Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTDFMQ00)

• DOT Name: Importin-7 (IPO7)
• Synonyms: Imp7; Ran-binding protein 7; RanBP7
• Gene Name: IPO7
• Related Disease:
  Immunodeficiency
  HIV infectious disease
  Advanced cancer
  Colorectal carcinoma
  Ependymoma
  Hepatocellular carcinoma
  Lung cancer
  Lung carcinoma
• UniProt ID: IPO7_HUMAN
• Pfam ID: PF08506 ; PF03810
• Sequence:
  MDPNTIIEALRGTMDPALREAAERQLNEAHKSLNFVSTLLQITMSEQLDLPVRQAGVIYL
  KNMITQYWPDRETAPGDISPYTIPEEDRHCIRENIVEAIIHSPELIRVQLTTCIHHIIKH
  DYPSRWTAIVDKIGFYLQSDNSACWLGILLCLYQLVKNYEYKKPEERSPLVAAMQHFLPV
  LKDRFIQLLSDQSDQSVLIQKQIFKIFYALVQYTLPLELINQQNLTEWIEILKTVVNRDV
  PNETLQVEEDDRPELPWWKCKKWALHILARLFERYGSPGNVSKEYNEFAEVFLKAFAVGV
  QQVLLKVLYQYKEKQYMAPRVLQQTLNYINQGVSHALTWKNLKPHIQGIIQDVIFPLMCY
  TDADEELWQEDPYEYIRMKFDVFEDFISPTTAAQTLLFTACSKRKEVLQKTMGFCYQILT
  EPNADPRKKDGALHMIGSLAEILLKKKIYKDQMEYMLQNHVFPLFSSELGYMRARACWVL
  HYFCEVKFKSDQNLQTALELTRRCLIDDREMPVKVEAAIALQVLISNQEKAKEYITPFIR
  PVMQALLHIIRETENDDLTNVIQKMICEYSEEVTPIAVEMTQHLAMTFNQVIQTGPDEEG
  SDDKAVTAMGILNTIDTLLSVVEDHKEITQQLEGICLQVIGTVLQQHVLEFYEEIFSLAH
  SLTCQQVSPQMWQLLPLVFEVFQQDGFDYFTDMMPLLHNYVTVDTDTLLSDTKYLEMIYS
  MCKKVLTGVAGEDAECHAAKLLEVIILQCKGRGIDQCIPLFVEAALERLTREVKTSELRT
  MCLQVAIAALYYNPHLLLNTLENLRFPNNVEPVTNHFITQWLNDVDCFLGLHDRKMCVLG
  LCALIDMEQIPQVLNQVSGQILPAFILLFNGLKRAYACHAEHENDSDDDDEAEDDDETEE
  LGSDEDDIDEDGQEYLEILAKQAGEDGDDEDWEEDDAEETALEGYSTIIDDEDNPVDEYQ
  IFKAIFQTIQNRNPVWYQALTHGLNEEQRKQLQDIATLADQRRAAHESKMIEKHGGYKFS
  APVVPSSFNFGGPAPGMN
• Function: Functions 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, is thought to serve itself as receptor for nuclear localization signals (NLS) and to 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. Mediates autonomously the nuclear import of ribosomal proteins RPL23A, RPS7 and RPL5. In association with KPNB1 mediates the nuclear import of H1 histone and the Ran-binding site of IPO7 is not required but synergizes with that of KPNB1 in importin/substrate complex dissociation. Promotes odontoblast differentiation via promoting nuclear translocation of DLX3, KLF4, SMAD2, thereby facilitating the transcription of target genes that play a role in odontoblast differentiation. Facilitates BMP4-induced translocation of SMAD1 to the nucleus and recruitment to the MSX1 gene promoter, thereby promotes the expression of the odontogenic regulator MSX1 in dental mesenchymal cells. Also promotes odontoblast differentiation by facilitating the nuclear translocation of HDAC6 and subsequent repression of RUNX2 expression. Inhibits osteoblast differentiation by inhibiting nuclear translocation of RUNX2 and therefore inhibition of RUNX2 target gene transcription. In vitro, mediates nuclear import of H2A, H2B, H3 and H4 histones; (Microbial infection) Mediates the nuclear import of HIV-1 reverse transcription complex (RTC) integrase. Binds and mediates the nuclear import of HIV-1 Rev.
• KEGG Pathway: Nucleocytoplasmic transport (hsa03013)

Molecular Interaction Atlas (MIA) of This DOT

8 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Immunodeficiency	DIS093I0	Strong	Biomarker	[1]
HIV infectious disease	DISO97HC	moderate	Biomarker	[2]
Advanced cancer	DISAT1Z9	Limited	Altered Expression	[3]
Colorectal carcinoma	DIS5PYL0	Limited	Altered Expression	[3]
Ependymoma	DISUMRNZ	Limited	Biomarker	[4]
Hepatocellular carcinoma	DIS0J828	Limited	Biomarker	[5]
Lung cancer	DISCM4YA	Limited	Altered Expression	[6]
Lung carcinoma	DISTR26C	Limited	Altered Expression	[6]

10 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 Importin-7 (IPO7).	[7]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Importin-7 (IPO7).	[8]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Importin-7 (IPO7).	[9]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of Importin-7 (IPO7).	[10]
Calcitriol	DM8ZVJ7	Approved	Calcitriol decreases the expression of Importin-7 (IPO7).	[11]
Marinol	DM70IK5	Approved	Marinol increases the expression of Importin-7 (IPO7).	[12]
Menadione	DMSJDTY	Approved	Menadione affects the expression of Importin-7 (IPO7).	[10]
Diethylstilbestrol	DMN3UXQ	Approved	Diethylstilbestrol increases the expression of Importin-7 (IPO7).	[13]
Piroxicam	DMTK234	Approved	Piroxicam decreases the expression of Importin-7 (IPO7).	[14]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Importin-7 (IPO7).	[16]

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-7 (IPO7).	[15]

References

• [1] Importin 7 may be dispensable for human immunodeficiency virus type 1 and simian immunodeficiency virus infection of primary macrophages.J Virol. 2005 Sep;79(17):11541-6. doi: 10.1128/JVI.79.17.11541-11546.2005.
• [2] Interaction of human immunodeficiency virus type 1 integrase with cellular nuclear import receptor importin 7 and its impact on viral replication.J Biol Chem. 2007 May 4;282(18):13456-67. doi: 10.1074/jbc.M610546200. Epub 2007 Mar 14.
• [3] Elevated levels of RanBP7 mRNA in colorectal carcinoma are associated with increased proliferation and are similar to the transcription pattern of the proto-oncogene c-myc.Biochem Biophys Res Commun. 2000 May 10;271(2):537-43. doi: 10.1006/bbrc.2000.2666.
• [4] Genomics and epigenetics: A study of ependymomas in pediatric patients.Clin Neurol Neurosurg. 2016 May;144:53-8. doi: 10.1016/j.clineuro.2016.02.041. Epub 2016 Mar 5.
• [5] 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.
• [6] Knockdown of Importin 7 Inhibits Lung Tumorigenesis in K-ras(LA1) Lung Cancer Mice.Anticancer Res. 2017 May;37(5):2381-2386. doi: 10.21873/anticanres.11576.
• [7] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [8] 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.
• [9] 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.
• [10] 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.
• [11] 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.
• [12] JunD is involved in the antiproliferative effect of Delta9-tetrahydrocannabinol on human breast cancer cells. Oncogene. 2008 Aug 28;27(37):5033-44.
• [13] Identification of biomarkers and outcomes of endocrine disruption in human ovarian cortex using In Vitro Models. Toxicology. 2023 Feb;485:153425. doi: 10.1016/j.tox.2023.153425. Epub 2023 Jan 5.
• [14] Apoptosis induced by piroxicam plus cisplatin combined treatment is triggered by p21 in mesothelioma. PLoS One. 2011;6(8):e23569.
• [15] 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.
• [16] Benzo[a]pyrene-induced changes in microRNA-mRNA networks. Chem Res Toxicol. 2012 Apr 16;25(4):838-49.