Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTW1V1L5)

• DOT Name: Protein BEX3 (BEX3)
• Synonyms: Brain-expressed X-linked protein 3; Nerve growth factor receptor-associated protein 1; Ovarian granulosa cell 13.0 kDa protein HGR74; p75NTR-associated cell death executor
• Gene Name: BEX3
• Related Disease:
  Thyroid gland papillary carcinoma
  Advanced cancer
  Glaucoma/ocular hypertension
  Neoplasm
  Tuberous sclerosis
  Nasopharyngeal carcinoma
  Neuroblastoma
• UniProt ID: BEX3_HUMAN
• Pfam ID: PF04538
• Sequence:
  MANIHQENEEMEQPMQNGEEDRPLGGGEGHQPAGNRRGQARRLAPNFRWAIPNRQINDGM
  GGDGDDMEIFMEEMREIRRKLRELQLRNCLRILMGELSNHHDHHDEFCLMP
• Function: May be a signaling adapter molecule involved in NGFR/p75NTR-mediated apoptosis induced by NGF. Plays a role in zinc-triggered neuronal death. In absence of reductive stress, acts as a pseudosubstrate for the CRL2(FEM1B) complex: associates with FEM1B via zinc, thereby preventing association between FEM1B and its substrates.
• Tissue Specificity: Found in ovarian granulosa cells, testis, prostate and seminal vesicle tissue. High levels also detected in liver.
• KEGG Pathway: Neurotrophin sig.ling pathway (hsa04722)
• Reactome Pathway: NADE modulates death signalling (R-HSA-205025)

Molecular Interaction Atlas (MIA) of This DOT

7 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Thyroid gland papillary carcinoma	DIS48YMM	Definitive	Biomarker	[1]
Advanced cancer	DISAT1Z9	Strong	Altered Expression	[2]
Glaucoma/ocular hypertension	DISLBXBY	Strong	Biomarker	[3]
Neoplasm	DISZKGEW	Strong	Biomarker	[4]
Tuberous sclerosis	DISEMUGZ	moderate	Biomarker	[5]
Nasopharyngeal carcinoma	DISAOTQ0	Limited	Altered Expression	[2]
Neuroblastoma	DISVZBI4	Limited	Biomarker	[4]

2 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 Protein BEX3 (BEX3).	[6]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Protein BEX3 (BEX3).	[14]

8 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 Protein BEX3 (BEX3).	[7]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Protein BEX3 (BEX3).	[8]
Doxorubicin	DMVP5YE	Approved	Doxorubicin increases the expression of Protein BEX3 (BEX3).	[9]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Protein BEX3 (BEX3).	[10]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of Protein BEX3 (BEX3).	[11]
Phenobarbital	DMXZOCG	Approved	Phenobarbital affects the expression of Protein BEX3 (BEX3).	[12]
Menthol	DMG2KW7	Approved	Menthol increases the expression of Protein BEX3 (BEX3).	[13]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Protein BEX3 (BEX3).	[15]

References

• [1] Identification of gene co-expression modules and hub genes associated with lymph node metastasis of papillary thyroid cancer.Endocrine. 2019 Dec;66(3):573-584. doi: 10.1007/s12020-019-02021-9. Epub 2019 Jul 22.
• [2] BEX3 contributes to cisplatin chemoresistance in nasopharyngeal carcinoma.Cancer Med. 2017 Feb;6(2):439-451. doi: 10.1002/cam4.982. Epub 2017 Jan 13.
• [3] Does elevated intraocular pressure reduce retinal TRKB-mediated survival signaling in experimental glaucoma?.Exp Eye Res. 2009 Dec;89(6):921-33. doi: 10.1016/j.exer.2009.08.003. Epub 2009 Aug 14.
• [4] Induction of Bex genes by curcumin is associated with apoptosis and activation of p53 in N2a neuroblastoma cells.Sci Rep. 2017 Feb 1;7:41420. doi: 10.1038/srep41420.
• [5] The TSC1 gene product hamartin interacts with NADE.Mol Cell Neurosci. 2007 May;35(1):100-8. doi: 10.1016/j.mcn.2007.02.007. Epub 2007 Feb 12.
• [6] 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.
• [7] 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.
• [8] Multiple microRNAs function as self-protective modules in acetaminophen-induced hepatotoxicity in humans. Arch Toxicol. 2018 Feb;92(2):845-858.
• [9] 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.
• [10] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [11] 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.
• [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] Repurposing L-menthol for systems medicine and cancer therapeutics? L-menthol induces apoptosis through caspase 10 and by suppressing HSP90. OMICS. 2016 Jan;20(1):53-64.
• [14] 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.
• [15] 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.