Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTWEA19O)

• DOT Name: Nuclear pore complex protein Nup214 (NUP214)
• Synonyms: 214 kDa nucleoporin; Nucleoporin Nup214; Protein CAN
• Gene Name: NUP214
• Related Disease:
  Acute lymphocytic leukaemia
  Acute monocytic leukemia
  Acute myelogenous leukaemia
  Breast cancer
  Dementia
  Encephalopathy, acute, infection-induced, susceptibility to, 9
  Isolated congenital microcephaly
  Mantle cell lymphoma
  Myelodysplastic syndrome
  Myeloid leukaemia
  Neoplasm
  Sarcoidosis
  Advanced cancer
  Breast carcinoma
  Chromosomal disorder
• UniProt ID: NU214_HUMAN
• PDB ID: 2OIT; 3FHC; 3FMO; 3FMP; 5DIS; 7R5J; 7R5K
• Pfam ID: PF18617
• Sequence:
  MGDEMDAMIPEREMKDFQFRALKKVRIFDSPEELPKERSSLLAVSNKYGLVFAGGASGLQ
  IFPTKNLLIQNKPGDDPNKIVDKVQGLLVPMKFPIHHLALSCDNLTLSACMMSSEYGSII
  AFFDVRTFSNEAKQQKRPFAYHKLLKDAGGMVIDMKWNPTVPSMVAVCLADGSIAVLQVT
  ETVKVCATLPSTVAVTSVCWSPKGKQLAVGKQNGTVVQYLPTLQEKKVIPCPPFYESDHP
  VRVLDVLWIGTYVFAIVYAAADGTLETSPDVVMALLPKKEEKHPEIFVNFMEPCYGSCTE
  RQHHYYLSYIEEWDLVLAASAASTEVSILARQSDQINWESWLLEDSSRAELPVTDKSDDS
  LPMGVVVDYTNQVEITISDEKTLPPAPVLMLLSTDGVLCPFYMINQNPGVKSLIKTPERL
  SLEGERQPKSPGSTPTTPTSSQAPQKLDASAAAAPASLPPSSPAAPIATFSLLPAGGAPT
  VFSFGSSSLKSSATVTGEPPSYSSGSDSSKAAPGPGPSTFSFVPPSKASLAPTPAASPVA
  PSAASFSFGSSGFKPTLESTPVPSVSAPNIAMKPSFPPSTSAVKVNLSEKFTAAATSTPV
  SSSQSAPPMSPFSSASKPAASGPLSHPTPLSAPPSSVPLKSSVLPSPSGRSAQGSSSPVP
  SMVQKSPRITPPAAKPGSPQAKSLQPAVAEKQGHQWKDSDPVMAGIGEEIAHFQKELEEL
  KARTSKACFQVGTSEEMKMLRTESDDLHTFLLEIKETTESLHGDISSLKTTLLEGFAGVE
  EAREQNERNRDSGYLHLLYKRPLDPKSEAQLQEIRRLHQYVKFAVQDVNDVLDLEWDQHL
  EQKKKQRHLLVPERETLFNTLANNREIINQQRKRLNHLVDSLQQLRLYKQTSLWSLSSAV
  PSQSSIHSFDSDLESLCNALLKTTIESHTKSLPKVPAKLSPMKQAQLRNFLAKRKTPPVR
  STAPASLSRSAFLSQRYYEDLDEVSSTSSVSQSLESEDARTSCKDDEAVVQAPRHAPVVR
  TPSIQPSLLPHAAPFAKSHLVHGSSPGVMGTSVATSASKIIPQGADSTMLATKTVKHGAP
  SPSHPISAPQAAAAAALRRQMASQAPAVNTLTESTLKNVPQVVNVQELKNNPATPSTAMG
  SSVPYSTAKTPHPVLTPVAANQAKQGSLINSLKPSGPTPASGQLSSGDKASGTAKIETAV
  TSTPSASGQFSKPFSFSPSGTGFNFGIITPTPSSNFTAAQGATPSTKESSQPDAFSSGGG
  SKPSYEAIPESSPPSGITSASNTTPGEPAASSSRPVAPSGTALSTTSSKLETPPSKLGEL
  LFPSSLAGETLGSFSGLRVGQADDSTKPTNKASSTSLTSTQPTKTSGVPSGFNFTAPPVL
  GKHTEPPVTSSATTTSVAPPAATSTSSTAVFGSLPVTSAGSSGVISFGGTSLSAGKTSFS
  FGSQQTNSTVPPSAPPPTTAATPLPTSFPTLSFGSLLSSATTPSLPMSAGRSTEEATSSA
  LPEKPGDSEVSASAASLLEEQQSAQLPQAPPQTSDSVKKEPVLAQPAVSNSGTAASSTSL
  VALSAEATPATTGVPDARTEAVPPASSFSVPGQTAVTAAAISSAGPVAVETSSTPIASST
  TSIVAPGPSAEAAAFGTVTSGSSVFAQPPAASSSSAFNQLTNNTATAPSATPVFGQVAAS
  TAPSLFGQQTGSTASTAAATPQVSSSGFSSPAFGTTAPGVFGQTTFGQASVFGQSASSAA
  SVFSFSQPGFSSVPAFGQPASSTPTSTSGSVFGAASSTSSSSSFSFGQSSPNTGGGLFGQ
  SNAPAFGQSPGFGQGGSVFGGTSAATTTAATSGFSFCQASGFGSSNTGSVFGQAASTGGI
  VFGQQSSSSSGSVFGSGNTGRGGGFFSGLGGKPSQDAANKNPFSSASGGFGSTATSNTSN
  LFGNSGAKTFGGFASSSFGEQKPTGTFSSGGGSVASQGFGFSSPNKTGGFGAAPVFGSPP
  TFGGSPGFGGVPAFGSAPAFTSPLGSTGGKVFGEGTAAASAGGFGFGSSSNTTSFGTLAS
  QNAPTFGSLSQQTSGFGTQSSGFSGFGSGTGGFSFGSNNSSVQGFGGWRS
• Function: Part of the nuclear pore complex. Has a critical role in nucleocytoplasmic transport. May serve as a docking site in the receptor-mediated import of substrates across the nuclear pore complex ; (Microbial infection) Required for capsid disassembly of the human adenovirus 5 (HadV-5) leading to release of the viral genome to the nucleus (in vitro).
• Tissue Specificity: Expressed in thymus, spleen, bone marrow, kidney, brain and testis, but hardly in all other tissues or in whole embryos during development.
• KEGG Pathway:
  Nucleocytoplasmic transport (hsa03013)
  Amyotrophic lateral sclerosis (hsa05014)
• Reactome Pathway:
  Transport of the SLBP independent Mature mRNA (R-HSA-159227)
  Transport of the SLBP Dependant Mature mRNA (R-HSA-159230)
  Transport of Mature mRNA Derived from an Intronless Transcript (R-HSA-159231)
  Transport of Mature mRNA derived from an Intron-Containing Transcript (R-HSA-159236)
  Rev-mediated nuclear export of HIV RNA (R-HSA-165054)
  Transport of Ribonucleoproteins into the Host Nucleus (R-HSA-168271)
  NS1 Mediated Effects on Host Pathways (R-HSA-168276)
  Viral Messenger RNA Synthesis (R-HSA-168325)
  NEP/NS2 Interacts with the Cellular Export Machinery (R-HSA-168333)
  Regulation of Glucokinase by Glucokinase Regulatory Protein (R-HSA-170822)
  Nuclear import of Rev protein (R-HSA-180746)
  Vpr-mediated nuclear import of PICs (R-HSA-180910)
  snRNP Assembly (R-HSA-191859)
  SUMOylation of DNA damage response and repair proteins (R-HSA-3108214)
  SUMOylation of ubiquitinylation proteins (R-HSA-3232142)
  Nuclear Pore Complex (NPC) Disassembly (R-HSA-3301854)
  Regulation of HSF1-mediated heat shock response (R-HSA-3371453)
  SUMOylation of SUMOylation proteins (R-HSA-4085377)
  HuR (ELAVL1) binds and stabilizes mRNA (R-HSA-450520)
  SUMOylation of chromatin organization proteins (R-HSA-4551638)
  SUMOylation of RNA binding proteins (R-HSA-4570464)
  SUMOylation of DNA replication proteins (R-HSA-4615885)
  Transcriptional regulation by small RNAs (R-HSA-5578749)
  Defective TPR may confer susceptibility towards thyroid papillary carcinoma (TPC) (R-HSA-5619107)
  tRNA processing in the nucleus (R-HSA-6784531)
  HCMV Early Events (R-HSA-9609690)
  HCMV Late Events (R-HSA-9610379)
  SARS-CoV-2 activates/modulates innate and adaptive immune responses (R-HSA-9705671)
  ISG15 antiviral mechanism (R-HSA-1169408)

Molecular Interaction Atlas (MIA) of This DOT

15 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Acute lymphocytic leukaemia	DISPX75S	Strong	Biomarker	[1]
Acute monocytic leukemia	DIS28NEL	Strong	Genetic Variation	[2]
Acute myelogenous leukaemia	DISCSPTN	Strong	Biomarker	[1]
Breast cancer	DIS7DPX1	Strong	Biomarker	[3]
Dementia	DISXL1WY	Strong	Biomarker	[4]
Encephalopathy, acute, infection-induced, susceptibility to, 9	DIS4AP6M	Strong	Autosomal recessive	[5]
Isolated congenital microcephaly	DISUXHZ6	Strong	Biomarker	[6]
Mantle cell lymphoma	DISFREOV	Strong	Genetic Variation	[7]
Myelodysplastic syndrome	DISYHNUI	Strong	Genetic Variation	[8]
Myeloid leukaemia	DISMN944	Strong	Biomarker	[9]
Neoplasm	DISZKGEW	Strong	Altered Expression	[10]
Sarcoidosis	DISE5B8Z	Strong	Biomarker	[11]
Advanced cancer	DISAT1Z9	Limited	Biomarker	[12]
Breast carcinoma	DIS2UE88	Limited	Biomarker	[3]
Chromosomal disorder	DISM5BB5	Limited	Biomarker	[13]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Nuclear pore complex protein Nup214 (NUP214).	[14]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Nuclear pore complex protein Nup214 (NUP214).	[15]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Nuclear pore complex protein Nup214 (NUP214).	[16]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Nuclear pore complex protein Nup214 (NUP214).	[17]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of Nuclear pore complex protein Nup214 (NUP214).	[19]
Marinol	DM70IK5	Approved	Marinol increases the expression of Nuclear pore complex protein Nup214 (NUP214).	[20]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Nuclear pore complex protein Nup214 (NUP214).	[23]
Rutin	DMEHRAJ	Investigative	Rutin increases the expression of Nuclear pore complex protein Nup214 (NUP214).	[24]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Quercetin	DM3NC4M	Approved	Quercetin affects the phosphorylation of Nuclear pore complex protein Nup214 (NUP214).	[18]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene affects the methylation of Nuclear pore complex protein Nup214 (NUP214).	[21]
TAK-243	DM4GKV2	Phase 1	TAK-243 decreases the sumoylation of Nuclear pore complex protein Nup214 (NUP214).	[22]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 affects the phosphorylation of Nuclear pore complex protein Nup214 (NUP214).	[18]
Coumarin	DM0N8ZM	Investigative	Coumarin increases the phosphorylation of Nuclear pore complex protein Nup214 (NUP214).	[18]

References

• [1] NUP214 in Leukemia: It's More than Transport.Cells. 2019 Jan 21;8(1):76. doi: 10.3390/cells8010076.
• [2] A novel variant translocation (1;9)(p22;q34) resulting in a DEK/NUP214 fusion gene in a patient with acute myeloid leukemia: A case report.Oncol Lett. 2017 Dec;14(6):7021-7024. doi: 10.3892/ol.2017.7133. Epub 2017 Oct 3.
• [3] Immunogenicity of chimeric MUC1-HER2 vaccine against breast cancer in mice.Iran J Basic Med Sci. 2018 Jan;21(1):26-32. doi: 10.22038/IJBMS.2017.25686.6335.
• [4] Whole volume brain extraction for multi-centre, multi-disease FLAIR MRI datasets.Magn Reson Imaging. 2020 Feb;66:116-130. doi: 10.1016/j.mri.2019.08.022. Epub 2019 Aug 28.
• [5] Pathogenic Variants in NUP214 Cause "Plugged" Nuclear Pore Channels and Acute Febrile Encephalopathy. Am J Hum Genet. 2019 Jul 3;105(1):48-64. doi: 10.1016/j.ajhg.2019.05.003. Epub 2019 Jun 6.
• [6] NUP214 deficiency causes severe encephalopathy and microcephaly in humans.Hum Genet. 2019 Mar;138(3):221-229. doi: 10.1007/s00439-019-01979-w. Epub 2019 Feb 13.
• [7] Mantle cell lymphoma-variant Richter syndrome: Detailed molecular-cytogenetic and backtracking analysis reveals slow evolution of a pre-MCL clone in parallel with CLL over several years.Int J Cancer. 2016 Nov 15;139(10):2252-60. doi: 10.1002/ijc.30263. Epub 2016 Aug 2.
• [8] Clinicopathologic and molecular characterization of myeloid neoplasms with isolated t(6;9)(p23;q34).Int J Lab Hematol. 2017 Aug;39(4):409-417. doi: 10.1111/ijlh.12641. Epub 2017 Mar 20.
• [9] t(6;9)(p22;q34)/DEK-NUP214-rearranged pediatric myeloid leukemia: an international study of 62 patients.Haematologica. 2014 May;99(5):865-72. doi: 10.3324/haematol.2013.098517. Epub 2014 Jan 17.
• [10] Nuclear pore proteins and cancer.Semin Cell Dev Biol. 2009 Jul;20(5):620-30. doi: 10.1016/j.semcdb.2009.03.003. Epub 2009 Mar 18.
• [11] Search for sarcoidosis candidate genes by integration of data from genomic, transcriptomic and proteomic studies.Med Sci Monit. 2009 Dec;15(12):SR22-8.
• [12] Inhibition of nucleoporin member Nup214 expression by miR-133b perturbs mitotic timing and leads to cell death.Mol Cancer. 2015 Feb 15;14:42. doi: 10.1186/s12943-015-0299-z.
• [13] Phenotypic and genetic characterization of adult T-cell acute lymphoblastic leukemia with del(9)(q34);SET-NUP214 rearrangement.Ann Hematol. 2012 Feb;91(2):193-201. doi: 10.1007/s00277-011-1289-x. Epub 2011 Jul 1.
• [14] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [15] 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.
• [16] 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.
• [17] 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.
• [18] 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.
• [19] 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.
• [20] THC exposure of human iPSC neurons impacts genes associated with neuropsychiatric disorders. Transl Psychiatry. 2018 Apr 25;8(1):89. doi: 10.1038/s41398-018-0137-3.
• [21] Effect of aflatoxin B(1), benzo[a]pyrene, and methapyrilene on transcriptomic and epigenetic alterations in human liver HepaRG cells. Food Chem Toxicol. 2018 Nov;121:214-223. doi: 10.1016/j.fct.2018.08.034. Epub 2018 Aug 26.
• [22] Inhibiting ubiquitination causes an accumulation of SUMOylated newly synthesized nuclear proteins at PML bodies. J Biol Chem. 2019 Oct 18;294(42):15218-15234. doi: 10.1074/jbc.RA119.009147. Epub 2019 Jul 8.
• [23] Low-dose Bisphenol A exposure alters the functionality and cellular environment in a human cardiomyocyte model. Environ Pollut. 2023 Oct 15;335:122359. doi: 10.1016/j.envpol.2023.122359. Epub 2023 Aug 9.
• [24] Epicatechin and a cocoa polyphenolic extract modulate gene expression in human Caco-2 cells. J Nutr. 2004 Oct;134(10):2509-16.