Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTJ4TAWK)

• DOT Name: Eukaryotic translation initiation factor 3 subunit J (EIF3J)
• Synonyms: eIF3j; Eukaryotic translation initiation factor 3 subunit 1; eIF-3-alpha; eIF3 p35
• Gene Name: EIF3J
• Related Disease:
  Advanced cancer
  Chronic hepatitis B virus infection
  Hepatocellular carcinoma
  Lung cancer
  Lung carcinoma
  Non-small-cell lung cancer
  Colorectal carcinoma
• UniProt ID: EIF3J_HUMAN
• PDB ID: 2KRB; 3BPJ; 6YBW; 6ZMW; 6ZVJ
• Pfam ID: PF08597
• Sequence:
  MAAAAAAAGDSDSWDADAFSVEDPVRKVGGGGTAGGDRWEGEDEDEDVKDNWDDDDDEKK
  EEAEVKPEVKISEKKKIAEKIKEKERQQKKRQEEIKKRLEEPEEPKVLTPEEQLADKLRL
  KKLQEESDLELAKETFGVNNAVYGIDAMNPSSRDDFTEFGKLLKDKITQYEKSLYYASFL
  EVLVRDVCISLEIDDLKKITNSLTVLCSEKQKQEKQSKAKKKKKGVVPGGGLKATMKDDL
  ADYGGYDGGYVQDYEDFM
• Function: Component of the eukaryotic translation initiation factor 3 (eIF-3) complex, which is required for several steps in the initiation of protein synthesis. The eIF-3 complex associates with the 40S ribosome and facilitates the recruitment of eIF-1, eIF-1A, eIF-2:GTP:methionyl-tRNAi and eIF-5 to form the 43S pre-initiation complex (43S PIC). The eIF-3 complex stimulates mRNA recruitment to the 43S PIC and scanning of the mRNA for AUG recognition. The eIF-3 complex is also required for disassembly and recycling of post-termination ribosomal complexes and subsequently prevents premature joining of the 40S and 60S ribosomal subunits prior to initiation. The eIF-3 complex specifically targets and initiates translation of a subset of mRNAs involved in cell proliferation, including cell cycling, differentiation and apoptosis, and uses different modes of RNA stem-loop binding to exert either translational activation or repression.
• Reactome Pathway:
  Translation initiation complex formation (R-HSA-72649)
  Formation of a pool of free 40S subunits (R-HSA-72689)
  Formation of the ternary complex, and subsequently, the 43S complex (R-HSA-72695)
  Ribosomal scanning and start codon recognition (R-HSA-72702)
  GTP hydrolysis and joining of the 60S ribosomal subunit (R-HSA-72706)
  L13a-mediated translational silencing of Ceruloplasmin expression (R-HSA-156827)

Molecular Interaction Atlas (MIA) of This DOT

7 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Advanced cancer	DISAT1Z9	Strong	Altered Expression	[1]
Chronic hepatitis B virus infection	DISHL4NT	Strong	Biomarker	[2]
Hepatocellular carcinoma	DIS0J828	Strong	Biomarker	[2]
Lung cancer	DISCM4YA	Strong	Genetic Variation	[1]
Lung carcinoma	DISTR26C	Strong	Genetic Variation	[1]
Non-small-cell lung cancer	DIS5Y6R9	Strong	Genetic Variation	[1]
Colorectal carcinoma	DIS5PYL0	moderate	Biomarker	[3]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the expression of Eukaryotic translation initiation factor 3 subunit J (EIF3J).	[4]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Eukaryotic translation initiation factor 3 subunit J (EIF3J).	[5]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Eukaryotic translation initiation factor 3 subunit J (EIF3J).	[6]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of Eukaryotic translation initiation factor 3 subunit J (EIF3J).	[7]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Eukaryotic translation initiation factor 3 subunit J (EIF3J).	[8]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Eukaryotic translation initiation factor 3 subunit J (EIF3J).	[9]
Temozolomide	DMKECZD	Approved	Temozolomide increases the expression of Eukaryotic translation initiation factor 3 subunit J (EIF3J).	[10]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of Eukaryotic translation initiation factor 3 subunit J (EIF3J).	[11]
Phenobarbital	DMXZOCG	Approved	Phenobarbital affects the expression of Eukaryotic translation initiation factor 3 subunit J (EIF3J).	[12]
Menadione	DMSJDTY	Approved	Menadione affects the expression of Eukaryotic translation initiation factor 3 subunit J (EIF3J).	[11]
Piroxicam	DMTK234	Approved	Piroxicam decreases the expression of Eukaryotic translation initiation factor 3 subunit J (EIF3J).	[13]
Clozapine	DMFC71L	Approved	Clozapine increases the expression of Eukaryotic translation initiation factor 3 subunit J (EIF3J).	[14]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Eukaryotic translation initiation factor 3 subunit J (EIF3J).	[18]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of Eukaryotic translation initiation factor 3 subunit J (EIF3J).	[19]

3 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 Eukaryotic translation initiation factor 3 subunit J (EIF3J).	[15]
TAK-243	DM4GKV2	Phase 1	TAK-243 decreases the sumoylation of Eukaryotic translation initiation factor 3 subunit J (EIF3J).	[16]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 affects the phosphorylation of Eukaryotic translation initiation factor 3 subunit J (EIF3J).	[17]

References

• [1] Association between eIF3 polymorphism and severe toxicity caused by platinum-based chemotherapy in non-small cell lung cancer patients.Br J Clin Pharmacol. 2013 Feb;75(2):516-23. doi: 10.1111/j.1365-2125.2012.04379.x.
• [2] New liver cancer biomarkers: PI3K/AKT/mTOR pathway members and eukaryotic translation initiation factors.Eur J Cancer. 2017 Sep;83:56-70. doi: 10.1016/j.ejca.2017.06.003. Epub 2017 Jul 14.
• [3] H3K27 acetylation-induced lncRNA EIF3J-AS1 improved proliferation and impeded apoptosis of colorectal cancer through miR-3163/YAP1 axis.J Cell Biochem. 2020 Feb;121(2):1923-1933. doi: 10.1002/jcb.29427. Epub 2019 Nov 11.
• [4] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [5] 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.
• [6] 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.
• [7] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [8] 17-Estradiol Activates HSF1 via MAPK Signaling in ER-Positive Breast Cancer Cells. Cancers (Basel). 2019 Oct 11;11(10):1533. doi: 10.3390/cancers11101533.
• [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] 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.
• [11] 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.
• [12] Reproducible chemical-induced changes in gene expression profiles in human hepatoma HepaRG cells under various experimental conditions. Toxicol In Vitro. 2009 Apr;23(3):466-75. doi: 10.1016/j.tiv.2008.12.018. Epub 2008 Dec 30.
• [13] Apoptosis induced by piroxicam plus cisplatin combined treatment is triggered by p21 in mesothelioma. PLoS One. 2011;6(8):e23569.
• [14] Cannabidiol Displays Proteomic Similarities to Antipsychotics in Cuprizone-Exposed Human Oligodendrocytic Cell Line MO3.13. Front Mol Neurosci. 2021 May 28;14:673144. doi: 10.3389/fnmol.2021.673144. eCollection 2021.
• [15] 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.
• [16] Inhibiting ubiquitination causes an accumulation of SUMOylated newly synthesized nuclear proteins at PML bodies. J Biol Chem. 2019 Oct 18;294(42):15218-15234. doi: 10.1074/jbc.RA119.009147. Epub 2019 Jul 8.
• [17] Quantitative phosphoproteomics reveal cellular responses from caffeine, coumarin and quercetin in treated HepG2 cells. Toxicol Appl Pharmacol. 2022 Aug 15;449:116110. doi: 10.1016/j.taap.2022.116110. Epub 2022 Jun 7.
• [18] Bisphenol A induces DSB-ATM-p53 signaling leading to cell cycle arrest, senescence, autophagy, stress response, and estrogen release in human fetal lung fibroblasts. Arch Toxicol. 2018 Apr;92(4):1453-1469.
• [19] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.