Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT7W2CM8)

• DOT Name: Transportin-1 (TNPO1)
• Synonyms: Importin beta-2; Karyopherin beta-2; M9 region interaction protein; MIP
• Gene Name: TNPO1
• Related Disease:
  Progressive external ophthalmoplegia
  Amyotrophic lateral sclerosis
  Bone disease
  Chronic obstructive pulmonary disease
  Classic Hodgkin lymphoma
  Dengue
  Hepatitis C virus infection
  Hutchinson-Gilford progeria syndrome
  Medulloblastoma
  Metastatic prostate carcinoma
  Mitochondrial disease
  Neuralgia
  Osteoarthritis
  Retinal vein occlusion
  Hepatocellular carcinoma
  Migraine disorder
  Plasma cell myeloma
  Tourette syndrome
• UniProt ID: TNPO1_HUMAN
• PDB ID: 1QBK; 2H4M; 2OT8; 2QMR; 2Z5J; 2Z5K; 2Z5M; 2Z5N; 2Z5O; 4FDD; 4FQ3; 4JLQ; 4OO6; 5J3V; 5TQC; 5YVG; 5YVH; 5YVI; 7CYL; 7VPW; 8SGH
• Pfam ID: PF02985 ; PF13513 ; PF03810
• Sequence:
  MVWDRQTKMEYEWKPDEQGLQQILQLLKESQSPDTTIQRTVQQKLEQLNQYPDFNNYLIF
  VLTKLKSEDEPTRSLSGLILKNNVKAHFQNFPNGVTDFIKSECLNNIGDSSPLIRATVGI
  LITTIASKGELQNWPDLLPKLCSLLDSEDYNTCEGAFGALQKICEDSAEILDSDVLDRPL
  NIMIPKFLQFFKHSSPKIRSHAVACVNQFIISRTQALMLHIDSFIENLFALAGDEEPEVR
  KNVCRALVMLLEVRMDRLLPHMHNIVEYMLQRTQDQDENVALEACEFWLTLAEQPICKDV
  LVRHLPKLIPVLVNGMKYSDIDIILLKGDVEEDETIPDSEQDIRPRFHRSRTVAQQHDED
  GIEEEDDDDDEIDDDDTISDWNLRKCSAAALDVLANVYRDELLPHILPLLKELLFHHEWV
  VKESGILVLGAIAEGCMQGMIPYLPELIPHLIQCLSDKKALVRSITCWTLSRYAHWVVSQ
  PPDTYLKPLMTELLKRILDSNKRVQEAACSAFATLEEEACTELVPYLAYILDTLVFAFSK
  YQHKNLLILYDAIGTLADSVGHHLNKPEYIQMLMPPLIQKWNMLKDEDKDLFPLLECLSS
  VATALQSGFLPYCEPVYQRCVNLVQKTLAQAMLNNAQPDQYEAPDKDFMIVALDLLSGLA
  EGLGGNIEQLVARSNILTLMYQCMQDKMPEVRQSSFALLGDLTKACFQHVKPCIADFMPI
  LGTNLNPEFISVCNNATWAIGEISIQMGIEMQPYIPMVLHQLVEIINRPNTPKTLLENTA
  ITIGRLGYVCPQEVAPMLQQFIRPWCTSLRNIRDNEEKDSAFRGICTMISVNPSGVIQDF
  IFFCDAVASWINPKDDLRDMFCKILHGFKNQVGDENWRRFSDQFPLPLKERLAAFYGV
• Function: Functions in nuclear protein import as nuclear transport receptor. Serves as receptor for nuclear localization signals (NLS) in cargo substrates. May mediate docking of the importin/substrate complex to the nuclear pore complex (NPC) through binding to nucleoporin and the complex is subsequently translocated through the pore by an energy requiring, Ran-dependent mechanism. At the nucleoplasmic side of the NPC, Ran binds to the importin, the importin/substrate complex dissociates and importin is re-exported from the nucleus to the cytoplasm where GTP hydrolysis releases Ran. The directionality of nuclear import is thought to be conferred by an asymmetric distribution of the GTP- and GDP-bound forms of Ran between the cytoplasm and nucleus. Involved in nuclear import of M9-containing proteins. In vitro, binds directly to the M9 region of the heterogeneous nuclear ribonucleoproteins (hnRNP), A1 and A2 and mediates their nuclear import. Involved in hnRNP A1/A2 nuclear export. Mediates the nuclear import of ribosomal proteins RPL23A, RPS7 and RPL5. In vitro, mediates nuclear import of H2A, H2B, H3 and H4 histones. In vitro, mediates nuclear import of SRP19. Mediates nuclear import of ADAR/ADAR1 isoform 1 and isoform 5 in a RanGTP-dependent manner ; (Microbial infection) In case of HIV-1 infection, binds and mediates the nuclear import of HIV-1 Rev.
• KEGG Pathway: Nucleocytoplasmic transport (hsa03013)
• Reactome Pathway:
  Intraflagellar transport (R-HSA-5620924)
  Postmitotic nuclear pore complex (NPC) reformation (R-HSA-9615933)
  Tristetraprolin (TTP, ZFP36) binds and destabilizes mRNA (R-HSA-450513)

Molecular Interaction Atlas (MIA) of This DOT

18 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Progressive external ophthalmoplegia	DISX4ATI	Definitive	Genetic Variation	[1]
Amyotrophic lateral sclerosis	DISF7HVM	Strong	Genetic Variation	[2]
Bone disease	DISE1F82	Strong	Biomarker	[3]
Chronic obstructive pulmonary disease	DISQCIRF	Strong	Genetic Variation	[4]
Classic Hodgkin lymphoma	DISV1LU6	Strong	Biomarker	[5]
Dengue	DISKH221	Strong	Biomarker	[6]
Hepatitis C virus infection	DISQ0M8R	Strong	Biomarker	[7]
Hutchinson-Gilford progeria syndrome	DISY55BU	Strong	Biomarker	[8]
Medulloblastoma	DISZD2ZL	Strong	Biomarker	[9]
Metastatic prostate carcinoma	DISVBEZ9	Strong	Biomarker	[10]
Mitochondrial disease	DISKAHA3	Strong	Genetic Variation	[11]
Neuralgia	DISWO58J	Strong	Biomarker	[12]
Osteoarthritis	DIS05URM	Strong	Biomarker	[13]
Retinal vein occlusion	DISSVWOE	Strong	Biomarker	[14]
Hepatocellular carcinoma	DIS0J828	Disputed	Altered Expression	[15]
Migraine disorder	DISFCQTG	Limited	Altered Expression	[16]
Plasma cell myeloma	DIS0DFZ0	Limited	Biomarker	[17]
Tourette syndrome	DISX9D54	No Known	Unknown	[18]

19 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 Transportin-1 (TNPO1).	[19]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Transportin-1 (TNPO1).	[20]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Transportin-1 (TNPO1).	[21]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Transportin-1 (TNPO1).	[22]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of Transportin-1 (TNPO1).	[23]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Transportin-1 (TNPO1).	[24]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Transportin-1 (TNPO1).	[25]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of Transportin-1 (TNPO1).	[26]
Calcitriol	DM8ZVJ7	Approved	Calcitriol decreases the expression of Transportin-1 (TNPO1).	[27]
Selenium	DM25CGV	Approved	Selenium decreases the expression of Transportin-1 (TNPO1).	[28]
Fulvestrant	DM0YZC6	Approved	Fulvestrant decreases the expression of Transportin-1 (TNPO1).	[24]
Testosterone enanthate	DMB6871	Approved	Testosterone enanthate affects the expression of Transportin-1 (TNPO1).	[29]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of Transportin-1 (TNPO1).	[30]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 decreases the expression of Transportin-1 (TNPO1).	[31]
Tamibarotene	DM3G74J	Phase 3	Tamibarotene decreases the expression of Transportin-1 (TNPO1).	[32]
Tocopherol	DMBIJZ6	Phase 2	Tocopherol decreases the expression of Transportin-1 (TNPO1).	[28]
Afimoxifene	DMFORDT	Phase 2	Afimoxifene decreases the expression of Transportin-1 (TNPO1).	[24]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Transportin-1 (TNPO1).	[34]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Transportin-1 (TNPO1).	[35]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Transportin-1 (TNPO1).	[33]

References

• [1] Mitochondrial and nuclear DNA defects in Saccharomyces cerevisiae with mutations in DNA polymerase gamma associated with progressive external ophthalmoplegia.Hum Mol Genet. 2006 Jan 15;15(2):363-74. doi: 10.1093/hmg/ddi454. Epub 2005 Dec 20.
• [2] R521C and R521H mutations in FUS result in weak binding with Karyopherin2 leading to Amyotrophic lateral sclerosis: a molecular docking and dynamics study.J Biomol Struct Dyn. 2017 Aug;35(10):2169-2185. doi: 10.1080/07391102.2016.1209130. Epub 2016 Aug 8.
• [3] New insights in myeloma-induced osteolysis.Leuk Lymphoma. 2003 Sep;44(9):1463-7. doi: 10.3109/10428190309178765.
• [4] Genetic landscape of chronic obstructive pulmonary disease identifies heterogeneous cell-type and phenotype associations.Nat Genet. 2019 Mar;51(3):494-505. doi: 10.1038/s41588-018-0342-2. Epub 2019 Feb 25.
• [5] The role of chemokines in Hodgkin's disease.Leuk Lymphoma. 2000 Jul;38(3-4):363-71. doi: 10.3109/10428190009087027.
• [6] MIP-1 alpha and MIP-1 beta induction by dengue virus.J Med Virol. 2001 Oct;65(2):324-30. doi: 10.1002/jmv.2037.
• [7] Pretreatment serum macrophage inflammatory protein (MIP)-1 levels predict sustained virological responses to re-treatment in patients with chronic hepatitis C virus infection.Int J Infect Dis. 2015 Apr;33:15-21. doi: 10.1016/j.ijid.2014.08.021. Epub 2014 Oct 24.
• [8] Inhibition of the acetyltransferase NAT10 normalizes progeric and aging cells by rebalancing the Transportin-1 nuclear import pathway.Sci Signal. 2018 Jul 3;11(537):eaar5401. doi: 10.1126/scisignal.aar5401.
• [9] Regulation of Gli ciliary localization and Hedgehog signaling by the PY-NLS/karyopherin-2 nuclear import system.PLoS Biol. 2017 Aug 4;15(8):e2002063. doi: 10.1371/journal.pbio.2002063. eCollection 2017 Aug.
• [10] Cysteine (C)-x-C receptor 4 undergoes transportin 1-dependent nuclear localization and remains functional at the nucleus of metastatic prostate cancer cells.PLoS One. 2013;8(2):e57194. doi: 10.1371/journal.pone.0057194. Epub 2013 Feb 28.
• [11] mip1 containing mutations associated with mitochondrial disease causes mutagenesis and depletion of mtDNA in Saccharomyces cerevisiae.Hum Mol Genet. 2010 Jun 1;19(11):2123-33. doi: 10.1093/hmg/ddq089. Epub 2010 Feb 25.
• [12] Involvement of Macrophage Inflammatory Protein-1 Family Members in the Development of Diabetic Neuropathy and Their Contribution to Effectiveness of Morphine.Front Immunol. 2018 Mar 12;9:494. doi: 10.3389/fimmu.2018.00494. eCollection 2018.
• [13] Expression profiling reveals alternative macrophage activation and impaired osteogenesis in periprosthetic osteolysis.J Orthop Res. 2008 Jan;26(1):106-16. doi: 10.1002/jor.20486.
• [14] The anti-inflammatory and anti-oxidative effects of conbercept in treatment of macular edema secondary to retinal vein occlusion.Biochem Biophys Res Commun. 2019 Jan 22;508(4):1264-1270. doi: 10.1016/j.bbrc.2018.12.049. Epub 2018 Dec 15.
• [15] Comprehensive characterization of cancer genes in hepatocellular carcinoma genomes.Oncol Lett. 2018 Feb;15(2):1503-1510. doi: 10.3892/ol.2017.7521. Epub 2017 Dec 5.
• [16] Increased Serum CD14 Level Is Associated with Depletion of TNF- in Monocytes in Migraine Patients during Interictal Period.Int J Mol Sci. 2017 Feb 13;18(2):398. doi: 10.3390/ijms18020398.
• [17] Vicious cycle between myeloma cell binding to bone marrow stromal cells via VLA-4-VCAM-1 adhesion and macrophage inflammatory protein-1alpha and MIP-1beta production.J Bone Miner Metab. 2009;27(1):16-23. doi: 10.1007/s00774-008-0012-z. Epub 2008 Dec 5.
• [18] De Novo Coding Variants Are Strongly Associated with Tourette Disorder. Neuron. 2017 May 3;94(3):486-499.e9. doi: 10.1016/j.neuron.2017.04.024.
• [19] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [20] 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.
• [21] 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.
• [22] Toxicogenomics-based prediction of acetaminophen-induced liver injury using human hepatic cell systems. Toxicol Lett. 2016 Jan 5;240(1):50-9.
• [23] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [24] Comparative gene expression profiling reveals partially overlapping but distinct genomic actions of different antiestrogens in human breast cancer cells. J Cell Biochem. 2006 Aug 1;98(5):1163-84.
• [25] 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.
• [26] Global gene expression analysis reveals differences in cellular responses to hydroxyl- and superoxide anion radical-induced oxidative stress in caco-2 cells. Toxicol Sci. 2010 Apr;114(2):193-203. doi: 10.1093/toxsci/kfp309. Epub 2009 Dec 31.
• [27] DNA microarray analysis of changes in gene expression induced by 1,25-dihydroxyvitamin D3 in human promyelocytic leukemia HL-60 cells. Biomed Res. 2006 Jun;27(3):99-109. doi: 10.2220/biomedres.27.99.
• [28] 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.
• [29] Transcriptional profiling of testosterone-regulated genes in the skeletal muscle of human immunodeficiency virus-infected men experiencing weight loss. J Clin Endocrinol Metab. 2007 Jul;92(7):2793-802. doi: 10.1210/jc.2006-2722. Epub 2007 Apr 17.
• [30] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [31] 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.
• [32] Differential modulation of PI3-kinase/Akt pathway during all-trans retinoic acid- and Am80-induced HL-60 cell differentiation revealed by DNA microarray analysis. Biochem Pharmacol. 2004 Dec 1;68(11):2177-86.
• [33] 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.
• [34] Cell-based two-dimensional morphological assessment system to predict cancer drug-induced cardiotoxicity using human induced pluripotent stem cell-derived cardiomyocytes. Toxicol Appl Pharmacol. 2019 Nov 15;383:114761. doi: 10.1016/j.taap.2019.114761. Epub 2019 Sep 15.
• [35] 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.