Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTU20K6L)

• DOT Name: Eukaryotic translation initiation factor 3 subunit F (EIF3F)
• Synonyms: eIF3f; Deubiquitinating enzyme eIF3f; EC 3.4.19.12; Eukaryotic translation initiation factor 3 subunit 5; eIF-3-epsilon; eIF3 p47
• Gene Name: EIF3F
• Related Disease:
  Syndromic intellectual disability
  Cervical cancer
  Cervical carcinoma
  Estrogen-receptor positive breast cancer
  Intellectual disability
  Lung adenocarcinoma
  Melanoma
  Neoplasm
  Non-insulin dependent diabetes
  Pancreatic cancer
  Pancreatic tumour
  Schizophrenia
  Sensorineural hearing loss disorder
  Advanced cancer
  Intellectual developmental disorder, autosomal recessive 67
• UniProt ID: EIF3F_HUMAN
• PDB ID: 3J8B; 3J8C; 6YBD; 6ZMW; 6ZON; 6ZP4; 6ZVJ; 7A09; 7QP6; 7QP7; 8PPL
• EC Number: 3.4.19.12
• Pfam ID: PF01398 ; PF13012
• Sequence:
  MATPAVPVSAPPATPTPVPAAAPASVPAPTPAPAAAPVPAAAPASSSDPAAAAAATAAPG
  QTPASAQAPAQTPAPALPGPALPGPFPGGRVVRLHPVILASIVDSYERRNEGAARVIGTL
  LGTVDKHSVEVTNCFSVPHNESEDEVAVDMEFAKNMYELHKKVSPNELILGWYATGHDIT
  EHSVLIHEYYSREAPNPIHLTVDTSLQNGRMSIKAYVSTLMGVPGRTMGVMFTPLTVKYA
  YYDTERIGVDLIMKTCFSPNRVIGLSSDLQQVGGASARIQDALSTVLQYAEDVLSGKVSA
  DNTVGRFLMSLVNQVPKIVPDDFETMLNSNINDLLMVTYLANLTQSQIALNEKLVNL
• 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 ; Deubiquitinates activated NOTCH1, promoting its nuclear import, thereby acting as a positive regulator of Notch signaling.
• 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

15 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Syndromic intellectual disability	DISH7SDF	Definitive	Autosomal recessive	[1]
Cervical cancer	DISFSHPF	Strong	Altered Expression	[2]
Cervical carcinoma	DIST4S00	Strong	Altered Expression	[2]
Estrogen-receptor positive breast cancer	DIS1H502	Strong	Altered Expression	[3]
Intellectual disability	DISMBNXP	Strong	Biomarker	[4]
Lung adenocarcinoma	DISD51WR	Strong	Biomarker	[5]
Melanoma	DIS1RRCY	Strong	Genetic Variation	[6]
Neoplasm	DISZKGEW	Strong	Altered Expression	[2]
Non-insulin dependent diabetes	DISK1O5Z	Strong	Biomarker	[7]
Pancreatic cancer	DISJC981	Strong	Posttranslational Modification	[8]
Pancreatic tumour	DIS3U0LK	Strong	Genetic Variation	[8]
Schizophrenia	DISSRV2N	Strong	Genetic Variation	[9]
Sensorineural hearing loss disorder	DISJV45Z	Strong	Biomarker	[4]
Advanced cancer	DISAT1Z9	moderate	Biomarker	[6]
Intellectual developmental disorder, autosomal recessive 67	DIS4AQ1M	Moderate	Autosomal recessive	[10]

10 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 F (EIF3F).	[11]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Eukaryotic translation initiation factor 3 subunit F (EIF3F).	[12]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Eukaryotic translation initiation factor 3 subunit F (EIF3F).	[13]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Eukaryotic translation initiation factor 3 subunit F (EIF3F).	[14]
Estradiol	DMUNTE3	Approved	Estradiol affects the expression of Eukaryotic translation initiation factor 3 subunit F (EIF3F).	[15]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Eukaryotic translation initiation factor 3 subunit F (EIF3F).	[16]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide increases the expression of Eukaryotic translation initiation factor 3 subunit F (EIF3F).	[18]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of Eukaryotic translation initiation factor 3 subunit F (EIF3F).	[19]
Epigallocatechin gallate	DMCGWBJ	Phase 3	Epigallocatechin gallate decreases the expression of Eukaryotic translation initiation factor 3 subunit F (EIF3F).	[20]
chloropicrin	DMSGBQA	Investigative	chloropicrin decreases the expression of Eukaryotic translation initiation factor 3 subunit F (EIF3F).	[23]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Quercetin	DM3NC4M	Approved	Quercetin affects the binding of Eukaryotic translation initiation factor 3 subunit F (EIF3F).	[17]

2 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 F (EIF3F).	[21]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 decreases the phosphorylation of Eukaryotic translation initiation factor 3 subunit F (EIF3F).	[22]

References

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• [2] eIF3f reduces tumor growth by directly interrupting clusterin with anti-apoptotic property in cancer cells.Oncotarget. 2016 Apr 5;7(14):18541-57. doi: 10.18632/oncotarget.8105.
• [3] Estrogen receptor promotes protein synthesis by fine-tuning the expression of the eukaryotic translation initiation factor 3 subunit f (eIF3f).J Biol Chem. 2019 Feb 15;294(7):2267-2278. doi: 10.1074/jbc.RA118.004383. Epub 2018 Dec 20.
• [4] Quantifying the contribution of recessive coding variation to developmental disorders. Science. 2018 Dec 7;362(6419):1161-1164. doi: 10.1126/science.aar6731. Epub 2018 Nov 8.
• [5] Nuclear control of lung cancer cells migration, invasion and bioenergetics by eukaryotic translation initiation factor 3F.Oncogene. 2020 Jan;39(3):617-636. doi: 10.1038/s41388-019-1009-x. Epub 2019 Sep 16.
• [6] Loss of the eukaryotic initiation factor 3f in melanoma.Mol Carcinog. 2008 Oct;47(10):806-13. doi: 10.1002/mc.20436.
• [7] Identification of variations of gene expression of visceral adipose and renal tissue in type 2 diabetic rats using cDNA representational difference analysis.Chin Med J (Engl). 2003 Apr;116(4):529-33.
• [8] Loss of the eukaryotic initiation factor 3f in pancreatic cancer.Mol Carcinog. 2008 Mar;47(3):235-44. doi: 10.1002/mc.20379.
• [9] Genome-wide association study of paliperidone efficacy.Pharmacogenet Genomics. 2017 Jan;27(1):7-18. doi: 10.1097/FPC.0000000000000250.
• [10] Classification of Genes: Standardized Clinical Validity Assessment of Gene-Disease Associations Aids Diagnostic Exome Analysis and Reclassifications. Hum Mutat. 2017 May;38(5):600-608. doi: 10.1002/humu.23183. Epub 2017 Feb 13.
• [11] A transcriptome-based classifier to identify developmental toxicants by stem cell testing: design, validation and optimization for histone deacetylase inhibitors. Arch Toxicol. 2015 Sep;89(9):1599-618.
• [12] 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.
• [13] Predictive toxicology using systemic biology and liver microfluidic "on chip" approaches: application to acetaminophen injury. Toxicol Appl Pharmacol. 2012 Mar 15;259(3):270-80.
• [14] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [15] Identification of novel low-dose bisphenol a targets in human foreskin fibroblast cells derived from hypospadias patients. PLoS One. 2012;7(5):e36711. doi: 10.1371/journal.pone.0036711. Epub 2012 May 4.
• [16] 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.
• [17] Biotinylated quercetin as an intrinsic photoaffinity proteomics probe for the identification of quercetin target proteins. Bioorg Med Chem. 2011 Aug 15;19(16):4710-20. doi: 10.1016/j.bmc.2011.07.005. Epub 2011 Jul 13.
• [18] Essential role of cell cycle regulatory genes p21 and p27 expression in inhibition of breast cancer cells by arsenic trioxide. Med Oncol. 2011 Dec;28(4):1225-54.
• [19] Hydrogen peroxide induces adaptive response and differential gene expression in human embryo lung fibroblast cells. Environ Toxicol. 2014 Apr;29(4):478-85. doi: 10.1002/tox.21775. Epub 2012 Apr 7.
• [20] Comparative proteomics reveals concordant and discordant biochemical effects of caffeine versus epigallocatechin-3-gallate in human endothelial cells. Toxicol Appl Pharmacol. 2019 Sep 1;378:114621. doi: 10.1016/j.taap.2019.114621. Epub 2019 Jun 10.
• [21] 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.
• [22] 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.
• [23] Molecular targets of chloropicrin in human airway epithelial cells. Toxicol In Vitro. 2017 Aug;42:247-254.