Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT419II2)

• DOT Name: Tumor necrosis factor receptor superfamily member 19L (RELT)
• Synonyms: Receptor expressed in lymphoid tissues
• Gene Name: RELT
• Related Disease:
  Amelogenesis imperfecta
  Amelogenesis imperfecta, type 3c
  Dental enamel hypoplasia
  Amelogenesis imperfecta type 1
  Schizophrenia
• UniProt ID: TR19L_HUMAN
• Pfam ID: PF12606
• Sequence:
  MKPSLLCRPLSCFLMLLPWPLATLTSTTLWQCPPGEEPDLDPGQGTLCRPCPPGTFSAAW
  GSSPCQPHARCSLWRRLEAQVGMATRDTLCGDCWPGWFGPWGVPRVPCQPCSWAPLGTHG
  CDEWGRRARRGVEVAAGASSGGETRQPGNGTRAGGPEETAAQYAVIAIVPVFCLMGLLGI
  LVCNLLKRKGYHCTAHKEVGPGPGGGGSGINPAYRTEDANEDTIGVLVRLITEKKENAAA
  LEELLKEYHSKQLVQTSHRPVSKLPPAPPNVPHICPHRHHLHTVQGLASLSGPCCSRCSQ
  KKWPEVLLSPEAVAATTPVPSLLPNPTRVPKAGAKAGRQGEITILSVGRFRVARIPEQRT
  SSMVSEVKTITEAGPSWGDLPDSPQPGLPPEQQALLGSGGSRTKWLKPPAENKAEENRYV
  VRLSESNLVI
• Function: May play a role in apoptosis. Induces activation of MAPK14/p38 and MAPK8/JNK MAPK cascades, when overexpressed. Involved in dental enamel formation.
• Tissue Specificity: Spleen, lymph node, brain, breast and peripheral blood leukocytes (at protein level) . Expressed highly in bone marrow and fetal liver. Very low levels in skeletal muscle, testis and colon. Not detected in kidney and pancreas.
• KEGG Pathway: Cytokine-cytokine receptor interaction (hsa04060)

Molecular Interaction Atlas (MIA) of This DOT

5 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Amelogenesis imperfecta	DISGYR9E	Strong	Genetic Variation	[1]
Amelogenesis imperfecta, type 3c	DISHHZEF	Strong	Autosomal recessive	[1]
Dental enamel hypoplasia	DISN6ZMR	Strong	Genetic Variation	[1]
Amelogenesis imperfecta type 1	DISVEG5A	Supportive	Autosomal dominant	[1]
Schizophrenia	DISSRV2N	No Known	Unknown	[2]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Tumor necrosis factor receptor superfamily member 19L (RELT).	[3]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Tumor necrosis factor receptor superfamily member 19L (RELT).	[4]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Tumor necrosis factor receptor superfamily member 19L (RELT).	[5]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Tumor necrosis factor receptor superfamily member 19L (RELT).	[6]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of Tumor necrosis factor receptor superfamily member 19L (RELT).	[7]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Tumor necrosis factor receptor superfamily member 19L (RELT).	[8]
Marinol	DM70IK5	Approved	Marinol decreases the expression of Tumor necrosis factor receptor superfamily member 19L (RELT).	[9]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of Tumor necrosis factor receptor superfamily member 19L (RELT).	[10]
GSK2110183	DMZHB37	Phase 2	GSK2110183 decreases the expression of Tumor necrosis factor receptor superfamily member 19L (RELT).	[11]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Tumor necrosis factor receptor superfamily member 19L (RELT).	[13]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Tumor necrosis factor receptor superfamily member 19L (RELT).	[14]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Tumor necrosis factor receptor superfamily member 19L (RELT).	[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 Tumor necrosis factor receptor superfamily member 19L (RELT).	[12]

References

• [1] Mutations in RELT cause autosomal recessive amelogenesis imperfecta. Clin Genet. 2019 Mar;95(3):375-383. doi: 10.1111/cge.13487. Epub 2018 Dec 21.
• [2] The Gene Curation Coalition: A global effort to harmonize gene-disease evidence resources. Genet Med. 2022 Aug;24(8):1732-1742. doi: 10.1016/j.gim.2022.04.017. Epub 2022 May 4.
• [3] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [4] Transcriptional and Metabolic Dissection of ATRA-Induced Granulocytic Differentiation in NB4 Acute Promyelocytic Leukemia Cells. Cells. 2020 Nov 5;9(11):2423. doi: 10.3390/cells9112423.
• [5] Multiple microRNAs function as self-protective modules in acetaminophen-induced hepatotoxicity in humans. Arch Toxicol. 2018 Feb;92(2):845-858.
• [6] 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.
• [7] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [8] 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.
• [9] THC exposure of human iPSC neurons impacts genes associated with neuropsychiatric disorders. Transl Psychiatry. 2018 Apr 25;8(1):89. doi: 10.1038/s41398-018-0137-3.
• [10] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [11] 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.
• [12] 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.
• [13] 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.
• [14] 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.
• [15] Bisphenol A induces DSB-ATM-p53 signaling leading to cell cycle arrest, senescence, autophagy, stress response, and estrogen release in human fetal lung fibroblasts. Arch Toxicol. 2018 Apr;92(4):1453-1469.