Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTTWVS2R)

• DOT Name: Eukaryotic translation initiation factor 4E type 3 (EIF4E3)
• Synonyms: eIF-4E type 3; eIF-4E3; eIF4E type 3; eIF4E-3
• Gene Name: EIF4E3
• Related Disease:
  B-cell lymphoma
  Medulloblastoma
  Advanced cancer
  Breast cancer
  Breast carcinoma
  Hepatocellular carcinoma
  Neoplasm
  Colorectal carcinoma
• UniProt ID: IF4E3_HUMAN
• Pfam ID: PF01652
• Sequence:
  MALPPAAAPPAGAREPPGSRAAAAAAAPEPPLGLQQLSALQPEPGGVPLHSSWTFWLDRS
  LPGATAAECASNLKKIYTVQTVQIFWSVYNNIPPVTSLPLRCSYHLMRGERRPLWEEESN
  AKGGVWKMKVPKDSTSTVWKELLLATIGEQFTDCAAADDEVIGVSVSVRDREDVVQVWNV
  NASLVGEATVLEKIYELLPHITFKAVFYKPHEEHHAFEGGRGKH
• Function: Recognizes and binds the 7-methylguanosine-containing mRNA cap during an early step in the initiation of protein synthesis. May act as an inhibitor of EIF4E1 activity.
• Reactome Pathway: ISG15 antiviral mechanism (R-HSA-1169408)

Molecular Interaction Atlas (MIA) of This DOT

8 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
B-cell lymphoma	DISIH1YQ	Strong	Altered Expression	[1]
Medulloblastoma	DISZD2ZL	Strong	Biomarker	[2]
Advanced cancer	DISAT1Z9	moderate	Biomarker	[3]
Breast cancer	DIS7DPX1	moderate	Altered Expression	[4]
Breast carcinoma	DIS2UE88	moderate	Altered Expression	[4]
Hepatocellular carcinoma	DIS0J828	moderate	Altered Expression	[5]
Neoplasm	DISZKGEW	moderate	Altered Expression	[3]
Colorectal carcinoma	DIS5PYL0	Disputed	Genetic Variation	[6]

8 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 Eukaryotic translation initiation factor 4E type 3 (EIF4E3).	[7]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide increases the expression of Eukaryotic translation initiation factor 4E type 3 (EIF4E3).	[8]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of Eukaryotic translation initiation factor 4E type 3 (EIF4E3).	[9]
Panobinostat	DM58WKG	Approved	Panobinostat decreases the expression of Eukaryotic translation initiation factor 4E type 3 (EIF4E3).	[10]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Eukaryotic translation initiation factor 4E type 3 (EIF4E3).	[12]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Eukaryotic translation initiation factor 4E type 3 (EIF4E3).	[13]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of Eukaryotic translation initiation factor 4E type 3 (EIF4E3).	[14]
Sulforaphane	DMQY3L0	Investigative	Sulforaphane increases the expression of Eukaryotic translation initiation factor 4E type 3 (EIF4E3).	[15]

1 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 decreases the methylation of Eukaryotic translation initiation factor 4E type 3 (EIF4E3).	[11]

References

• [1] MNKs act as a regulatory switch for eIF4E1 and eIF4E3 driven mRNA translation in DLBCL.Nat Commun. 2014 Nov 18;5:5413. doi: 10.1038/ncomms6413.
• [2] MiR-584-5p potentiates vincristine and radiation response by inducing spindle defects and DNA damage in medulloblastoma.Nat Commun. 2018 Oct 31;9(1):4541. doi: 10.1038/s41467-018-06808-8.
• [3] eIF4E3 acts as a tumor suppressor by utilizing an atypical mode of methyl-7-guanosine cap recognition.Proc Natl Acad Sci U S A. 2013 Mar 5;110(10):3877-82. doi: 10.1073/pnas.1216862110. Epub 2013 Feb 19.
• [4] Hypoxia-inducible factor-1 (HIF-1) promotes cap-dependent translation of selective mRNAs through up-regulating initiation factor eIF4E1 in breast cancer cells under hypoxia conditions.J Biol Chem. 2013 Jun 28;288(26):18732-42. doi: 10.1074/jbc.M113.471466. Epub 2013 May 10.
• [5] miR-503 inhibits proliferation making human hepatocellular carcinoma cells susceptible to 5fluorouracil by targeting EIF4E.Oncol Rep. 2017 Jan;37(1):563-570. doi: 10.3892/or.2016.5220. Epub 2016 Nov 7.
• [6] Associations between genetic variation in RUNX1, RUNX2, RUNX3, MAPK1 and eIF4E and riskof colon and rectal cancer: additional support for a TGF--signaling pathway.Carcinogenesis. 2011 Mar;32(3):318-26. doi: 10.1093/carcin/bgq245. Epub 2010 Nov 18.
• [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 profile induced by arsenic trioxide in chronic lymphocytic leukemia cells reveals a central role for heme oxygenase-1 in apoptosis and regulation of matrix metalloproteinase-9. Oncotarget. 2016 Dec 13;7(50):83359-83377.
• [9] Gene Expression Regulation and Pathway Analysis After Valproic Acid and Carbamazepine Exposure in a Human Embryonic Stem Cell-Based Neurodevelopmental Toxicity Assay. Toxicol Sci. 2015 Aug;146(2):311-20. doi: 10.1093/toxsci/kfv094. Epub 2015 May 15.
• [10] 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.
• [11] 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.
• [12] 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.
• [13] 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.
• [14] From transient transcriptome responses to disturbed neurodevelopment: role of histone acetylation and methylation as epigenetic switch between reversible and irreversible drug effects. Arch Toxicol. 2014 Jul;88(7):1451-68.
• [15] Sulforaphane-induced apoptosis in human leukemia HL-60 cells through extrinsic and intrinsic signal pathways and altering associated genes expression assayed by cDNA microarray. Environ Toxicol. 2017 Jan;32(1):311-328.