Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT3EDGXO)

DOT Name Tumor necrosis factor receptor superfamily member 21 (TNFRSF21)
Synonyms Death receptor 6; CD antigen CD358
Gene Name TNFRSF21
UniProt ID
TNR21_HUMAN
3D Structure
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2D Sequence (FASTA)
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3D Structure (PDB)
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PDB ID
2DBH; 3QO4; 3U3P; 3U3Q; 3U3S; 3U3T; 3U3V
Pfam ID
PF00531 ; PF00020
Sequence
MGTSPSSSTALASCSRIARRATATMIAGSLLLLGFLSTTTAQPEQKASNLIGTYRHVDRA
TGQVLTCDKCPAGTYVSEHCTNTSLRVCSSCPVGTFTRHENGIEKCHDCSQPCPWPMIEK
LPCAALTDRECTCPPGMFQSNATCAPHTVCPVGWGVRKKGTETEDVRCKQCARGTFSDVP
SSVMKCKAYTDCLSQNLVVIKPGTKETDNVCGTLPSFSSSTSPSPGTAIFPRPEHMETHE
VPSSTYVPKGMNSTESNSSASVRPKVLSSIQEGTVPDNTSSARGKEDVNKTLPNLQVVNH
QQGPHHRHILKLLPSMEATGGEKSSTPIKGPKRGHPRQNLHKHFDINEHLPWMIVLFLLL
VLVVIVVCSIRKSSRTLKKGPRQDPSAIVEKAGLKKSMTPTQNREKWIYYCNGHGIDILK
LVAAQVGSQWKDIYQFLCNASEREVAAFSNGYTADHERAYAALQHWTIRGPEASLAQLIS
ALRQHRRNDVVEKIRGLMEDTTQLETDKLALPMSPSPLSPSPIPSPNAKLENSALLTVEP
SPQDKNKGFFVDESEPLLRCDSTSSGSSALSRNGSFITKEKKDTVLRQVRLDPCDLQPIF
DDMLHFLNPEELRVIEEIPQAEDKLDRLFEIIGVKSQEASQTLLDSVYSHLPDLL
Function
Promotes apoptosis, possibly via a pathway that involves the activation of NF-kappa-B. Can also promote apoptosis mediated by BAX and by the release of cytochrome c from the mitochondria into the cytoplasm. Plays a role in neuronal apoptosis, including apoptosis in response to amyloid peptides derived from APP, and is required for both normal cell body death and axonal pruning. Trophic-factor deprivation triggers the cleavage of surface APP by beta-secretase to release sAPP-beta which is further cleaved to release an N-terminal fragment of APP (N-APP). N-APP binds TNFRSF21; this triggers caspase activation and degeneration of both neuronal cell bodies (via caspase-3) and axons (via caspase-6). Negatively regulates oligodendrocyte survival, maturation and myelination. Plays a role in signaling cascades triggered by stimulation of T-cell receptors, in the adaptive immune response and in the regulation of T-cell differentiation and proliferation. Negatively regulates T-cell responses and the release of cytokines such as IL4, IL5, IL10, IL13 and IFNG by Th2 cells. Negatively regulates the production of IgG, IgM and IgM in response to antigens. May inhibit the activation of JNK in response to T-cell stimulation. Also acts as a regulator of pyroptosis: recruits CASP8 in response to reactive oxygen species (ROS) and subsequent oxidation, leading to activation of GSDMC.
Tissue Specificity
Detected in fetal spinal cord and in brain neurons, with higher levels in brain from Alzheimer disease patients (at protein level). Highly expressed in heart, brain, placenta, pancreas, lymph node, thymus and prostate. Detected at lower levels in lung, skeletal muscle, kidney, testis, uterus, small intestine, colon, spleen, bone marrow and fetal liver. Very low levels were found in adult liver and peripheral blood leukocytes.
KEGG Pathway
Cytokine-cytokine receptor interaction (hsa04060 )
Reactome Pathway
PPARA activates gene expression (R-HSA-1989781 )

Molecular Interaction Atlas (MIA) of This DOT

Molecular Interaction Atlas (MIA) Jump to Detail Molecular Interaction Atlas of This DOT
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 Tumor necrosis factor receptor superfamily member 21 (TNFRSF21). [1]
PMID28870136-Compound-52 DMFDERP Patented PMID28870136-Compound-52 increases the phosphorylation of Tumor necrosis factor receptor superfamily member 21 (TNFRSF21). [24]
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33 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 receptor superfamily member 21 (TNFRSF21). [2]
Tretinoin DM49DUI Approved Tretinoin decreases the expression of Tumor necrosis factor receptor superfamily member 21 (TNFRSF21). [3]
Acetaminophen DMUIE76 Approved Acetaminophen increases the expression of Tumor necrosis factor receptor superfamily member 21 (TNFRSF21). [4]
Doxorubicin DMVP5YE Approved Doxorubicin decreases the expression of Tumor necrosis factor receptor superfamily member 21 (TNFRSF21). [5]
Cupric Sulfate DMP0NFQ Approved Cupric Sulfate increases the expression of Tumor necrosis factor receptor superfamily member 21 (TNFRSF21). [6]
Cisplatin DMRHGI9 Approved Cisplatin decreases the expression of Tumor necrosis factor receptor superfamily member 21 (TNFRSF21). [7]
Estradiol DMUNTE3 Approved Estradiol decreases the expression of Tumor necrosis factor receptor superfamily member 21 (TNFRSF21). [8]
Quercetin DM3NC4M Approved Quercetin increases the expression of Tumor necrosis factor receptor superfamily member 21 (TNFRSF21). [9]
Arsenic trioxide DM61TA4 Approved Arsenic trioxide affects the expression of Tumor necrosis factor receptor superfamily member 21 (TNFRSF21). [10]
Hydrogen peroxide DM1NG5W Approved Hydrogen peroxide decreases the expression of Tumor necrosis factor receptor superfamily member 21 (TNFRSF21). [11]
Calcitriol DM8ZVJ7 Approved Calcitriol increases the expression of Tumor necrosis factor receptor superfamily member 21 (TNFRSF21). [12]
Carbamazepine DMZOLBI Approved Carbamazepine affects the expression of Tumor necrosis factor receptor superfamily member 21 (TNFRSF21). [13]
Methotrexate DM2TEOL Approved Methotrexate increases the expression of Tumor necrosis factor receptor superfamily member 21 (TNFRSF21). [14]
Zoledronate DMIXC7G Approved Zoledronate decreases the expression of Tumor necrosis factor receptor superfamily member 21 (TNFRSF21). [2]
Phenobarbital DMXZOCG Approved Phenobarbital affects the expression of Tumor necrosis factor receptor superfamily member 21 (TNFRSF21). [15]
Progesterone DMUY35B Approved Progesterone increases the expression of Tumor necrosis factor receptor superfamily member 21 (TNFRSF21). [16]
Troglitazone DM3VFPD Approved Troglitazone increases the expression of Tumor necrosis factor receptor superfamily member 21 (TNFRSF21). [17]
Rosiglitazone DMILWZR Approved Rosiglitazone increases the expression of Tumor necrosis factor receptor superfamily member 21 (TNFRSF21). [18]
Indomethacin DMSC4A7 Approved Indomethacin decreases the expression of Tumor necrosis factor receptor superfamily member 21 (TNFRSF21). [19]
Menthol DMG2KW7 Approved Menthol decreases the expression of Tumor necrosis factor receptor superfamily member 21 (TNFRSF21). [20]
Fenofibrate DMFKXDY Approved Fenofibrate increases the expression of Tumor necrosis factor receptor superfamily member 21 (TNFRSF21). [18]
Ibuprofen DM8VCBE Approved Ibuprofen decreases the expression of Tumor necrosis factor receptor superfamily member 21 (TNFRSF21). [19]
Phenol DM1QSM3 Phase 2/3 Phenol increases the expression of Tumor necrosis factor receptor superfamily member 21 (TNFRSF21). [21]
Benzo(a)pyrene DMN7J43 Phase 1 Benzo(a)pyrene increases the expression of Tumor necrosis factor receptor superfamily member 21 (TNFRSF21). [22]
Leflunomide DMR8ONJ Phase 1 Trial Leflunomide increases the expression of Tumor necrosis factor receptor superfamily member 21 (TNFRSF21). [23]
Bisphenol A DM2ZLD7 Investigative Bisphenol A increases the expression of Tumor necrosis factor receptor superfamily member 21 (TNFRSF21). [25]
Trichostatin A DM9C8NX Investigative Trichostatin A increases the expression of Tumor necrosis factor receptor superfamily member 21 (TNFRSF21). [26]
Coumestrol DM40TBU Investigative Coumestrol decreases the expression of Tumor necrosis factor receptor superfamily member 21 (TNFRSF21). [8]
Sulforaphane DMQY3L0 Investigative Sulforaphane increases the expression of Tumor necrosis factor receptor superfamily member 21 (TNFRSF21). [27]
methyl p-hydroxybenzoate DMO58UW Investigative methyl p-hydroxybenzoate decreases the expression of Tumor necrosis factor receptor superfamily member 21 (TNFRSF21). [28]
Paraquat DMR8O3X Investigative Paraquat decreases the expression of Tumor necrosis factor receptor superfamily member 21 (TNFRSF21). [29]
cinnamaldehyde DMZDUXG Investigative cinnamaldehyde increases the expression of Tumor necrosis factor receptor superfamily member 21 (TNFRSF21). [30]
biochanin A DM0HPWY Investigative biochanin A decreases the expression of Tumor necrosis factor receptor superfamily member 21 (TNFRSF21). [31]
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⏷ Show the Full List of 33 Drug(s)

References

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3 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.
4 Multiple microRNAs function as self-protective modules in acetaminophen-induced hepatotoxicity in humans. Arch Toxicol. 2018 Feb;92(2):845-858.
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10 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.
11 Oxidative stress modulates theophylline effects on steroid responsiveness. Biochem Biophys Res Commun. 2008 Dec 19;377(3):797-802.
12 Large-scale in silico and microarray-based identification of direct 1,25-dihydroxyvitamin D3 target genes. Mol Endocrinol. 2005 Nov;19(11):2685-95.
13 Gene Expression Regulation and Pathway Analysis After Valproic Acid and Carbamazepine Exposure in a Human Embryonic Stem Cell-Based Neurodevelopmental Toxicity Assay. Toxicol Sci. 2015 Aug;146(2):311-20. doi: 10.1093/toxsci/kfv094. Epub 2015 May 15.
14 Functional gene expression profile underlying methotrexate-induced senescence in human colon cancer cells. Tumour Biol. 2011 Oct;32(5):965-76.
15 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.
16 Effects of progesterone treatment on expression of genes involved in uterine quiescence. Reprod Sci. 2011 Aug;18(8):781-97.
17 Effects of ciglitazone and troglitazone on the proliferation of human stomach cancer cells. World J Gastroenterol. 2009 Jan 21;15(3):310-20.
18 Transcriptomic analysis of untreated and drug-treated differentiated HepaRG cells over a 2-week period. Toxicol In Vitro. 2015 Dec 25;30(1 Pt A):27-35.
19 Tumor necrosis factor-alpha induces the expression of DR6, a member of the TNF receptor family, through activation of NF-kappaB. Oncogene. 2001 Nov 29;20(55):7965-75. doi: 10.1038/sj.onc.1204985.
20 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.
21 Classification of heavy-metal toxicity by human DNA microarray analysis. Environ Sci Technol. 2007 May 15;41(10):3769-74.
22 Benzo[a]pyrene-induced changes in microRNA-mRNA networks. Chem Res Toxicol. 2012 Apr 16;25(4):838-49.
23 Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
24 Quantitative phosphoproteomics reveal cellular responses from caffeine, coumarin and quercetin in treated HepG2 cells. Toxicol Appl Pharmacol. 2022 Aug 15;449:116110. doi: 10.1016/j.taap.2022.116110. Epub 2022 Jun 7.
25 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.
26 From transient transcriptome responses to disturbed neurodevelopment: role of histone acetylation and methylation as epigenetic switch between reversible and irreversible drug effects. Arch Toxicol. 2014 Jul;88(7):1451-68.
27 Transcriptome and DNA methylation changes modulated by sulforaphane induce cell cycle arrest, apoptosis, DNA damage, and suppression of proliferation in human liver cancer cells. Food Chem Toxicol. 2020 Feb;136:111047. doi: 10.1016/j.fct.2019.111047. Epub 2019 Dec 12.
28 Differential effect of methyl-, butyl- and propylparaben and 17-estradiol on selected cell cycle and apoptosis gene and protein expression in MCF-7 breast cancer cells and MCF-10A non-malignant cells. J Appl Toxicol. 2014 Sep;34(9):1041-50. doi: 10.1002/jat.2978. Epub 2014 Jan 30.
29 Identification of genes associated with paraquat-induced toxicity in SH-SY5Y cells by PCR array focused on apoptotic pathways. J Toxicol Environ Health A. 2008;71(22):1457-67. doi: 10.1080/15287390802329364.
30 Comparative DNA microarray analysis of human monocyte derived dendritic cells and MUTZ-3 cells exposed to the moderate skin sensitizer cinnamaldehyde. Toxicol Appl Pharmacol. 2009 Sep 15;239(3):273-83.
31 Mechanisms of the growth inhibitory effects of the isoflavonoid biochanin A on LNCaP cells and xenografts. Prostate. 2002 Aug 1;52(3):201-12.