Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT647WOR)

• DOT Name: Nuclear pore complex protein Nup88 (NUP88)
• Synonyms: 88 kDa nucleoporin; Nucleoporin Nup88
• Gene Name: NUP88
• Related Disease:
  Acute lymphocytic leukaemia
  Breast cancer
  Breast carcinoma
  Colorectal carcinoma
  Fetal akinesia deformation sequence 4
  Hepatocellular carcinoma
  HIV infectious disease
  Neoplasm
  Rheumatoid arthritis
  Advanced cancer
  Fetal akinesia deformation sequence 1
  Intestinal neoplasm
• UniProt ID: NUP88_HUMAN
• PDB ID: 7MNI; 7R5J; 7R5K
• Pfam ID: PF10168
• Sequence:
  MAAAEGPVGDGELWQTWLPNHVVFLRLREGLKNQSPTEAEKPASSSLPSSPPPQLLTRNV
  VFGLGGELFLWDGEDSSFLVVRLRGPSGGGEEPALSQYQRLLCINPPLFEIYQVLLSPTQ
  HHVALIGIKGLMVLELPKRWGKNSEFEGGKSTVNCSTTPVAERFFTSSTSLTLKHAAWYP
  SEILDPHVVLLTSDNVIRIYSLREPQTPTNVIILSEAEEESLVLNKGRAYTASLGETAVA
  FDFGPLAAVPKTLFGQNGKDEVVAYPLYILYENGETFLTYISLLHSPGNIGKLLGPLPMH
  PAAEDNYGYDACAVLCLPCVPNILVIATESGMLYHCVVLEGEEEDDHTSEKSWDSRIDLI
  PSLYVFECVELELALKLASGEDDPFDSDFSCPVKLHRDPKCPSRYHCTHEAGVHSVGLTW
  IHKLHKFLGSDEEDKDSLQELSTEQKCFVEHILCTKPLPCRQPAPIRGFWIVPDILGPTM
  ICITSTYECLIWPLLSTVHPASPPLLCTREDVEVAESPLRVLAETPDSFEKHIRSILQRS
  VANPAFLKASEKDIAPPPEECLQLLSRATQVFREQYILKQDLAKEEIQRRVKLLCDQKKK
  QLEDLSYCREERKSLREMAERLADKYEEAKEKQEDIMNRMKKLLHSFHSELPVLSDSERD
  MKKELQLIPDQLRHLGNAIKQVTMKKDYQQQKMEKVLSLPKPTIILSAYQRKCIQSILKE
  EGEHIREMVKQINDIRNHVNF
• Function: Component of nuclear pore complex.
• Tissue Specificity: Ubiquitous.
• 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)
  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

12 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Acute lymphocytic leukaemia	DISPX75S	Strong	Biomarker	[1]
Breast cancer	DIS7DPX1	Strong	Altered Expression	[2]
Breast carcinoma	DIS2UE88	Strong	Altered Expression	[2]
Colorectal carcinoma	DIS5PYL0	Strong	Altered Expression	[3]
Fetal akinesia deformation sequence 4	DISGIHHK	Strong	Autosomal recessive	[4]
Hepatocellular carcinoma	DIS0J828	Strong	Altered Expression	[5]
HIV infectious disease	DISO97HC	Strong	Biomarker	[6]
Neoplasm	DISZKGEW	Strong	Biomarker	[7]
Rheumatoid arthritis	DISTSB4J	Strong	Genetic Variation	[8]
Advanced cancer	DISAT1Z9	moderate	Biomarker	[9]
Fetal akinesia deformation sequence 1	DISKDI9L	Supportive	Autosomal recessive	[4]
Intestinal neoplasm	DISK0GUH	Limited	Biomarker	[9]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Methotrexate	DM2TEOL	Approved	Nuclear pore complex protein Nup88 (NUP88) affects the response to substance of Methotrexate.	[27]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the expression of Nuclear pore complex protein Nup88 (NUP88).	[10]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Nuclear pore complex protein Nup88 (NUP88).	[11]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Nuclear pore complex protein Nup88 (NUP88).	[12]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Nuclear pore complex protein Nup88 (NUP88).	[13]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Nuclear pore complex protein Nup88 (NUP88).	[14]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Nuclear pore complex protein Nup88 (NUP88).	[15]
Piroxicam	DMTK234	Approved	Piroxicam decreases the expression of Nuclear pore complex protein Nup88 (NUP88).	[17]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Nuclear pore complex protein Nup88 (NUP88).	[18]
DNCB	DMDTVYC	Phase 2	DNCB increases the expression of Nuclear pore complex protein Nup88 (NUP88).	[19]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the mutagenesis of Nuclear pore complex protein Nup88 (NUP88).	[20]
Eugenol	DM7US1H	Patented	Eugenol increases the expression of Nuclear pore complex protein Nup88 (NUP88).	[19]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of Nuclear pore complex protein Nup88 (NUP88).	[23]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of Nuclear pore complex protein Nup88 (NUP88).	[24]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of Nuclear pore complex protein Nup88 (NUP88).	[25]
Deguelin	DMXT7WG	Investigative	Deguelin decreases the expression of Nuclear pore complex protein Nup88 (NUP88).	[26]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Quercetin	DM3NC4M	Approved	Quercetin increases the phosphorylation of Nuclear pore complex protein Nup88 (NUP88).	[16]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Nuclear pore complex protein Nup88 (NUP88).	[22]

2 Drug(s) Affected the Protein Interaction/Cellular Processes of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
LY294002	DMY1AFS	Phase 1	LY294002 affects the localization of Nuclear pore complex protein Nup88 (NUP88).	[21]
PD98059	DMZC90M	Investigative	PD98059 affects the localization of Nuclear pore complex protein Nup88 (NUP88).	[21]

References

• [1] The nuclear pore proteins Nup88/214 and T-cell acute lymphatic leukemia-associated NUP214 fusion proteins regulate Notch signaling.J Biol Chem. 2019 Aug 2;294(31):11741-11750. doi: 10.1074/jbc.RA118.006357. Epub 2019 Jun 11.
• [2] Nup88 mRNA overexpression is associated with high aggressiveness of breast cancer.Int J Cancer. 2004 May 1;109(5):717-20. doi: 10.1002/ijc.20034.
• [3] Increased serum level of Nup88 protein is associated with the development of colorectal cancer.Med Oncol. 2012 Sep;29(3):1789-95. doi: 10.1007/s12032-011-0047-1. Epub 2011 Aug 24.
• [4] Biallelic mutations in nucleoporin NUP88 cause lethal fetal akinesia deformation sequence. PLoS Genet. 2018 Dec 13;14(12):e1007845. doi: 10.1371/journal.pgen.1007845. eCollection 2018 Dec.
• [5] Nucleoporin 88 expression in hepatitis B and C virus-related liver diseases.World J Gastroenterol. 2006 Sep 28;12(36):5870-4. doi: 10.3748/wjg.v12.i36.5870.
• [6] Host cell gene expression during human immunodeficiency virus type 1 latency and reactivation and effects of targeting genes that are differentially expressed in viral latency.J Virol. 2004 Sep;78(17):9458-73. doi: 10.1128/JVI.78.17.9458-9473.2004.
• [7] The role of vimentin in the tumor marker Nup88-dependent multinucleated phenotype.BMC Cancer. 2018 May 3;18(1):519. doi: 10.1186/s12885-018-4454-y.
• [8] Genetic influences on susceptibility to rheumatoid arthritis in African-Americans.Hum Mol Genet. 2019 Mar 1;28(5):858-874. doi: 10.1093/hmg/ddy395.
• [9] Nuclear pore protein NUP88 activates anaphase-promoting complex to promote aneuploidy.J Clin Invest. 2016 Feb;126(2):543-59. doi: 10.1172/JCI82277. Epub 2016 Jan 5.
• [10] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [11] 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.
• [12] Transcriptional and Metabolic Dissection of ATRA-Induced Granulocytic Differentiation in NB4 Acute Promyelocytic Leukemia Cells. Cells. 2020 Nov 5;9(11):2423. doi: 10.3390/cells9112423.
• [13] Gene expression analysis of precision-cut human liver slices indicates stable expression of ADME-Tox related genes. Toxicol Appl Pharmacol. 2011 May 15;253(1):57-69.
• [14] 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.
• [15] 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.
• [16] 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.
• [17] Apoptosis induced by piroxicam plus cisplatin combined treatment is triggered by p21 in mesothelioma. PLoS One. 2011;6(8):e23569.
• [18] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [19] Microarray analyses in dendritic cells reveal potential biomarkers for chemical-induced skin sensitization. Mol Immunol. 2007 May;44(12):3222-33.
• [20] Exome-wide mutation profile in benzo[a]pyrene-derived post-stasis and immortal human mammary epithelial cells. Mutat Res Genet Toxicol Environ Mutagen. 2014 Dec;775-776:48-54. doi: 10.1016/j.mrgentox.2014.10.011. Epub 2014 Nov 4.
• [21] Dissecting the signaling events that impact classical nuclear import and target nuclear transport factors. PLoS One. 2009 Dec 24;4(12):e8420. doi: 10.1371/journal.pone.0008420.
• [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] A trichostatin A expression signature identified by TempO-Seq targeted whole transcriptome profiling. PLoS One. 2017 May 25;12(5):e0178302. doi: 10.1371/journal.pone.0178302. eCollection 2017.
• [24] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [25] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.
• [26] 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.
• [27] 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.