLSPL
  LTGTESPFDLEQQWQDLMSIMEMQAMEVNTSASEILYSAPPGDPLSTNYSLAPNTPINQN
  VSLHQASLGGCSQDFLLFSPEVESLPVASSSTLLPLAPSNSTSLNSTFGSTNLTGLFFPP
  QLNGTANDTAGPELPDPLGGLLDEAMLDEISLMDLAIEEGFNPVQASQLEEEFDSDSGLS
  LDSSHSPSSLSSSEGSSSSSSSSSSSSSSASSSASSSFSEEGAVGYSSDSETLDLEEAEG
  AVGYQPEYSKFCRMSYQDPAQLSCLPYLEHVGHNHTYNMAPSALDSADLPPPSALKKGSK
  EKQADFLDKQMSRDEHRARAMKIPFTNDKIINLPVEEFNELLSKYQLSEAQLSLIRDIRR
  RGKNKMAAQNCRKRKLDTILNLERDVEDLQRDKARLLREKVEFLRSLRQMKQKVQSLYQE
  VFGRLRDENGRPYSPSQYALQYAGDGSVLLIPRTMADQQARRQERKPKDRRK
• Function: [Endoplasmic reticulum membrane sensor NFE2L1]: Endoplasmic reticulum membrane sensor that translocates into the nucleus in response to various stresses to act as a transcription factor. Constitutes a precursor of the transcription factor NRF1. Able to detect various cellular stresses, such as cholesterol excess, oxidative stress or proteasome inhibition. In response to stress, it is released from the endoplasmic reticulum membrane following cleavage by the protease DDI2 and translocates into the nucleus to form the transcription factor NRF1. Acts as a key sensor of cholesterol excess: in excess cholesterol conditions, the endoplasmic reticulum membrane form of the protein directly binds cholesterol via its CRAC motif, preventing cleavage and release of the transcription factor NRF1, thereby allowing expression of genes promoting cholesterol removal, such as CD36. Involved in proteasome homeostasis: in response to proteasome inhibition, it is released from the endoplasmic reticulum membrane, translocates to the nucleus and activates expression of genes encoding proteasome subunits ; [Transcription factor NRF1]: CNC-type bZIP family transcription factor that translocates to the nucleus and regulates expression of target genes in response to various stresses. Heterodimerizes with small-Maf proteins (MAFF, MAFG or MAFK) and binds DNA motifs including the antioxidant response elements (AREs), which regulate expression of genes involved in oxidative stress response. Activates or represses expression of target genes, depending on the context. Plays a key role in cholesterol homeostasis by acting as a sensor of cholesterol excess: in low cholesterol conditions, translocates into the nucleus and represses expression of genes involved in defense against cholesterol excess, such as CD36. In excess cholesterol conditions, the endoplasmic reticulum membrane form of the protein directly binds cholesterol via its CRAC motif, preventing cleavage and release of the transcription factor NRF1, thereby allowing expression of genes promoting cholesterol removal. Critical for redox balance in response to oxidative stress: acts by binding the AREs motifs on promoters and mediating activation of oxidative stress response genes, such as GCLC, GCLM, GSS, MT1 and MT2. Plays an essential role during fetal liver hematopoiesis: probably has a protective function against oxidative stress and is involved in lipid homeostasis in the liver. Involved in proteasome homeostasis: in response to proteasome inhibition, mediates the 'bounce-back' of proteasome subunits by translocating into the nucleus and activating expression of genes encoding proteasome subunits. Also involved in regulating glucose flux. Together with CEBPB; represses expression of DSPP during odontoblast differentiation. In response to ascorbic acid induction, activates expression of SP7/Osterix in osteoblasts.

Molecular Interaction Atlas (MIA) of This DOT

21 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Neuroblastoma	DISVZBI4	Definitive	Biomarker	[1]
Adult T-cell leukemia/lymphoma	DIS882XU	Strong	Altered Expression	[2]
Alzheimer disease	DISF8S70	Strong	Biomarker	[3]
Autosomal dominant optic atrophy, classic form	DISXUAV9	Strong	Altered Expression	[4]
B-cell lymphoma	DISIH1YQ	Strong	Biomarker	[5]
B-cell neoplasm	DISVY326	Strong	Altered Expression	[6]
Breast cancer	DIS7DPX1	Strong	Biomarker	[7]
Breast carcinoma	DIS2UE88	Strong	Biomarker	[7]
Cardiac failure	DISDC067	Strong	Biomarker	[8]
Congestive heart failure	DIS32MEA	Strong	Biomarker	[8]
Cytomegalovirus infection	DISCEMGC	Strong	Biomarker	[9]
Fragile X syndrome	DISE8W3A	Strong	Biomarker	[10]
Insulinoma	DISIU1JS	Strong	Biomarker	[11]
Neoplasm	DISZKGEW	Strong	Biomarker	[11]
Non-insulin dependent diabetes	DISK1O5Z	Strong	Biomarker	[12]
Obesity	DIS47Y1K	Strong	Biomarker	[13]
Retinoblastoma	DISVPNPB	Strong	Biomarker	[14]
T-cell leukaemia	DISJ6YIF	Strong	Altered Expression	[2]
Microphthalmia	DISGEBES	Limited	Biomarker	[15]
Nervous system inflammation	DISB3X5A	Limited	Altered Expression	[16]
Parkinson disease	DISQVHKL	Limited	Biomarker	[17]

This DOT Affected the Drug Response of 1 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Methotrexate	DM2TEOL	Approved	Endoplasmic reticulum membrane sensor NFE2L1 (NFE2L1) affects the response to substance of Methotrexate.	[41]

28 Drug(s) Affected the Gene/Protein Processing of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate affects the expression of Endoplasmic reticulum membrane sensor NFE2L1 (NFE2L1).	[18]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Endoplasmic reticulum membrane sensor NFE2L1 (NFE2L1).	[19]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Endoplasmic reticulum membrane sensor NFE2L1 (NFE2L1).	[20]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Endoplasmic reticulum membrane sensor NFE2L1 (NFE2L1).	[21]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Endoplasmic reticulum membrane sensor NFE2L1 (NFE2L1).	[22]
Arsenic	DMTL2Y1	Approved	Arsenic increases the expression of Endoplasmic reticulum membrane sensor NFE2L1 (NFE2L1).	[23]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide decreases the expression of Endoplasmic reticulum membrane sensor NFE2L1 (NFE2L1).	[24]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of Endoplasmic reticulum membrane sensor NFE2L1 (NFE2L1).	[18]
Nicotine	DMWX5CO	Approved	Nicotine increases the splicing of Endoplasmic reticulum membrane sensor NFE2L1 (NFE2L1).	[26]
Piroxicam	DMTK234	Approved	Piroxicam decreases the expression of Endoplasmic reticulum membrane sensor NFE2L1 (NFE2L1).	[27]
Cocaine	DMSOX7I	Approved	Cocaine increases the expression of Endoplasmic reticulum membrane sensor NFE2L1 (NFE2L1).	[28]
Sulindac	DM2QHZU	Approved	Sulindac increases the expression of Endoplasmic reticulum membrane sensor NFE2L1 (NFE2L1).	[29]
Vitamin C	DMXJ7O8	Approved	Vitamin C increases the expression of Endoplasmic reticulum membrane sensor NFE2L1 (NFE2L1).	[22]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of Endoplasmic reticulum membrane sensor NFE2L1 (NFE2L1).	[30]
Resveratrol	DM3RWXL	Phase 3	Resveratrol increases the expression of Endoplasmic reticulum membrane sensor NFE2L1 (NFE2L1).	[22]
Curcumin	DMQPH29	Phase 3	Curcumin increases the expression of Endoplasmic reticulum membrane sensor NFE2L1 (NFE2L1).	[31]
Tocopherol	DMBIJZ6	Phase 2	Tocopherol increases the expression of Endoplasmic reticulum membrane sensor NFE2L1 (NFE2L1).	[32]
MG-132	DMKA2YS	Preclinical	MG-132 increases the expression of Endoplasmic reticulum membrane sensor NFE2L1 (NFE2L1).	[34]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of Endoplasmic reticulum membrane sensor NFE2L1 (NFE2L1).	[35]
Milchsaure	DM462BT	Investigative	Milchsaure increases the expression of Endoplasmic reticulum membrane sensor NFE2L1 (NFE2L1).	[36]
Deguelin	DMXT7WG	Investigative	Deguelin increases the expression of Endoplasmic reticulum membrane sensor NFE2L1 (NFE2L1).	[37]
D-glucose	DMMG2TO	Investigative	D-glucose increases the expression of Endoplasmic reticulum membrane sensor NFE2L1 (NFE2L1).	[34]
geraniol	DMS3CBD	Investigative	geraniol increases the expression of Endoplasmic reticulum membrane sensor NFE2L1 (NFE2L1).	[38]
4-hydroxy-2-nonenal	DM2LJFZ	Investigative	4-hydroxy-2-nonenal decreases the expression of Endoplasmic reticulum membrane sensor NFE2L1 (NFE2L1).	[24]
acrolein	DMAMCSR	Investigative	acrolein decreases the expression of Endoplasmic reticulum membrane sensor NFE2L1 (NFE2L1).	[39]
2-tert-butylbenzene-1,4-diol	DMNXI1E	Investigative	2-tert-butylbenzene-1,4-diol increases the expression of Endoplasmic reticulum membrane sensor NFE2L1 (NFE2L1).	[34]
Dorsomorphin	DMKYXJW	Investigative	Dorsomorphin decreases the expression of Endoplasmic reticulum membrane sensor NFE2L1 (NFE2L1).	[34]
PATULIN	DM0RV9C	Investigative	PATULIN increases the expression of Endoplasmic reticulum membrane sensor NFE2L1 (NFE2L1).	[40]

2 Drug(s) Affected the Post-Translational Modifications of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Decitabine	DMQL8XJ	Approved	Decitabine affects the methylation of Endoplasmic reticulum membrane sensor NFE2L1 (NFE2L1).	[25]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the methylation of Endoplasmic reticulum membrane sensor NFE2L1 (NFE2L1).	[33]

References

• [1] Novel genes FAM134C, C3orf10 and ENOX1 are regulated by NRF-1 and differentially regulate neurite outgrowth in neuroblastoma cells and hippocampal neurons.Gene. 2013 Oct 15;529(1):7-15. doi: 10.1016/j.gene.2013.08.006. Epub 2013 Aug 9.
• [2] HTLV-1 bZIP factor suppresses TDP1 expression through inhibition of NRF-1 in adult T-cell leukemia.Sci Rep. 2017 Oct 9;7(1):12849. doi: 10.1038/s41598-017-12924-0.
• [3] Brain in situ hybridization maps as a source for reverse-engineering transcriptional regulatory networks: Alzheimer's disease insights.Gene. 2016 Jul 15;586(1):77-86. doi: 10.1016/j.gene.2016.03.045. Epub 2016 Apr 3.
• [4] Testosterone induces up-regulation of mitochondrial gene expression in murine C2C12 skeletal muscle cells accompanied by an increase of nuclear respiratory factor-1 and its downstream effectors.Mol Cell Endocrinol. 2020 Jan 15;500:110631. doi: 10.1016/j.mce.2019.110631. Epub 2019 Oct 30.
• [5] Nuclear factor erythroid 2-related factors 1 and 2 are able to define the worst prognosis group among high-risk diffuse large B cell lymphomas treated with R-CHOEP.J Clin Pathol. 2019 Apr;72(4):316-321. doi: 10.1136/jclinpath-2018-205584. Epub 2019 Feb 12.
• [6] Effects of nuclear respiratory factor? on apoptosis and mitochondrial dysfunction induced by cobalt chloride in H9C2 cells.Mol Med Rep. 2019 Mar;19(3):2153-2163. doi: 10.3892/mmr.2019.9839. Epub 2019 Jan 10.
• [7] A regulation loop between Nrf1 and MRTF-A controls migration and invasion in MDA-MB-231 breast cancer cells.Int J Mol Med. 2018 Nov;42(5):2459-2468. doi: 10.3892/ijmm.2018.3816. Epub 2018 Aug 9.
• [8] High expression of nuclear factor 90 (NF90) leads to mitochondrial degradation in skeletal and cardiac muscles.PLoS One. 2012;7(8):e43340. doi: 10.1371/journal.pone.0043340. Epub 2012 Aug 17.
• [9] The Human Cytomegalovirus US27 Gene Product Constitutively Activates Antioxidant Response Element-Mediated Transcription through G(), Phosphoinositide 3-Kinase, and Nuclear Respiratory Factor 1.J Virol. 2018 Nov 12;92(23):e00644-18. doi: 10.1128/JVI.00644-18. Print 2018 Dec 1.
• [10] Interaction of the transcription factors USF1, USF2, and alpha -Pal/Nrf-1 with the FMR1 promoter. Implications for Fragile X mental retardation syndrome.J Biol Chem. 2001 Feb 9;276(6):4357-64. doi: 10.1074/jbc.M009629200. Epub 2000 Oct 31.
• [11] Nfe2l1-silenced insulinoma cells acquire aggressiveness and chemoresistance.Endocr Relat Cancer. 2018 Mar;25(3):185-200. doi: 10.1530/ERC-17-0458. Epub 2017 Dec 4.
• [12] Exercise increases hyper-acetylation of histones on the Cis-element of NRF-1 binding to the Mef2a promoter: Implications on type 2 diabetes.Biochem Biophys Res Commun. 2017 Apr 22;486(1):83-87. doi: 10.1016/j.bbrc.2017.03.002. Epub 2017 Mar 2.
• [13] Brown adipose tissue thermogenic adaptation requires Nrf1-mediated proteasomal activity.Nat Med. 2018 Mar;24(3):292-303. doi: 10.1038/nm.4481. Epub 2018 Feb 5.
• [14] Tetramethylpyrazine downregulates transcription of the CXC receptor4 (CXCR4) via nuclear respiratory factor? (Nrf?) in WERIRb1 retinoblastoma cells.Oncol Rep. 2019 Sep;42(3):1214-1224. doi: 10.3892/or.2019.7233. Epub 2019 Jul 15.
• [15] Perivascular epithelioid cell neoplasm (PEComa) of the gynecologic tract: clinicopathologic and immunohistochemical characterization of 16 cases.Am J Surg Pathol. 2014 Feb;38(2):176-88. doi: 10.1097/PAS.0000000000000133.
• [16] Decreased levels of constitutive proteasomes in experimental autoimmune encephalomyelitis may be caused by a combination of subunit displacement and reduced Nfe2l1 expression.J Neurochem. 2020 Mar;152(5):585-601. doi: 10.1111/jnc.14912. Epub 2019 Dec 2.
• [17] Inhibition of ZNF746 suppresses invasion and epithelial to mesenchymal transition in H460 non-small cell lung cancer cells.Oncol Rep. 2014 Jan;31(1):73-8. doi: 10.3892/or.2013.2801. Epub 2013 Oct 22.
• [18] Gene Expression Regulation and Pathway Analysis After Valproic Acid and Carbamazepine Exposure in a Human Embryonic Stem Cell-Based Neurodevelopmental Toxicity Assay. Toxicol Sci. 2015 Aug;146(2):311-20. doi: 10.1093/toxsci/kfv094. Epub 2015 May 15.
• [19] Comparison of HepG2 and HepaRG by whole-genome gene expression analysis for the purpose of chemical hazard identification. Toxicol Sci. 2010 May;115(1):66-79.
• [20] Multiple microRNAs function as self-protective modules in acetaminophen-induced hepatotoxicity in humans. Arch Toxicol. 2018 Feb;92(2):845-858.
• [21] Bringing in vitro analysis closer to in vivo: studying doxorubicin toxicity and associated mechanisms in 3D human microtissues with PBPK-based dose modelling. Toxicol Lett. 2018 Sep 15;294:184-192.
• [22] Natural antioxidants exhibit chemopreventive characteristics through the regulation of CNC b-Zip transcription factors in estrogen-induced breast carcinogenesis. J Biochem Mol Toxicol. 2014 Dec;28(12):529-38.
• [23] Chronic exposure to arsenic causes increased cell survival, DNA damage, and increased expression of mitochondrial transcription factor A (mtTFA) in human prostate epithelial cells. Chem Res Toxicol. 2011 Mar 21;24(3):340-9. doi: 10.1021/tx1003112. Epub 2011 Jan 14.
• [24] Microarray analysis of H2O2-, HNE-, or tBH-treated ARPE-19 cells. Free Radic Biol Med. 2002 Nov 15;33(10):1419-32.
• [25] Ornithine decarboxylase antizyme upregulates DNA-dependent protein kinase and enhances the nonhomologous end-joining repair of DNA double-strand breaks in human oral cancer cells. Biochemistry. 2007 Aug 7;46(31):8920-32. doi: 10.1021/bi7000328. Epub 2007 Jul 14.
• [26] Characterizing the genetic basis for nicotine induced cancer development: a transcriptome sequencing study. PLoS One. 2013 Jun 18;8(6):e67252.
• [27] Apoptosis induced by piroxicam plus cisplatin combined treatment is triggered by p21 in mesothelioma. PLoS One. 2011;6(8):e23569.
• [28] Gene expression in human hippocampus from cocaine abusers identifies genes which regulate extracellular matrix remodeling. PLoS One. 2007 Nov 14;2(11):e1187. doi: 10.1371/journal.pone.0001187.
• [29] Expression profile analysis of colon cancer cells in response to sulindac or aspirin. Biochem Biophys Res Commun. 2002 Mar 29;292(2):498-512.
• [30] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [31] Curcumin protects human keratinocytes against inorganic arsenite-induced acute cytotoxicity through an NRF2-dependent mechanism. Oxid Med Cell Longev. 2013;2013:412576.
• [32] Selenium and vitamin E: cell type- and intervention-specific tissue effects in prostate cancer. J Natl Cancer Inst. 2009 Mar 4;101(5):306-20.
• [33] Air pollution and DNA methylation alterations in lung cancer: A systematic and comparative study. Oncotarget. 2017 Jan 3;8(1):1369-1391. doi: 10.18632/oncotarget.13622.
• [34] Metformin leads to accumulation of reactive oxygen species by inhibiting the NFE2L1 expression in human hepatocellular carcinoma cells. Toxicol Appl Pharmacol. 2021 Jun 1;420:115523. doi: 10.1016/j.taap.2021.115523. Epub 2021 Apr 8.
• [35] Bisphenol A activates the Nrf1/2-antioxidant response element pathway in HEK 293 cells. Chem Res Toxicol. 2013 Mar 18;26(3):498-506.
• [36] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.
• [37] Neurotoxicity and underlying cellular changes of 21 mitochondrial respiratory chain inhibitors. Arch Toxicol. 2021 Feb;95(2):591-615. doi: 10.1007/s00204-020-02970-5. Epub 2021 Jan 29.
• [38] Geraniol suppresses prostate cancer growth through down-regulation of E2F8. Cancer Med. 2016 Oct;5(10):2899-2908.
• [39] Hydroxytyrosol protects retinal pigment epithelial cells from acrolein-induced oxidative stress and mitochondrial dysfunction. J Neurochem. 2007 Dec;103(6):2690-700. doi: 10.1111/j.1471-4159.2007.04954.x.
• [40] The Nrf1 transcription factor is induced by patulin and protects against patulin cytotoxicity. Toxicology. 2022 Apr 15;471:153173. doi: 10.1016/j.tox.2022.153173. Epub 2022 Mar 31.
• [41] Gene expression profiling of 30 cancer cell lines predicts resistance towards 11 anticancer drugs at clinically achieved concentrations. Int J Cancer. 2006 Apr 1;118(7):1699-712. doi: 10.1002/ijc.21570.