Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT5QRF09)

• DOT Name: Tumor necrosis factor ligand superfamily member 14 (TNFSF14)
• Synonyms: Herpes virus entry mediator ligand; HVEM-L; Herpesvirus entry mediator ligand; CD antigen CD258
• Gene Name: TNFSF14
• UniProt ID: TNF14_HUMAN
• PDB ID: 4EN0; 4J6G; 4KG8; 4KGG; 4KGQ; 4RSU; 7MSG
• Pfam ID: PF00229
• Sequence:
  MEESVVRPSVFVVDGQTDIPFTRLGRSHRRQSCSVARVGLGLLLLLMGAGLAVQGWFLLQ
  LHWRLGEMVTRLPDGPAGSWEQLIQERRSHEVNPAAHLTGANSSLTGSGGPLLWETQLGL
  AFLRGLSYHDGALVVTKAGYYYIYSKVQLGGVGCPLGLASTITHGLYKRTPRYPEELELL
  VSQQSPCGRATSSSRVWWDSSFLGGVVHLEAGEKVVVRVLDERLVRLRDGTRSYFGAFMV
• Function: Cytokine that binds to TNFRSF3/LTBR. Binding to the decoy receptor TNFRSF6B modulates its effects. Acts as a ligand for TNFRSF14/HVEM. Upon binding to TNFRSF14/HVEM, delivers costimulatory signals to T cells, leading to T cell proliferation and IFNG production.
• Tissue Specificity: Predominantly expressed in the spleen but also found in the brain. Weakly expressed in peripheral lymphoid tissues and in heart, placenta, liver, lung, appendix, and kidney, and no expression seen in fetal tissues, endocrine glands, or nonhematopoietic tumor lines.
• KEGG Pathway:
  Cytokine-cytokine receptor interaction (hsa04060)
  Viral protein interaction with cytokine and cytokine receptor (hsa04061)
  NF-kappa B sig.ling pathway (hsa04064)
  Herpes simplex virus 1 infection (hsa05168)
• Reactome Pathway:
  TNFs bind their physiological receptors (R-HSA-5669034)
  TNF receptor superfamily (TNFSF) members mediating non-canonical NF-kB pathway (R-HSA-5676594)
  TNFR2 non-canonical NF-kB pathway (R-HSA-5668541)

Molecular Interaction Atlas (MIA) of This DOT

13 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 Tumor necrosis factor ligand superfamily member 14 (TNFSF14).	[1]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Tumor necrosis factor ligand superfamily member 14 (TNFSF14).	[2]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Tumor necrosis factor ligand superfamily member 14 (TNFSF14).	[3]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Tumor necrosis factor ligand superfamily member 14 (TNFSF14).	[4]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide decreases the expression of Tumor necrosis factor ligand superfamily member 14 (TNFSF14).	[5]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of Tumor necrosis factor ligand superfamily member 14 (TNFSF14).	[6]
Methotrexate	DM2TEOL	Approved	Methotrexate increases the expression of Tumor necrosis factor ligand superfamily member 14 (TNFSF14).	[7]
Menthol	DMG2KW7	Approved	Menthol decreases the expression of Tumor necrosis factor ligand superfamily member 14 (TNFSF14).	[8]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of Tumor necrosis factor ligand superfamily member 14 (TNFSF14).	[9]
Tamibarotene	DM3G74J	Phase 3	Tamibarotene increases the expression of Tumor necrosis factor ligand superfamily member 14 (TNFSF14).	[2]
PF-3758309	DM36PKZ	Phase 1	PF-3758309 increases the expression of Tumor necrosis factor ligand superfamily member 14 (TNFSF14).	[11]
Sulforaphane	DMQY3L0	Investigative	Sulforaphane increases the expression of Tumor necrosis factor ligand superfamily member 14 (TNFSF14).	[12]
Phencyclidine	DMQBEYX	Investigative	Phencyclidine increases the expression of Tumor necrosis factor ligand superfamily member 14 (TNFSF14).	[13]

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 affects the methylation of Tumor necrosis factor ligand superfamily member 14 (TNFSF14).	[10]

References

• [1] 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.
• [2] Differential modulation of PI3-kinase/Akt pathway during all-trans retinoic acid- and Am80-induced HL-60 cell differentiation revealed by DNA microarray analysis. Biochem Pharmacol. 2004 Dec 1;68(11):2177-86.
• [3] Blood transcript immune signatures distinguish a subset of people with elevated serum ALT from others given acetaminophen. Clin Pharmacol Ther. 2016 Apr;99(4):432-41.
• [4] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [5] Global effects of inorganic arsenic on gene expression profile in human macrophages. Mol Immunol. 2009 Feb;46(4):649-56.
• [6] Minimal peroxide exposure of neuronal cells induces multifaceted adaptive responses. PLoS One. 2010 Dec 17;5(12):e14352. doi: 10.1371/journal.pone.0014352.
• [7] Peripheral blood expression profiles of bone morphogenetic proteins, tumor necrosis factor-superfamily molecules, and transcription factor Runx2 could be used as markers of the form of arthritis, disease activity, and therapeutic responsiveness. J Rheumatol. 2010 Feb;37(2):246-56. doi: 10.3899/jrheum.090167. Epub 2009 Dec 15.
• [8] 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.
• [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] Inhibition of neuroblastoma proliferation by PF-3758309, a small-molecule inhibitor that targets p21-activated kinase 4. Oncol Rep. 2017 Nov;38(5):2705-2716. doi: 10.3892/or.2017.5989. Epub 2017 Sep 22.
• [12] 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.
• [13] Microarray Analysis of Gene Expression Alteration in Human Middle Ear Epithelial Cells Induced by Asian Sand Dust. Clin Exp Otorhinolaryngol. 2015 Dec;8(4):345-53. doi: 10.3342/ceo.2015.8.4.345. Epub 2015 Nov 10.