Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTYY2WS5)

• DOT Name: Eukaryotic translation initiation factor 4E-binding protein 3 (EIF4EBP3)
• Synonyms: 4E-BP3; eIF4E-binding protein 3
• Gene Name: EIF4EBP3
• Related Disease:
  Cervical cancer
  Cervical carcinoma
  Malignant tumor of parathyroid gland
  Multiple endocrine neoplasia type 1
  Parathyroid gland carcinoma
  Colorectal carcinoma
  Advanced cancer
  Thyroid gland papillary carcinoma
• UniProt ID: 4EBP3_HUMAN
• Pfam ID: PF05456
• Sequence:
  MSTSTSCPIPGGRDQLPDCYSTTPGGTLYATTPGGTRIIYDRKFLLECKNSPIARTPPCC
  LPQIPGVTTPPTAPLSKLEELKEQETEEEIPDDAQFEMDI
• Function: Repressor of translation initiation that regulates EIF4E activity by preventing its assembly into the eIF4F complex: the hypophosphorylated form competes with EIF4G1/EIF4G3 and strongly binds to EIF4E, leading to repression of translation. In contrast, the hyperphosphorylated form dissociates from EIF4E, allowing interaction between EIF4G1/EIF4G3 and EIF4E, leading to initiation of translation. Inhibits EIF4E-mediated mRNA nuclear export.
• Tissue Specificity: Expression is highest in skeletal muscle, heart, kidney, and pancreas, whereas there is very little expression in brain and thymus.

Molecular Interaction Atlas (MIA) of This DOT

8 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Cervical cancer	DISFSHPF	Strong	Biomarker	[1]
Cervical carcinoma	DIST4S00	Strong	Biomarker	[1]
Malignant tumor of parathyroid gland	DIS4X92K	Strong	Biomarker	[2]
Multiple endocrine neoplasia type 1	DIS0RJRK	Strong	Biomarker	[2]
Parathyroid gland carcinoma	DISEER2W	Strong	Biomarker	[2]
Colorectal carcinoma	DIS5PYL0	Disputed	Biomarker	[3]
Advanced cancer	DISAT1Z9	Limited	Biomarker	[4]
Thyroid gland papillary carcinoma	DIS48YMM	Limited	Genetic Variation	[5]

4 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 4E-binding protein 3 (EIF4EBP3).	[6]
Momelotinib	DMF98Q0	Approved	Momelotinib increases the expression of Eukaryotic translation initiation factor 4E-binding protein 3 (EIF4EBP3).	[8]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of Eukaryotic translation initiation factor 4E-binding protein 3 (EIF4EBP3).	[9]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Eukaryotic translation initiation factor 4E-binding protein 3 (EIF4EBP3).	[11]

2 Drug(s) Affected the Post-Translational Modifications of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Quercetin	DM3NC4M	Approved	Quercetin decreases the phosphorylation of Eukaryotic translation initiation factor 4E-binding protein 3 (EIF4EBP3).	[7]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Eukaryotic translation initiation factor 4E-binding protein 3 (EIF4EBP3).	[10]

References

• [1] MiR-22-3p Regulates Cell Proliferation and Inhibits Cell Apoptosis through Targeting the eIF4EBP3 Gene in Human Cervical Squamous Carcinoma Cells.Int J Med Sci. 2018 Jan 1;15(2):142-152. doi: 10.7150/ijms.21645. eCollection 2018.
• [2] The EIF4EBP3 translational repressor is a marker of CDC73 tumor suppressor haploinsufficiency in a parathyroid cancer syndrome.Cell Death Dis. 2012 Feb 2;3(2):266. doi: 10.1038/cddis.2012.6.
• [3] 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.
• [4] Translation control during prolonged mTORC1 inhibition mediated by 4E-BP3.Nat Commun. 2016 Jun 20;7:11776. doi: 10.1038/ncomms11776.
• [5] Amplification of thymosin beta 10 and AKAP13 genes in metastatic and aggressive papillary thyroid carcinomas.Pathol Oncol Res. 2012 Apr;18(2):449-58. doi: 10.1007/s12253-011-9467-7. Epub 2011 Dec 11.
• [6] The neuroprotective action of the mood stabilizing drugs lithium chloride and sodium valproate is mediated through the up-regulation of the homeodomain protein Six1. Toxicol Appl Pharmacol. 2009 Feb 15;235(1):124-34.
• [7] Quercetin potentiates UVB-Induced c-Fos expression: implications for its use as a chemopreventive agent. Cancer Prev Res (Phila). 2010 Jul;3(7):876-84. doi: 10.1158/1940-6207.CAPR-09-0220. Epub 2010 Jun 15.
• [8] The effect of quercetin nanoparticle on cervical cancer progression by inducing apoptosis, autophagy and anti-proliferation via JAK2 suppression. Biomed Pharmacother. 2016 Aug;82:595-605. doi: 10.1016/j.biopha.2016.05.029. Epub 2016 Jun 9.
• [9] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [10] 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.
• [11] 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.