Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTOPAP55)

• DOT Name: Ecotropic viral integration site 5 protein homolog (EVI5)
• Synonyms: EVI-5; Neuroblastoma stage 4S gene protein
• Gene Name: EVI5
• Related Disease:
  Hepatocellular carcinoma
  Leukemia
  Neoplasm
  Multiple sclerosis
  Neuroblastoma
  Asthma
  Plasma cell myeloma
  Systemic lupus erythematosus
• UniProt ID: EVI5_HUMAN
• Pfam ID: PF00566
• Sequence:
  MVTNKMTAAFRNPSGKQVATDKVAEKLSSTLSWVKNTVSHTVSQMASQVASPSTSLHTTS
  SSTTLSTPALSPSSPSQLSPDDLELLAKLEEQNRLLETDSKSLRSVNGSRRNSGSSLVSS
  SSASSNLSHLEEDSWILWGRIVNEWEDVRKKKEKQVKELVHKGIPHHFRAIVWQLLCSAQ
  SMPIKDQYSELLKMTSPCEKLIRRDIARTYPEHNFFKEKDSLGQEVLFNVMKAYSLVDRE
  VGYCQGSAFIVGLLLMQMPEEEAFCVFVKLMQDYRLRELFKPSMAELGLCMYQFECMIQE
  HLPELFVHFQSQSFHTSMYASSWFLTIFLTTFPLPIATRIFDIFMSEGLEIVFRVGLALL
  QMNQAELMQLDMEGMLQHFQKVIPHQFDGVPDKLIQAAYQVKYNSKKMKKLEKEYTTIKT
  KEMEEQVEIKRLRTENRLLKQRIETLEKHKCSSNYNEDFVLQLEKELVQARLSEAESQCA
  LKEMQDKVLDIEKRNNSLPDENNIARLQEELIAVKLREAEAIMGLKELRQQVKDLEEHWQ
  RHLARTTGRWKDPPKKNAMNELQDELMTIRLREAETQAEIREIKQRMMEMETQNQINSNH
  LRRAEQEVISLQEKVQYLSAQNKGLLTQLSEAKRKQAEIECKNKEEVMAVRLREADSIAA
  VAELRQHIAELEIQKEEGKLQGQLNKSDSNQYIGELKDQIAELNHELRCLKGQRGFSGQP
  PFDGIHIVNHLIGDDESFHSSDEDFIDNSLQETGVGFPLHGKSGSMSLDPAVADGSESET
  EDSVLETRESNQVVQKERPPRRRESYSTTV
• Function: Functions as a regulator of cell cycle progression by stabilizing the FBXO5 protein and promoting cyclin-A accumulation during interphase. May play a role in cytokinesis.
• Tissue Specificity: Expressed in various cell lines (at protein level). Expressed in a wide range of tissues including brain and adrenal.

Molecular Interaction Atlas (MIA) of This DOT

8 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Hepatocellular carcinoma	DIS0J828	Strong	Altered Expression	[1]
Leukemia	DISNAKFL	Strong	Altered Expression	[2]
Neoplasm	DISZKGEW	Strong	Altered Expression	[1]
Multiple sclerosis	DISB2WZI	moderate	Genetic Variation	[3]
Neuroblastoma	DISVZBI4	moderate	Posttranslational Modification	[4]
Asthma	DISW9QNS	Limited	Genetic Variation	[5]
Plasma cell myeloma	DIS0DFZ0	Limited	Biomarker	[6]
Systemic lupus erythematosus	DISI1SZ7	Limited	Genetic Variation	[7]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Mitoxantrone	DMM39BF	Approved	Ecotropic viral integration site 5 protein homolog (EVI5) affects the response to substance of Mitoxantrone.	[25]

18 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 Ecotropic viral integration site 5 protein homolog (EVI5).	[8]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Ecotropic viral integration site 5 protein homolog (EVI5).	[9]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of Ecotropic viral integration site 5 protein homolog (EVI5).	[10]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Ecotropic viral integration site 5 protein homolog (EVI5).	[11]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of Ecotropic viral integration site 5 protein homolog (EVI5).	[13]
Calcitriol	DM8ZVJ7	Approved	Calcitriol increases the expression of Ecotropic viral integration site 5 protein homolog (EVI5).	[14]
Vorinostat	DMWMPD4	Approved	Vorinostat decreases the expression of Ecotropic viral integration site 5 protein homolog (EVI5).	[15]
Methotrexate	DM2TEOL	Approved	Methotrexate increases the expression of Ecotropic viral integration site 5 protein homolog (EVI5).	[16]
Selenium	DM25CGV	Approved	Selenium decreases the expression of Ecotropic viral integration site 5 protein homolog (EVI5).	[17]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of Ecotropic viral integration site 5 protein homolog (EVI5).	[18]
Tocopherol	DMBIJZ6	Phase 2	Tocopherol decreases the expression of Ecotropic viral integration site 5 protein homolog (EVI5).	[17]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Ecotropic viral integration site 5 protein homolog (EVI5).	[19]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 increases the expression of Ecotropic viral integration site 5 protein homolog (EVI5).	[20]
Geldanamycin	DMS7TC5	Discontinued in Phase 2	Geldanamycin increases the expression of Ecotropic viral integration site 5 protein homolog (EVI5).	[21]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of Ecotropic viral integration site 5 protein homolog (EVI5).	[8]
Coumestrol	DM40TBU	Investigative	Coumestrol decreases the expression of Ecotropic viral integration site 5 protein homolog (EVI5).	[23]
[3H]methyltrienolone	DMTSGOW	Investigative	[3H]methyltrienolone increases the expression of Ecotropic viral integration site 5 protein homolog (EVI5).	[24]
Forskolin	DM6ITNG	Investigative	Forskolin increases the expression of Ecotropic viral integration site 5 protein homolog (EVI5).	[24]

2 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 Ecotropic viral integration site 5 protein homolog (EVI5).	[12]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Ecotropic viral integration site 5 protein homolog (EVI5).	[22]

References

• [1] EVI5 is a novel independent prognostic predictor in hepatocellular carcinoma after radical hepatectomy.Oncol Rep. 2017 Oct;38(4):2251-2258. doi: 10.3892/or.2017.5862. Epub 2017 Aug 1.
• [2] Stem cell exhaustion due to Runx1 deficiency is prevented by Evi5 activation in leukemogenesis.Blood. 2010 Feb 25;115(8):1610-20. doi: 10.1182/blood-2009-07-232249. Epub 2009 Dec 14.
• [3] Ecotropic Viral Integration Site 5 (EVI5) variants are associated with multiple sclerosis in Iranian population.Mult Scler Relat Disord. 2017 Nov;18:15-19. doi: 10.1016/j.msard.2017.09.011. Epub 2017 Sep 14.
• [4] The NBPF1 promoter has been recruited from the unrelated EVI5 gene before simian radiation.Mol Biol Evol. 2009 Jun;26(6):1321-32. doi: 10.1093/molbev/msp047. Epub 2009 Mar 12.
• [5] A genome-wide cross-trait analysis from UK Biobank highlights the shared genetic architecture of asthma and allergic diseases.Nat Genet. 2018 Jun;50(6):857-864. doi: 10.1038/s41588-018-0121-0. Epub 2018 May 21.
• [6] RPL5 on 1p22.1 is recurrently deleted in multiple myeloma and its expression is linked to bortezomib response.Leukemia. 2017 Aug;31(8):1706-1714. doi: 10.1038/leu.2016.370. Epub 2016 Dec 2.
• [7] Transancestral mapping and genetic load in systemic lupus erythematosus.Nat Commun. 2017 Jul 17;8:16021. doi: 10.1038/ncomms16021.
• [8] From transient transcriptome responses to disturbed neurodevelopment: role of histone acetylation and methylation as epigenetic switch between reversible and irreversible drug effects. Arch Toxicol. 2014 Jul;88(7):1451-68.
• [9] Predictive toxicology using systemic biology and liver microfluidic "on chip" approaches: application to acetaminophen injury. Toxicol Appl Pharmacol. 2012 Mar 15;259(3):270-80.
• [10] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [11] Low doses of cisplatin induce gene alterations, cell cycle arrest, and apoptosis in human promyelocytic leukemia cells. Biomark Insights. 2016 Aug 24;11:113-21.
• [12] 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.
• [13] Minimal peroxide exposure of neuronal cells induces multifaceted adaptive responses. PLoS One. 2010 Dec 17;5(12):e14352. doi: 10.1371/journal.pone.0014352.
• [14] Large-scale in silico and microarray-based identification of direct 1,25-dihydroxyvitamin D3 target genes. Mol Endocrinol. 2005 Nov;19(11):2685-95.
• [15] Definition of transcriptome-based indices for quantitative characterization of chemically disturbed stem cell development: introduction of the STOP-Toxukn and STOP-Toxukk tests. Arch Toxicol. 2017 Feb;91(2):839-864.
• [16] Global molecular effects of tocilizumab therapy in rheumatoid arthritis synovium. Arthritis Rheumatol. 2014 Jan;66(1):15-23.
• [17] 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.
• [18] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [19] Transcriptional signature of human macrophages exposed to the environmental contaminant benzo(a)pyrene. Toxicol Sci. 2010 Apr;114(2):247-59.
• [20] Inhibition of BRD4 attenuates tumor cell self-renewal and suppresses stem cell signaling in MYC driven medulloblastoma. Oncotarget. 2014 May 15;5(9):2355-71.
• [21] Identification of transcriptome signatures and biomarkers specific for potential developmental toxicants inhibiting human neural crest cell migration. Arch Toxicol. 2016 Jan;90(1):159-80.
• [22] DNA methylome-wide alterations associated with estrogen receptor-dependent effects of bisphenols in breast cancer. Clin Epigenetics. 2019 Oct 10;11(1):138. doi: 10.1186/s13148-019-0725-y.
• [23] Pleiotropic combinatorial transcriptomes of human breast cancer cells exposed to mixtures of dietary phytoestrogens. Food Chem Toxicol. 2009 Apr;47(4):787-95.
• [24] Identification of genes targeted by the androgen and PKA signaling pathways in prostate cancer cells. Oncogene. 2006 Nov 23;25(55):7311-23.
• [25] 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.