Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTL4E94L)

• DOT Name: Negative elongation factor E (NELFE)
• Synonyms: NELF-E; RNA-binding protein RD
• Gene Name: NELFE
• Related Disease:
  Neoplasm
  Age-related macular degeneration
  Dystonia
  Glioma
  Graves disease
  Hepatitis
  Hepatitis A virus infection
  Hepatitis C virus infection
  Hepatocellular carcinoma
  Multiple sclerosis
  Pancreatic adenocarcinoma
  Parkinson disease
  Proliferative diabetic retinopathy
  X-linked reticulate pigmentary disorder
  Pancreatic cancer
  Systemic lupus erythematosus
  Glycogen storage disease type II
  Migraine, familial hemiplegic, 2
  Parkinsonian disorder
• UniProt ID: NELFE_HUMAN
• PDB ID: 1X5P; 2BZ2; 2JX2; 5OOB; 6GML; 7YCX
• Pfam ID: PF00076
• Sequence:
  MLVIPPGLSEEEEALQKKFNKLKKKKKALLALKKQSSSSTTSQGGVKRSLSEQPVMDTAT
  ATEQAKQLVKSGAISAIKAETKNSGFKRSRTLEGKLKDPEKGPVPTFQPFQRSISADDDL
  QESSRRPQRKSLYESFVSSSDRLRELGPDGEEAEGPGAGDGPPRSFDWGYEERSGAHSSA
  SPPRSRSRDRSHERNRDRDRDRERDRDRDRDRDRERDRDRDRDRDRDRERDRDRERDRDR
  DREGPFRRSDSFPERRAPRKGNTLYVYGEDMTPTLLRGAFSPFGNIIDLSMDPPRNCAFV
  TYEKMESADQAVAELNGTQVESVQLKVNIARKQPMLDAATGKSVWGSLAVQNSPKGCHRD
  KRTQIVYSDDVYKENLVDGF
• Function: Essential component of the NELF complex, a complex that negatively regulates the elongation of transcription by RNA polymerase II. The NELF complex, which acts via an association with the DSIF complex and causes transcriptional pausing, is counteracted by the P-TEFb kinase complex. Provides the strongest RNA binding activity of the NELF complex and may initially recruit the NELF complex to RNA ; (Microbial infection) The NELF complex is involved in HIV-1 latency possibly involving recruitment of PCF11 to paused RNA polymerase II.
• Tissue Specificity: Widely expressed. Expressed in heart, brain, lung, placenta, liver, skeletal muscle, kidney and pancreas.
• KEGG Pathway: Viral life cycle - HIV-1 (hsa03250)
• Reactome Pathway:
  Formation of the Early Elongation Complex (R-HSA-113418)
  Formation of HIV elongation complex in the absence of HIV Tat (R-HSA-167152)
  Formation of the HIV-1 Early Elongation Complex (R-HSA-167158)
  Formation of HIV-1 elongation complex containing HIV-1 Tat (R-HSA-167200)
  Pausing and recovery of Tat-mediated HIV elongation (R-HSA-167238)
  Abortive elongation of HIV-1 transcript in the absence of Tat (R-HSA-167242)
  Tat-mediated HIV elongation arrest and recovery (R-HSA-167243)
  Tat-mediated elongation of the HIV-1 transcript (R-HSA-167246)
  HIV elongation arrest and recovery (R-HSA-167287)
  Pausing and recovery of HIV elongation (R-HSA-167290)
  RNA Polymerase II Pre-transcription Events (R-HSA-674695)
  TP53 Regulates Transcription of DNA Repair Genes (R-HSA-6796648)
  RNA Polymerase II Transcription Elongation (R-HSA-75955)
  Formation of RNA Pol II elongation complex (R-HSA-112382)

Molecular Interaction Atlas (MIA) of This DOT

19 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Neoplasm	DISZKGEW	Definitive	Altered Expression	[1]
Age-related macular degeneration	DIS0XS2C	Strong	Genetic Variation	[2]
Dystonia	DISJLFGW	Strong	Biomarker	[3]
Glioma	DIS5RPEH	Strong	Biomarker	[4]
Graves disease	DISU4KOQ	Strong	Genetic Variation	[5]
Hepatitis	DISXXX35	Strong	Altered Expression	[6]
Hepatitis A virus infection	DISUMFQV	Strong	Altered Expression	[6]
Hepatitis C virus infection	DISQ0M8R	Strong	Altered Expression	[6]
Hepatocellular carcinoma	DIS0J828	Strong	Biomarker	[7]
Multiple sclerosis	DISB2WZI	Strong	Genetic Variation	[8]
Pancreatic adenocarcinoma	DISKHX7S	Strong	Biomarker	[9]
Parkinson disease	DISQVHKL	Strong	Biomarker	[10]
Proliferative diabetic retinopathy	DISQZ13G	Strong	Biomarker	[11]
X-linked reticulate pigmentary disorder	DIS0RB5A	Strong	Biomarker	[11]
Pancreatic cancer	DISJC981	moderate	Altered Expression	[1]
Systemic lupus erythematosus	DISI1SZ7	moderate	Genetic Variation	[12]
Glycogen storage disease type II	DISXZPBC	Limited	Genetic Variation	[13]
Migraine, familial hemiplegic, 2	DISJPXBR	Limited	Biomarker	[3]
Parkinsonian disorder	DISHGY45	Limited	Biomarker	[3]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the expression of Negative elongation factor E (NELFE).	[14]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Negative elongation factor E (NELFE).	[15]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Negative elongation factor E (NELFE).	[16]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Negative elongation factor E (NELFE).	[17]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Negative elongation factor E (NELFE).	[18]
Quercetin	DM3NC4M	Approved	Quercetin increases the expression of Negative elongation factor E (NELFE).	[20]
Temozolomide	DMKECZD	Approved	Temozolomide increases the expression of Negative elongation factor E (NELFE).	[21]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Negative elongation factor E (NELFE).	[24]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of Negative elongation factor E (NELFE).	[19]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the methylation of Negative elongation factor E (NELFE).	[22]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 decreases the phosphorylation of Negative elongation factor E (NELFE).	[23]
Coumarin	DM0N8ZM	Investigative	Coumarin increases the phosphorylation of Negative elongation factor E (NELFE).	[23]
Hexadecanoic acid	DMWUXDZ	Investigative	Hexadecanoic acid decreases the phosphorylation of Negative elongation factor E (NELFE).	[25]

References

• [1] NELFE promoted pancreatic cancer metastasis and the epithelialtomesenchymal transition by decreasing the stabilization of NDRG2 mRNA.Int J Oncol. 2019 Dec;55(6):1313-1323. doi: 10.3892/ijo.2019.4890. Epub 2019 Oct 2.
• [2] Genetic factors in nonsmokers with age-related macular degeneration revealed through genome-wide gene-environment interaction analysis.Ann Hum Genet. 2013 May;77(3):215-31. doi: 10.1111/ahg.12011.
• [3] Migraine- and dystonia-related disease-mutations of Na+/K+-ATPases: relevance of behavioral studies in mice to disease symptoms and neurological manifestations in humans.Neurosci Biobehav Rev. 2012 Feb;36(2):855-71. doi: 10.1016/j.neubiorev.2011.10.005. Epub 2011 Nov 2.
• [4] Targeted therapy of intracranial glioma model mice with curcumin nanoliposomes.Int J Nanomedicine. 2018 Mar 15;13:1601-1610. doi: 10.2147/IJN.S157019. eCollection 2018.
• [5] Identification of independent risk loci for Graves' disease within the MHC in the Japanese population.J Hum Genet. 2011 Nov;56(11):772-8. doi: 10.1038/jhg.2011.99. Epub 2011 Sep 8.
• [6] Overexpression of the RD RNA binding protein in hepatitis C virus-related hepatocellular carcinoma.Oncol Rep. 2012 Aug;28(2):728-34. doi: 10.3892/or.2012.1821. Epub 2012 May 18.
• [7] NELFE-Dependent MYC Signature Identifies a Unique Cancer Subtype in Hepatocellular Carcinoma.Sci Rep. 2019 Mar 4;9(1):3369. doi: 10.1038/s41598-019-39727-9.
• [8] Evidence for VAV2 and ZNF433 as susceptibility genes for multiple sclerosis.J Neuroimmunol. 2010 Oct 8;227(1-2):162-6. doi: 10.1016/j.jneuroim.2010.06.003. Epub 2010 Jul 2.
• [9] Comparison of robotic vs laparoscopic vs open distal pancreatectomy. A systematic review and network meta-analysis.HPB (Oxford). 2019 Oct;21(10):1268-1276. doi: 10.1016/j.hpb.2019.04.010. Epub 2019 May 9.
• [10] A novel peptide delivers plasmids across blood-brain barrier into neuronal cells as a single-component transfer vector.PLoS One. 2013;8(3):e59642. doi: 10.1371/journal.pone.0059642. Epub 2013 Mar 29.
• [11] Retinal Nonperfusion Characteristics on Ultra-Widefield Angiography in Eyes With Severe Nonproliferative Diabetic Retinopathy and Proliferative Diabetic Retinopathy.JAMA Ophthalmol. 2019 Jun 1;137(6):626-631. doi: 10.1001/jamaophthalmol.2019.0440.
• [12] GWAS identifies novel SLE susceptibility genes and explains the association of the HLA region.Genes Immun. 2014 Sep;15(6):347-54. doi: 10.1038/gene.2014.23. Epub 2014 May 29.
• [13] Associations of the C2-CFB-RDBP-SKIV2L locus with age-related macular degeneration and polypoidal choroidal vasculopathy.Ophthalmology. 2013 Apr;120(4):837-43. doi: 10.1016/j.ophtha.2012.10.003. Epub 2012 Dec 20.
• [14] Integrative omics data analyses of repeated dose toxicity of valproic acid in vitro reveal new mechanisms of steatosis induction. Toxicology. 2018 Jan 15;393:160-170.
• [15] 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.
• [16] Increased mitochondrial ROS formation by acetaminophen in human hepatic cells is associated with gene expression changes suggesting disruption of the mitochondrial electron transport chain. Toxicol Lett. 2015 Apr 16;234(2):139-50.
• [17] 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.
• [18] Quantitative proteomics reveals a broad-spectrum antiviral property of ivermectin, benefiting for COVID-19 treatment. J Cell Physiol. 2021 Apr;236(4):2959-2975. doi: 10.1002/jcp.30055. Epub 2020 Sep 22.
• [19] Prenatal arsenic exposure and the epigenome: identifying sites of 5-methylcytosine alterations that predict functional changes in gene expression in newborn cord blood and subsequent birth outcomes. Toxicol Sci. 2015 Jan;143(1):97-106. doi: 10.1093/toxsci/kfu210. Epub 2014 Oct 10.
• [20] Comparison of phenotypic and transcriptomic effects of false-positive genotoxins, true genotoxins and non-genotoxins using HepG2 cells. Mutagenesis. 2011 Sep;26(5):593-604.
• [21] Temozolomide induces activation of Wnt/-catenin signaling in glioma cells via PI3K/Akt pathway: implications in glioma therapy. Cell Biol Toxicol. 2020 Jun;36(3):273-278. doi: 10.1007/s10565-019-09502-7. Epub 2019 Nov 22.
• [22] 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.
• [23] Quantitative phosphoproteomics reveal cellular responses from caffeine, coumarin and quercetin in treated HepG2 cells. Toxicol Appl Pharmacol. 2022 Aug 15;449:116110. doi: 10.1016/j.taap.2022.116110. Epub 2022 Jun 7.
• [24] Environmental pollutant induced cellular injury is reflected in exosomes from placental explants. Placenta. 2020 Jan 1;89:42-49. doi: 10.1016/j.placenta.2019.10.008. Epub 2019 Oct 17.
• [25] Functional lipidomics: Palmitic acid impairs hepatocellular carcinoma development by modulating membrane fluidity and glucose metabolism. Hepatology. 2017 Aug;66(2):432-448. doi: 10.1002/hep.29033. Epub 2017 Jun 16.