Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT2N5020)

• DOT Name: Importin-4 (IPO4)
• Synonyms: Imp4; Importin-4b; Imp4b; Ran-binding protein 4; RanBP4
• Gene Name: IPO4
• Related Disease:
  Bacteremia
  Gastric cancer
  Lung adenocarcinoma
  Stomach cancer
• UniProt ID: IPO4_HUMAN
• PDB ID: 5XAH; 5XBK; 7UNK; 8DYO
• Pfam ID: PF13513 ; PF03810
• Sequence:
  MESAGLEQLLRELLLPDTERIRRATEQLQIVLRAPAALPALCDLLASAADPQIRQFAAVL
  TRRRLNTRWRRLAAEQRESLKSLILTALQRETEHCVSLSLAQLSATIFRKEGLEAWPQLL
  QLLQHSTHSPHSPEREMGLLLLSVVVTSRPEAFQPHHRELLRLLNETLGEVGSPGLLFYS
  LRTLTTMAPYLSTEDVPLARMLVPKLIMAMQTLIPIDEAKACEALEALDELLESEVPVIT
  PYLSEVLTFCLEVARNVALGNAIRIRILCCLTFLVKVKSKALLKNRLLPPLLHTLFPIVA
  AEPPPGQLDPEDQDSEEEELEIELMGETPKHFAVQVVDMLALHLPPEKLCPQLMPMLEEA
  LRSESPYQRKAGLLVLAVLSDGAGDHIRQRLLPPLLQIVCKGLEDPSQVVRNAALFALGQ
  FSENLQPHISSYSREVMPLLLAYLKSVPLGHTHHLAKACYALENFVENLGPKVQPYLPEL
  MECMLQLLRNPSSPRAKELAVSALGAIATAAQASLLPYFPAIMEHLREFLLTGREDLQPV
  QIQSLETLGVLARAVGEPMRPLAEECCQLGLGLCDQVDDPDLRRCTYSLFAALSGLMGEG
  LAPHLEQITTLMLLSLRSTEGIVPQYDGSSSFLLFDDESDGEEEEELMDEDVEEEDDSEI
  SGYSVENAFFDEKEDTCAAVGEISVNTSVAFLPYMESVFEEVFKLLECPHLNVRKAAHEA
  LGQFCCALHKACQSCPSEPNTAALQAALARVVPSYMQAVNRERERQVVMAVLEALTGVLR
  SCGTLTLKPPGRLAELCGVLKAVLQRKTACQDTDEEEEEEDDDQAEYDAMLLEHAGEAIP
  ALAAAAGGDSFAPFFAGFLPLLVCKTKQGCTVAEKSFAVGTLAETIQGLGAASAQFVSRL
  LPVLLSTAQEADPEVRSNAIFGMGVLAEHGGHPAQEHFPKLLGLLFPLLARERHDRVRDN
  ICGALARLLMASPTRKPEPQVLAALLHALPLKEDLEEWVTIGRLFSFLYQSSPDQVIDVA
  PELLRICSLILADNKIPPDTKAALLLLLTFLAKQHTDSFQAALGSLPVDKAQELQAVLGL
  S
• Function: Nuclear transport receptor that mediates nuclear import of proteins, such as histones, RPS3A, TNP2 and VDR. Serves as receptor for nuclear localization signals (NLS) in cargo substrates. Is thought to 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. Mediates the nuclear import of the histone H3-H4 dimer when in complex with ASF1 (ASF1A or ASF1B). Mediates the ligand-independent nuclear import of vitamin D receptor (VDR). In vitro, mediates the nuclear import of human cytomegalovirus UL84 by recognizing a non-classical NLS.
• KEGG Pathway: Nucleocytoplasmic transport (hsa03013)

Molecular Interaction Atlas (MIA) of This DOT

4 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Bacteremia	DIS6N9RZ	Definitive	Biomarker	[1]
Gastric cancer	DISXGOUK	Strong	Altered Expression	[2]
Lung adenocarcinoma	DISD51WR	Strong	Biomarker	[3]
Stomach cancer	DISKIJSX	Strong	Altered Expression	[2]

This DOT Affected the Drug Response of 2 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Temozolomide	DMKECZD	Approved	Importin-4 (IPO4) affects the response to substance of Temozolomide.	[20]
DTI-015	DMXZRW0	Approved	Importin-4 (IPO4) affects the response to substance of DTI-015.	[20]

4 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 Importin-4 (IPO4).	[4]
Fulvestrant	DM0YZC6	Approved	Fulvestrant increases the methylation of Importin-4 (IPO4).	[15]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene affects the methylation of Importin-4 (IPO4).	[16]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Importin-4 (IPO4).	[15]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Importin-4 (IPO4).	[5]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Importin-4 (IPO4).	[6]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Importin-4 (IPO4).	[7]
Doxorubicin	DMVP5YE	Approved	Doxorubicin increases the expression of Importin-4 (IPO4).	[8]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Importin-4 (IPO4).	[9]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Importin-4 (IPO4).	[10]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Importin-4 (IPO4).	[11]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of Importin-4 (IPO4).	[12]
Testosterone	DM7HUNW	Approved	Testosterone increases the expression of Importin-4 (IPO4).	[13]
Progesterone	DMUY35B	Approved	Progesterone decreases the expression of Importin-4 (IPO4).	[14]
Genistein	DM0JETC	Phase 2/3	Genistein increases the expression of Importin-4 (IPO4).	[10]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Importin-4 (IPO4).	[17]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Importin-4 (IPO4).	[18]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of Importin-4 (IPO4).	[19]

References

• [1] First reported nosocomial outbreak of Serratia marcescens harboring bla (IMP-4) and bla (VIM-2) in a neonatal intensive care unit in Cairo, Egypt.Infect Drug Resist. 2018 Nov 8;11:2211-2217. doi: 10.2147/IDR.S174869. eCollection 2018.
• [2] Importin-4 functions as a driving force in human primary gastric cancer.J Cell Biochem. 2019 Aug;120(8):12638-12646. doi: 10.1002/jcb.28530. Epub 2019 Mar 12.
• [3] c-Myc targeted regulators of cell metabolism in a transgenic mouse model of papillary lung adenocarcinoma.Oncotarget. 2016 Oct 4;7(40):65514-65539. doi: 10.18632/oncotarget.11804.
• [4] 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.
• [5] Cyclosporine A--induced oxidative stress in human renal mesangial cells: a role for ERK 1/2 MAPK signaling. Toxicol Sci. 2012 Mar;126(1):101-13.
• [6] Phenotypic characterization of retinoic acid differentiated SH-SY5Y cells by transcriptional profiling. PLoS One. 2013 May 28;8(5):e63862.
• [7] 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.
• [8] 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.
• [9] Low doses of cisplatin induce gene alterations, cell cycle arrest, and apoptosis in human promyelocytic leukemia cells. Biomark Insights. 2016 Aug 24;11:113-21.
• [10] Genistein and bisphenol A exposure cause estrogen receptor 1 to bind thousands of sites in a cell type-specific manner. Genome Res. 2012 Nov;22(11):2153-62.
• [11] 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.
• [12] 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.
• [13] The exosome-like vesicles derived from androgen exposed-prostate stromal cells promote epithelial cells proliferation and epithelial-mesenchymal transition. Toxicol Appl Pharmacol. 2021 Jan 15;411:115384. doi: 10.1016/j.taap.2020.115384. Epub 2020 Dec 25.
• [14] Gene expression in endometrial cancer cells (Ishikawa) after short time high dose exposure to progesterone. Steroids. 2008 Jan;73(1):116-28.
• [15] 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.
• [16] Effect of aflatoxin B(1), benzo[a]pyrene, and methapyrilene on transcriptomic and epigenetic alterations in human liver HepaRG cells. Food Chem Toxicol. 2018 Nov;121:214-223. doi: 10.1016/j.fct.2018.08.034. Epub 2018 Aug 26.
• [17] Bromodomain-containing protein 4 (BRD4) regulates RNA polymerase II serine 2 phosphorylation in human CD4+ T cells. J Biol Chem. 2012 Dec 14;287(51):43137-55.
• [18] 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.
• [19] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [20] Tumor necrosis factor-alpha-induced protein 3 as a putative regulator of nuclear factor-kappaB-mediated resistance to O6-alkylating agents in human glioblastomas. J Clin Oncol. 2006 Jan 10;24(2):274-87. doi: 10.1200/JCO.2005.02.9405. Epub 2005 Dec 19.