Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTDF5K8Y)

• DOT Name: Nucleoporin Nup43 (NUP43)
• Synonyms: Nup107-160 subcomplex subunit Nup43; p42
• Gene Name: NUP43
• Related Disease:
  Adult glioblastoma
  Glioblastoma multiforme
  Hepatocellular carcinoma
  Acute myelogenous leukaemia
  Breast cancer
  Breast carcinoma
  Breast neoplasm
  Carcinoma
  Her2-receptor negative breast cancer
  HER2/NEU overexpressing breast cancer
  Promyelocytic leukaemia
  Prostate cancer
  Prostate carcinoma
  Brain infarction
• UniProt ID: NUP43_HUMAN
• PDB ID: 4I79; 5A9Q; 7PEQ; 7R5J; 7R5K
• Pfam ID: PF00400
• Sequence:
  MEEIYAKFVSQKISKTRWRPLPPGSLQTAETFATGSWDNEENYISLWSIGDFGNLDSDGG
  FEGDHQLLCDIRHHGDVMDLQFFDQERIVAASSTGCVTVFLHHPNNQTLSVNQQWTTAHY
  HTGPGSPSYSSAPCTGVVCNNPEIVTVGEDGRINLFRADHKEAVRTIDNADSSTLHAVTF
  LRTPEILTVNSIGQLKIWDFRQQGNEPSQILSLTGDRVPLHCVDRHPNQQHVVATGGQDG
  MLSIWDVRQGTMPVSLLKAHEAEMWEVHFHPSNPEHLFTCSEDGSLWHWDASTDVPEKSS
  LFHQGGRSSTFLSHSISNQANVHQSVISSWLSTDPAKDRIEITSLLPSRSLSVNTLDVLG
  PCLVCGTDAEAIYVTRHLFS
• Function: Component of the Nup107-160 subcomplex of the nuclear pore complex (NPC). The Nup107-160 subcomplex is required for the assembly of a functional NPC. The Nup107-160 subcomplex is also required for normal kinetochore microtubule attachment, mitotic progression and chromosome segregation.
• KEGG Pathway:
  Nucleocytoplasmic transport (hsa03013)
  Amyotrophic lateral sclerosis (hsa05014)
• Reactome Pathway:
  Amplification of signal from unattached kinetochores via a MAD2 inhibitory signal (R-HSA-141444)
  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)
  Separation of Sister Chromatids (R-HSA-2467813)
  Resolution of Sister Chromatid Cohesion (R-HSA-2500257)
  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)
  RHO GTPases Activate Formins (R-HSA-5663220)
  tRNA processing in the nucleus (R-HSA-6784531)
  Mitotic Prometaphase (R-HSA-68877)
  HCMV Early Events (R-HSA-9609690)
  HCMV Late Events (R-HSA-9610379)
  Postmitotic nuclear pore complex (NPC) reformation (R-HSA-9615933)
  EML4 and NUDC in mitotic spindle formation (R-HSA-9648025)
  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

14 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Adult glioblastoma	DISVP4LU	Definitive	Altered Expression	[1]
Glioblastoma multiforme	DISK8246	Definitive	Altered Expression	[1]
Hepatocellular carcinoma	DIS0J828	Definitive	Biomarker	[2]
Acute myelogenous leukaemia	DISCSPTN	Strong	Biomarker	[3]
Breast cancer	DIS7DPX1	Strong	Biomarker	[4]
Breast carcinoma	DIS2UE88	Strong	Biomarker	[4]
Breast neoplasm	DISNGJLM	Strong	Altered Expression	[4]
Carcinoma	DISH9F1N	Strong	Altered Expression	[5]
Her2-receptor negative breast cancer	DISS605N	Strong	Altered Expression	[4]
HER2/NEU overexpressing breast cancer	DISYKID5	Strong	Altered Expression	[4]
Promyelocytic leukaemia	DISYGG13	Strong	Biomarker	[6]
Prostate cancer	DISF190Y	moderate	Biomarker	[7]
Prostate carcinoma	DISMJPLE	moderate	Biomarker	[7]
Brain infarction	DISPPGYK	Limited	Genetic Variation	[8]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the methylation of Nucleoporin Nup43 (NUP43).	[9]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Nucleoporin Nup43 (NUP43).	[14]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Nucleoporin Nup43 (NUP43).	[16]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Nucleoporin Nup43 (NUP43).	[10]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Nucleoporin Nup43 (NUP43).	[11]
Estradiol	DMUNTE3	Approved	Estradiol affects the expression of Nucleoporin Nup43 (NUP43).	[12]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Nucleoporin Nup43 (NUP43).	[13]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide decreases the expression of Nucleoporin Nup43 (NUP43).	[15]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of Nucleoporin Nup43 (NUP43).	[17]
Nickel chloride	DMI12Y8	Investigative	Nickel chloride decreases the expression of Nucleoporin Nup43 (NUP43).	[18]

References

• [1] EBP1 protein modulates the expression of human MHC class II molecules in non-hematopoietic cancer cells.Int J Oncol. 2015 Aug;47(2):481-9. doi: 10.3892/ijo.2015.3051. Epub 2015 Jun 16.
• [2] YC-1 Antagonizes Wnt/-Catenin Signaling Through the EBP1 p42 Isoform in Hepatocellular Carcinoma.Cancers (Basel). 2019 May 13;11(5):661. doi: 10.3390/cancers11050661.
• [3] The presence of C/EBP and its degradation are both required for TRIB2-mediated leukaemia.Oncogene. 2016 Oct 6;35(40):5272-5281. doi: 10.1038/onc.2016.66. Epub 2016 Mar 21.
• [4] High NUP43 expression might independently predict poor overall survival in luminal A and in HER2+ breast cancer.Future Oncol. 2018 Jun;14(15):1431-1442. doi: 10.2217/fon-2017-0690. Epub 2018 Feb 6.
• [5] Overexpression of the Ets-1 transcription factor in human breast cancer.Br J Cancer. 2004 Oct 4;91(7):1308-15. doi: 10.1038/sj.bjc.6602128.
• [6] Restoration of CCAAT enhancer binding protein P42 induces myeloid differentiation and overcomes all-trans retinoic acid resistance in human acute promyelocytic leukemia NB4-R1 cells.Int J Oncol. 2015 Nov;47(5):1685-95. doi: 10.3892/ijo.2015.3163. Epub 2015 Sep 14.
• [7] Novel identification of the ETS-1 splice variants p42 and p27 in prostate cancer cell lines.Oncol Rep. 2012 May;27(5):1321-4. doi: 10.3892/or.2012.1667. Epub 2012 Feb 1.
• [8] Thrombin Preconditioning Enhances Therapeutic Efficacy of Human Wharton's Jelly-Derived Mesenchymal Stem Cells in Severe Neonatal Hypoxic Ischemic Encephalopathy.Int J Mol Sci. 2019 May 20;20(10):2477. doi: 10.3390/ijms20102477.
• [9] 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.
• [10] 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.
• [11] 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.
• [12] Identification of novel low-dose bisphenol a targets in human foreskin fibroblast cells derived from hypospadias patients. PLoS One. 2012;7(5):e36711. doi: 10.1371/journal.pone.0036711. Epub 2012 May 4.
• [13] 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.
• [14] 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.
• [15] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [16] 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.
• [17] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.
• [18] The contact allergen nickel triggers a unique inflammatory and proangiogenic gene expression pattern via activation of NF-kappaB and hypoxia-inducible factor-1alpha. J Immunol. 2007 Mar 1;178(5):3198-207.