Details of Drug Off-Target (DOT)

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

• DOT Name: Importin-8 (IPO8)
• Synonyms: Imp8; Ran-binding protein 8; RanBP8
• Gene Name: IPO8
• Related Disease:
  Endometrial carcinoma
  Inflammatory bowel disease
  Lung cancer
  Lung carcinoma
  Non-small-cell lung cancer
  Osteoarthritis
  VISS syndrome
  Bipolar disorder
  Bone osteosarcoma
  Osteosarcoma
  Schizoaffective disorder
  Schizophrenia
  Hepatocellular carcinoma
• UniProt ID: IPO8_HUMAN
• Pfam ID: PF08506 ; PF03810
• Sequence:
  MDLNRIIQALKGTIDPKLRIAAENELNQSYKIINFAPSLLRIIVSDHVEFPVRQAAAIYL
  KNMVTQYWPDREPPPGEAIFPFNIHENDRQQIRDNIVEGIIRSPDLVRVQLTMCLRAIIK
  HDFPGHWPGVVDKIDYYLQSQSSASWLGSLLCLYQLVKTYEYKKAEEREPLIIAMQIFLP
  RIQQQIVQLLPDSSYYSVLLQKQILKIFYALVQYALPLQLVNNQTMTTWMEIFRTIIDRT
  VPPETLHIDEDDRPELVWWKCKKWALHIVARLFERYGSPGNVTKEYFEFSEFFLKTYAVG
  IQQVLLKILDQYRQKEYVAPRVLQQAFNYLNQGVVHSITWKQMKPHIQNISEDVIFSVMC
  YKDEDEELWQEDPYEYIRMKFDIFEDYASPTTAAQTLLYTAAKKRKEVLPKMMAFCYQIL
  TDPNFDPRKKDGALHVIGSLAEILLKKSLFKDQMELFLQNHVFPLLLSNLGYLRARSCWV
  LHAFSSLKFHNELNLRNAVELAKKSLIEDKEMPVKVEAALALQSLISNQIQAKEYMKPHV
  RPIMQELLHIVRETENDDVTNVIQKMICEYSQEVASIAVDMTQHLAEIFGKVLQSDEYEE
  VEDKTVMAMGILHTIDTILTVVEDHKEITQQLENICLRIIDLVLQKHVIEFYEEILSLAY
  SLTCHSISPQMWQLLGILYEVFQQDCFEYFTDMMPLLHNYVTIDTDTLLSNAKHLEILFT
  MCRKVLCGDAGEDAECHAAKLLEVIILQCKGRGIDQCIPLFVQLVLERLTRGVKTSELRT
  MCLQVAIAALYYNPDLLLHTLERIQLPHNPGPITVQFINQWMNDTDCFLGHHDRKMCIIG
  LSILLELQNRPPAVDAVVGQIVPSILFLFLGLKQVCATRQLVNREDRSKAEKADMEENEE
  ISSDEEETNVTAQAMQSNNGRGEDEEEEDDDWDEEVLEETALEGFSTPLDLDNSVDEYQF
  FTQALITVQSRDAAWYQLLMAPLSEDQRTALQEVYTLAEHRRTVAEAKKKIEQQGGFTFE
  NKGVLSAFNFGTVPSNN
• Function: Involved in nuclear protein import, either by acting as autonomous nuclear transport receptor or as an adapter-like protein in association with the importin-beta subunit KPNB1. Acting autonomously, may serve as receptor for nuclear localization signals (NLS) and promote translocation of import substrates through the nuclear pore complex (NPC) by an energy requiring, Ran-dependent mechanism. At the nucleoplasmic side of the NPC, Ran binds to 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. In vitro mediates the nuclear import of the signal recognition particle protein SRP19. May also be involved in cytoplasm-to-nucleus shuttling of a broad spectrum of other cargos, including Argonaute-microRNAs complexes, the JUN protein, RELA/NF-kappa-B p65 subunit, the translation initiation factor EIF4E and a set of receptor-activated mothers against decapentaplegic homolog (SMAD) transcription factors that play a critical role downstream of the large family of transforming growth factor beta and bone morphogenetic protein (BMP) cytokines (Probable).
• KEGG Pathway: Nucleocytoplasmic transport (hsa03013)
• Reactome Pathway: Transcriptional regulation by small RNAs (R-HSA-5578749)

Molecular Interaction Atlas (MIA) of This DOT

13 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Endometrial carcinoma	DISXR5CY	Strong	Altered Expression	[1]
Inflammatory bowel disease	DISGN23E	Strong	Biomarker	[2]
Lung cancer	DISCM4YA	Strong	Biomarker	[3]
Lung carcinoma	DISTR26C	Strong	Biomarker	[3]
Non-small-cell lung cancer	DIS5Y6R9	Strong	Biomarker	[4]
Osteoarthritis	DIS05URM	Strong	Altered Expression	[5]
VISS syndrome	DIS6CMG5	Strong	Autosomal recessive	[6]
Bipolar disorder	DISAM7J2	moderate	Genetic Variation	[7]
Bone osteosarcoma	DIST1004	moderate	Altered Expression	[8]
Osteosarcoma	DISLQ7E2	moderate	Altered Expression	[8]
Schizoaffective disorder	DISLBW6B	moderate	Genetic Variation	[7]
Schizophrenia	DISSRV2N	moderate	Genetic Variation	[7]
Hepatocellular carcinoma	DIS0J828	Limited	Biomarker	[9]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the methylation of Importin-8 (IPO8).	[10]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Importin-8 (IPO8).	[11]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Importin-8 (IPO8).	[12]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of Importin-8 (IPO8).	[13]
Temozolomide	DMKECZD	Approved	Temozolomide decreases the expression of Importin-8 (IPO8).	[14]
Calcitriol	DM8ZVJ7	Approved	Calcitriol decreases the expression of Importin-8 (IPO8).	[15]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Importin-8 (IPO8).	[17]
Geldanamycin	DMS7TC5	Discontinued in Phase 2	Geldanamycin increases the expression of Importin-8 (IPO8).	[18]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Importin-8 (IPO8).	[19]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of Importin-8 (IPO8).	[20]
methyl p-hydroxybenzoate	DMO58UW	Investigative	methyl p-hydroxybenzoate decreases the expression of Importin-8 (IPO8).	[21]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
DNCB	DMDTVYC	Phase 2	DNCB affects the binding of Importin-8 (IPO8).	[16]

References

• [1] Validation of endogenous control reference genes for normalizing gene expression studies in endometrial carcinoma.Mol Hum Reprod. 2015 Sep;21(9):723-35. doi: 10.1093/molehr/gav033. Epub 2015 Jun 29.
• [2] Expression stability of common housekeeping genes is differently affected by bowel inflammation and cancer: implications for finding suitable normalizers for inflammatory bowel disease studies.Inflamm Bowel Dis. 2014 Jul;20(7):1147-56. doi: 10.1097/MIB.0000000000000067.
• [3] Identification of importin 8 (IPO8) as the most accurate reference gene for the clinicopathological analysis of lung specimens.BMC Mol Biol. 2008 Nov 17;9:103. doi: 10.1186/1471-2199-9-103.
• [4] Identification of stable housekeeping genes in response to ionizing radiation in cancer research.Sci Rep. 2017 Mar 6;7:43763. doi: 10.1038/srep43763.
• [5] Identification of suitable reference genes in bone marrow stromal cells from osteoarthritic donors.Stem Cell Res. 2013 Nov;11(3):1288-98. doi: 10.1016/j.scr.2013.08.015. Epub 2013 Sep 9.
• [6] A human importin--related disorder: Syndromic thoracic aortic aneurysm caused by bi-allelic loss-of-function variants in IPO8. Am J Hum Genet. 2021 Jun 3;108(6):1115-1125. doi: 10.1016/j.ajhg.2021.04.019. Epub 2021 May 18.
• [7] Genome-wide association studies of smooth pursuit and antisaccade eye movements in psychotic disorders: findings from the B-SNIP study.Transl Psychiatry. 2017 Oct 24;7(10):e1249. doi: 10.1038/tp.2017.210.
• [8] RUNX2 controls human IPO8 basal transcription in Saos-2 cells.Mol Med Rep. 2016 Aug;14(2):1418-24. doi: 10.3892/mmr.2016.5356. Epub 2016 Jun 1.
• [9] Compound Astragalus and Salvia miltiorrhiza extract inhibits hepatocarcinogenesis via modulating TGF-/TR and Imp7/8.Exp Ther Med. 2018 Aug;16(2):1052-1060. doi: 10.3892/etm.2018.6292. Epub 2018 Jun 12.
• [10] 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.
• [11] 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.
• [12] 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.
• [13] Comparison of phenotypic and transcriptomic effects of false-positive genotoxins, true genotoxins and non-genotoxins using HepG2 cells. Mutagenesis. 2011 Sep;26(5):593-604.
• [14] Temozolomide induces activation of Wnt/-catenin signaling in glioma cells via PI3K/Akt pathway: implications in glioma therapy. Cell Biol Toxicol. 2020 Jun;36(3):273-278. doi: 10.1007/s10565-019-09502-7. Epub 2019 Nov 22.
• [15] 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.
• [16] Proteomic analysis of the cellular response to a potent sensitiser unveils the dynamics of haptenation in living cells. Toxicology. 2020 Dec 1;445:152603. doi: 10.1016/j.tox.2020.152603. Epub 2020 Sep 28.
• [17] Targeting MYCN in neuroblastoma by BET bromodomain inhibition. Cancer Discov. 2013 Mar;3(3):308-23.
• [18] 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.
• [19] Environmental pollutant induced cellular injury is reflected in exosomes from placental explants. Placenta. 2020 Jan 1;89:42-49. doi: 10.1016/j.placenta.2019.10.008. Epub 2019 Oct 17.
• [20] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.
• [21] Transcriptome dynamics of alternative splicing events revealed early phase of apoptosis induced by methylparaben in H1299 human lung carcinoma cells. Arch Toxicol. 2020 Jan;94(1):127-140. doi: 10.1007/s00204-019-02629-w. Epub 2019 Nov 20.