Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTB82PFO)

• DOT Name: Tumor necrosis factor receptor superfamily member 14 (TNFRSF14)
• Synonyms: Herpes virus entry mediator A; Herpesvirus entry mediator A; HveA; Tumor necrosis factor receptor-like 2; TR2; CD antigen CD270
• Gene Name: TNFRSF14
• UniProt ID: TNR14_HUMAN
• PDB ID: 1JMA; 2AW2; 4FHQ; 4RSU; 5T2Q; 5T2R; 6NG3; 7MSG
• Pfam ID: PF00020
• Sequence:
  MEPPGDWGPPPWRSTPKTDVLRLVLYLTFLGAPCYAPALPSCKEDEYPVGSECCPKCSPG
  YRVKEACGELTGTVCEPCPPGTYIAHLNGLSKCLQCQMCDPAMGLRASRNCSRTENAVCG
  CSPGHFCIVQDGDHCAACRAYATSSPGQRVQKGGTESQDTLCQNCPPGTFSPNGTLEECQ
  HQTKCSWLVTKAGAGTSSSHWVWWFLSGSLVIVIVCSTVGLIICVKRRKPRGDVVKVIVS
  VQRKRQEAEGEATVIEALQAPPDVTTVAVEETIPSFTGRSPNH
• Function: Receptor for four distinct ligands: The TNF superfamily members TNFSF14/LIGHT and homotrimeric LTA/lymphotoxin-alpha and the immunoglobulin superfamily members BTLA and CD160, altogether defining a complex stimulatory and inhibitory signaling network. Signals via the TRAF2-TRAF3 E3 ligase pathway to promote immune cell survival and differentiation. Participates in bidirectional cell-cell contact signaling between antigen presenting cells and lymphocytes. In response to ligation of TNFSF14/LIGHT, delivers costimulatory signals to T cells, promoting cell proliferation and effector functions. Interacts with CD160 on NK cells, enhancing IFNG production and anti-tumor immune response. In the context of bacterial infection, acts as a signaling receptor on epithelial cells for CD160 from intraepithelial lymphocytes, triggering the production of antimicrobial proteins and pro-inflammatory cytokines. Upon binding to CD160 on activated CD4+ T cells, down-regulates CD28 costimulatory signaling, restricting memory and alloantigen-specific immune response. May interact in cis (on the same cell) or in trans (on other cells) with BTLA. In cis interactions, appears to play an immune regulatory role inhibiting in trans interactions in naive T cells to maintain a resting state. In trans interactions, can predominate during adaptive immune response to provide survival signals to effector T cells ; (Microbial infection) Acts as a receptor for Herpes simplex virus 1/HHV-1; (Microbial infection) Acts as a receptor for Herpes simplex virus 2/HHV-2.
• Tissue Specificity: Widely expressed, with the highest expression in lung, spleen and thymus. Expressed in a subpopulation of B cells and monocytes . Expressed in naive T cells .
• KEGG Pathway:
  Virion - Herpesvirus (hsa03266)
  Cytokine-cytokine receptor interaction (hsa04060)
  Viral protein interaction with cytokine and cytokine receptor (hsa04061)
  Herpes simplex virus 1 infection (hsa05168)
• Reactome Pathway:
  TNFs bind their physiological receptors (R-HSA-5669034)
  Costimulation by the CD28 family (R-HSA-388841)

Molecular Interaction Atlas (MIA) of This DOT

1 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 Tumor necrosis factor receptor superfamily member 14 (TNFRSF14).	[1]

23 Drug(s) Affected the Gene/Protein Processing of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Tumor necrosis factor receptor superfamily member 14 (TNFRSF14).	[2]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Tumor necrosis factor receptor superfamily member 14 (TNFRSF14).	[3]
Doxorubicin	DMVP5YE	Approved	Doxorubicin increases the expression of Tumor necrosis factor receptor superfamily member 14 (TNFRSF14).	[4]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Tumor necrosis factor receptor superfamily member 14 (TNFRSF14).	[5]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Tumor necrosis factor receptor superfamily member 14 (TNFRSF14).	[6]
Quercetin	DM3NC4M	Approved	Quercetin increases the expression of Tumor necrosis factor receptor superfamily member 14 (TNFRSF14).	[7]
Temozolomide	DMKECZD	Approved	Temozolomide decreases the expression of Tumor necrosis factor receptor superfamily member 14 (TNFRSF14).	[8]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide decreases the expression of Tumor necrosis factor receptor superfamily member 14 (TNFRSF14).	[9]
Zoledronate	DMIXC7G	Approved	Zoledronate increases the expression of Tumor necrosis factor receptor superfamily member 14 (TNFRSF14).	[10]
Phenobarbital	DMXZOCG	Approved	Phenobarbital affects the expression of Tumor necrosis factor receptor superfamily member 14 (TNFRSF14).	[11]
Folic acid	DMEMBJC	Approved	Folic acid affects the expression of Tumor necrosis factor receptor superfamily member 14 (TNFRSF14).	[12]
Etoposide	DMNH3PG	Approved	Etoposide increases the expression of Tumor necrosis factor receptor superfamily member 14 (TNFRSF14).	[13]
Menthol	DMG2KW7	Approved	Menthol increases the expression of Tumor necrosis factor receptor superfamily member 14 (TNFRSF14).	[14]
Cocaine	DMSOX7I	Approved	Cocaine increases the expression of Tumor necrosis factor receptor superfamily member 14 (TNFRSF14).	[15]
Cyclophosphamide	DM4O2Z7	Approved	Cyclophosphamide increases the expression of Tumor necrosis factor receptor superfamily member 14 (TNFRSF14).	[13]
Exemestane	DM9HPW3	Approved	Exemestane increases the expression of Tumor necrosis factor receptor superfamily member 14 (TNFRSF14).	[16]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Tumor necrosis factor receptor superfamily member 14 (TNFRSF14).	[17]
Tamibarotene	DM3G74J	Phase 3	Tamibarotene increases the expression of Tumor necrosis factor receptor superfamily member 14 (TNFRSF14).	[2]
Chlorpromazine	DMBGZI3	Phase 3 Trial	Chlorpromazine increases the expression of Tumor necrosis factor receptor superfamily member 14 (TNFRSF14).	[18]
GSK2110183	DMZHB37	Phase 2	GSK2110183 increases the expression of Tumor necrosis factor receptor superfamily member 14 (TNFRSF14).	[19]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the expression of Tumor necrosis factor receptor superfamily member 14 (TNFRSF14).	[7]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Tumor necrosis factor receptor superfamily member 14 (TNFRSF14).	[20]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of Tumor necrosis factor receptor superfamily member 14 (TNFRSF14).	[21]

References

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• [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] Multiple microRNAs function as self-protective modules in acetaminophen-induced hepatotoxicity in humans. Arch Toxicol. 2018 Feb;92(2):845-858.
• [4] 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.
• [5] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [6] Low doses of cisplatin induce gene alterations, cell cycle arrest, and apoptosis in human promyelocytic leukemia cells. Biomark Insights. 2016 Aug 24;11:113-21.
• [7] Comparison of phenotypic and transcriptomic effects of false-positive genotoxins, true genotoxins and non-genotoxins using HepG2 cells. Mutagenesis. 2011 Sep;26(5):593-604.
• [8] Temozolomide induces activation of Wnt/-catenin signaling in glioma cells via PI3K/Akt pathway: implications in glioma therapy. Cell Biol Toxicol. 2020 Jun;36(3):273-278. doi: 10.1007/s10565-019-09502-7. Epub 2019 Nov 22.
• [9] Arsenic trioxide induces different gene expression profiles of genes related to growth and apoptosis in glioma cells dependent on the p53 status. Mol Biol Rep. 2008 Sep;35(3):421-9.
• [10] Interleukin-19 as a translational indicator of renal injury. Arch Toxicol. 2015 Jan;89(1):101-6.
• [11] 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.
• [12] Effects of folate deficiency on gene expression in the apoptosis and cancer pathways in colon cancer cells. Carcinogenesis. 2006 May;27(5):916-24. doi: 10.1093/carcin/bgi312. Epub 2005 Dec 16.
• [13] Genomic profiling uncovers a molecular pattern for toxicological characterization of mutagens and promutagens in vitro. Toxicol Sci. 2011 Jul;122(1):185-97.
• [14] 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.
• [15] Gene expression profiling reveals distinct cocaine-responsive genes in human fetal CNS cell types. J Addict Med. 2009 Dec;3(4):218-26. doi: 10.1097/ADM.0b013e318199d863.
• [16] Effects of aromatase inhibitors on human osteoblast and osteoblast-like cells: a possible androgenic bone protective effects induced by exemestane. Bone. 2007 Apr;40(4):876-87. doi: 10.1016/j.bone.2006.11.029. Epub 2006 Dec 28.
• [17] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [18] Effects of chlorpromazine with and without UV irradiation on gene expression of HepG2 cells. Mutat Res. 2005 Aug 4;575(1-2):47-60. doi: 10.1016/j.mrfmmm.2005.03.002. Epub 2005 Apr 26.
• [19] Novel ATP-competitive Akt inhibitor afuresertib suppresses the proliferation of malignant pleural mesothelioma cells. Cancer Med. 2017 Nov;6(11):2646-2659. doi: 10.1002/cam4.1179. Epub 2017 Sep 27.
• [20] 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.
• [21] Bisphenol A and bisphenol S induce distinct transcriptional profiles in differentiating human primary preadipocytes. PLoS One. 2016 Sep 29;11(9):e0163318.