Details of Drug Off-Target (DOT)

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

• DOT Name: Tumor necrosis factor receptor type 1-associated DEATH domain protein (TRADD)
• Synonyms: TNFR1-associated DEATH domain protein; TNFRSF1A-associated via death domain
• Gene Name: TRADD
• Related Disease:
  Adult glioblastoma
  Neural tube defect
  Acute myelogenous leukaemia
  Alzheimer disease
  Bone osteosarcoma
  Brain cancer
  Breast cancer
  Breast carcinoma
  Breast neoplasm
  Carcinoma of liver and intrahepatic biliary tract
  Glioblastoma multiforme
  Glioma
  Hematologic disease
  Hepatocellular carcinoma
  Liver cancer
  Neoplasm
  Osteosarcoma
  Uterine fibroids
• UniProt ID: TRADD_HUMAN
• PDB ID: 1F2H; 1F3V; 5XME; 6AC0; 7CSQ
• Pfam ID: PF00531 ; PF09034
• Sequence:
  MAAGQNGHEEWVGSAYLFVESSLDKVVLSDAYAHPQQKVAVYRALQAALAESGGSPDVLQ
  MLKIHRSDPQLIVQLRFCGRQPCGRFLRAYREGALRAALQRSLAAALAQHSVPLQLELRA
  GAERLDALLADEERCLSCILAQQPDRLRDEELAELEDALRNLKCGSGARGGDGEVASAPL
  QPPVPSLSEVKPPPPPPPAQTFLFQGQPVVNRPLSLKDQQTFARSVGLKWRKVGRSLQRG
  CRALRDPALDSLAYEYEREGLYEQAFQLLRRFVQAEGRRATLQRLVEALEENELTSLAED
  LLGLTDPNGGLA
• Function: Adapter molecule for TNFRSF1A/TNFR1 that specifically associates with the cytoplasmic domain of activated TNFRSF1A/TNFR1 mediating its interaction with FADD. Overexpression of TRADD leads to two major TNF-induced responses, apoptosis and activation of NF-kappa-B. The nuclear form acts as a tumor suppressor by preventing ubiquitination and degradation of isoform p19ARF/ARF of CDKN2A by TRIP12: acts by interacting with TRIP12, leading to disrupt interaction between TRIP12 and isoform p19ARF/ARF of CDKN2A.
• Tissue Specificity: Found in all examined tissues.
• KEGG Pathway:
  MAPK sig.ling pathway (hsa04010)
  NF-kappa B sig.ling pathway (hsa04064)
  Sphingolipid sig.ling pathway (hsa04071)
  Apoptosis (hsa04210)
  Necroptosis (hsa04217)
  RIG-I-like receptor sig.ling pathway (hsa04622)
  IL-17 sig.ling pathway (hsa04657)
  TNF sig.ling pathway (hsa04668)
  Adipocytokine sig.ling pathway (hsa04920)
  Alcoholic liver disease (hsa04936)
  Pathogenic Escherichia coli infection (hsa05130)
  Shigellosis (hsa05131)
  Salmonella infection (hsa05132)
  Tuberculosis (hsa05152)
  Hepatitis C (hsa05160)
  Measles (hsa05162)
  Human cytomegalovirus infection (hsa05163)
  Influenza A (hsa05164)
  Human papillomavirus infection (hsa05165)
  Kaposi sarcoma-associated herpesvirus infection (hsa05167)
  Herpes simplex virus 1 infection (hsa05168)
  Epstein-Barr virus infection (hsa05169)
  Human immunodeficiency virus 1 infection (hsa05170)
  Viral carcinogenesis (hsa05203)
• Reactome Pathway:
  Regulation by c-FLIP (R-HSA-3371378)
  RIPK1-mediated regulated necrosis (R-HSA-5213460)
  CASP8 activity is inhibited (R-HSA-5218900)
  TNFR1-induced proapoptotic signaling (R-HSA-5357786)
  Regulation of TNFR1 signaling (R-HSA-5357905)
  TNFR1-induced NF-kappa-B signaling pathway (R-HSA-5357956)
  Regulation of necroptotic cell death (R-HSA-5675482)
  Dimerization of procaspase-8 (R-HSA-69416)
  TNF signaling (R-HSA-75893)
  Defective RIPK1-mediated regulated necrosis (R-HSA-9693928)
  Caspase activation via Death Receptors in the presence of ligand (R-HSA-140534)

Molecular Interaction Atlas (MIA) of This DOT

18 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Adult glioblastoma	DISVP4LU	Definitive	Biomarker	[1]
Neural tube defect	DIS5J95E	Definitive	Altered Expression	[2]
Acute myelogenous leukaemia	DISCSPTN	Strong	Biomarker	[3]
Alzheimer disease	DISF8S70	Strong	Altered Expression	[4]
Bone osteosarcoma	DIST1004	Strong	Biomarker	[5]
Brain cancer	DISBKFB7	Strong	Altered Expression	[6]
Breast cancer	DIS7DPX1	Strong	Altered Expression	[7]
Breast carcinoma	DIS2UE88	Strong	Altered Expression	[7]
Breast neoplasm	DISNGJLM	Strong	Altered Expression	[8]
Carcinoma of liver and intrahepatic biliary tract	DIS8WA0W	Strong	Altered Expression	[9]
Glioblastoma multiforme	DISK8246	Strong	Biomarker	[1]
Glioma	DIS5RPEH	Strong	Altered Expression	[6]
Hematologic disease	DIS9XD9A	Strong	Genetic Variation	[10]
Hepatocellular carcinoma	DIS0J828	Strong	Biomarker	[11]
Liver cancer	DISDE4BI	Strong	Altered Expression	[9]
Neoplasm	DISZKGEW	Strong	Biomarker	[12]
Osteosarcoma	DISLQ7E2	Strong	Biomarker	[5]
Uterine fibroids	DISBZRMJ	Strong	Biomarker	[13]

This DOT Affected the Drug Response of 1 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Cisplatin	DMRHGI9	Approved	Tumor necrosis factor receptor type 1-associated DEATH domain protein (TRADD) decreases the response to substance of Cisplatin.	[38]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the expression of Tumor necrosis factor receptor type 1-associated DEATH domain protein (TRADD).	[14]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Tumor necrosis factor receptor type 1-associated DEATH domain protein (TRADD).	[15]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Tumor necrosis factor receptor type 1-associated DEATH domain protein (TRADD).	[16]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of Tumor necrosis factor receptor type 1-associated DEATH domain protein (TRADD).	[17]
Ivermectin	DMDBX5F	Approved	Ivermectin increases the expression of Tumor necrosis factor receptor type 1-associated DEATH domain protein (TRADD).	[18]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of Tumor necrosis factor receptor type 1-associated DEATH domain protein (TRADD).	[19]
Triclosan	DMZUR4N	Approved	Triclosan increases the expression of Tumor necrosis factor receptor type 1-associated DEATH domain protein (TRADD).	[20]
Methotrexate	DM2TEOL	Approved	Methotrexate increases the expression of Tumor necrosis factor receptor type 1-associated DEATH domain protein (TRADD).	[21]
Zoledronate	DMIXC7G	Approved	Zoledronate increases the expression of Tumor necrosis factor receptor type 1-associated DEATH domain protein (TRADD).	[22]
Phenobarbital	DMXZOCG	Approved	Phenobarbital affects the expression of Tumor necrosis factor receptor type 1-associated DEATH domain protein (TRADD).	[23]
Menadione	DMSJDTY	Approved	Menadione affects the expression of Tumor necrosis factor receptor type 1-associated DEATH domain protein (TRADD).	[19]
Fluorouracil	DMUM7HZ	Approved	Fluorouracil affects the expression of Tumor necrosis factor receptor type 1-associated DEATH domain protein (TRADD).	[24]
Hydroquinone	DM6AVR4	Approved	Hydroquinone increases the expression of Tumor necrosis factor receptor type 1-associated DEATH domain protein (TRADD).	[25]
Irinotecan	DMP6SC2	Approved	Irinotecan increases the expression of Tumor necrosis factor receptor type 1-associated DEATH domain protein (TRADD).	[26]
Menthol	DMG2KW7	Approved	Menthol increases the expression of Tumor necrosis factor receptor type 1-associated DEATH domain protein (TRADD).	[27]
Simvastatin	DM30SGU	Approved	Simvastatin decreases the expression of Tumor necrosis factor receptor type 1-associated DEATH domain protein (TRADD).	[28]
Hesperidin	DMI5DW1	Approved	Hesperidin increases the expression of Tumor necrosis factor receptor type 1-associated DEATH domain protein (TRADD).	[29]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of Tumor necrosis factor receptor type 1-associated DEATH domain protein (TRADD).	[30]
Curcumin	DMQPH29	Phase 3	Curcumin decreases the expression of Tumor necrosis factor receptor type 1-associated DEATH domain protein (TRADD).	[31]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide decreases the expression of Tumor necrosis factor receptor type 1-associated DEATH domain protein (TRADD).	[32]
PF-3758309	DM36PKZ	Phase 1	PF-3758309 increases the expression of Tumor necrosis factor receptor type 1-associated DEATH domain protein (TRADD).	[33]
Dioscin	DM5H2W9	Preclinical	Dioscin increases the expression of Tumor necrosis factor receptor type 1-associated DEATH domain protein (TRADD).	[34]
Coumarin	DM0N8ZM	Investigative	Coumarin increases the expression of Tumor necrosis factor receptor type 1-associated DEATH domain protein (TRADD).	[35]
Paraquat	DMR8O3X	Investigative	Paraquat decreases the expression of Tumor necrosis factor receptor type 1-associated DEATH domain protein (TRADD).	[36]
RHEIN	DMS6IJ0	Investigative	RHEIN increases the expression of Tumor necrosis factor receptor type 1-associated DEATH domain protein (TRADD).	[37]

References

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• [3] Tumor Necrosis Factor Receptor Type 1-Associated Death Domain Protein Is a Potential Prognostic Biomarker in Acute Myeloid Leukemia.Am J Med Sci. 2019 Feb;357(2):111-115. doi: 10.1016/j.amjms.2018.10.015. Epub 2018 Nov 20.
• [4] No difference in expression of apoptosis-related proteins and apoptotic morphology in control, pathologically aged and Alzheimer's disease cases.Neurobiol Dis. 2006 May;22(2):323-33. doi: 10.1016/j.nbd.2005.11.010. Epub 2006 Jan 9.
• [5] Mutation analysis of the apoptotic "death-receptors" and the adaptors TRADD and FADD/MORT-1 in osteosarcoma tumor samples and osteosarcoma cell lines.Int J Cancer. 2004 May 1;109(5):661-7. doi: 10.1002/ijc.20008.
• [6] Cytoplasmic TRADD confers a worse prognosis in glioblastoma.Neoplasia. 2013 Aug;15(8):888-97. doi: 10.1593/neo.13608.
• [7] MicroRNA-30c-2-3p negatively regulates NF-B signaling and cell cycle progression through downregulation of TRADD and CCNE1 in breast cancer.Mol Oncol. 2015 Jun;9(6):1106-19. doi: 10.1016/j.molonc.2015.01.008. Epub 2015 Feb 10.
• [8] Tumor necrosis factor receptor-associated death domain protein is involved in the neurotrophin receptor-mediated antiapoptotic activity of nerve growth factor in breast cancer cells.J Biol Chem. 2003 May 9;278(19):16952-6. doi: 10.1074/jbc.M300631200. Epub 2003 Feb 25.
• [9] miR-149* Suppresses Liver Cancer Progression by Down-Regulating Tumor Necrosis Factor Receptor 1-Associated Death Domain Protein Expression.Am J Pathol. 2020 Feb;190(2):469-483. doi: 10.1016/j.ajpath.2019.10.010. Epub 2019 Nov 26.
• [10] Screening, identification, and functional analysis of three novel missense mutations in the TRADD gene in children with ALL and ALPS.Pediatr Blood Cancer. 2008 Nov;51(5):616-20. doi: 10.1002/pbc.21672.
• [11] Anticancer activity of an antisense oligonucleotide targeting TRADD combined with proteasome inhibitors in chemoresistant hepatocellular carcinoma cells.J Chemother. 2013 Oct;25(5):292-7. doi: 10.1179/1973947813Y.0000000087.
• [12] Prognostic significance of CpG island methylator phenotype in surgically resected small cell lung carcinoma.Cancer Sci. 2016 Mar;107(3):320-5. doi: 10.1111/cas.12876. Epub 2016 Feb 19.
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• [17] Molecular mechanism of action of bisphenol and bisphenol A mediated by oestrogen receptor alpha in growth and apoptosis of breast cancer cells. Br J Pharmacol. 2013 May;169(1):167-78.
• [18] Quantitative proteomics reveals a broad-spectrum antiviral property of ivermectin, benefiting for COVID-19 treatment. J Cell Physiol. 2021 Apr;236(4):2959-2975. doi: 10.1002/jcp.30055. Epub 2020 Sep 22.
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• [21] Global molecular effects of tocilizumab therapy in rheumatoid arthritis synovium. Arthritis Rheumatol. 2014 Jan;66(1):15-23.
• [22] Effect of zoledronic acid on oral fibroblasts and epithelial cells: a potential mechanism of bisphosphonate-associated osteonecrosis. Br J Haematol. 2009 Mar;144(5):667-76. doi: 10.1111/j.1365-2141.2008.07504.x. Epub 2008 Nov 20.
• [23] 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.
• [24] New insights into the mechanisms underlying 5-fluorouracil-induced intestinal toxicity based on transcriptomic and metabolomic responses in human intestinal organoids. Arch Toxicol. 2021 Aug;95(8):2691-2718. doi: 10.1007/s00204-021-03092-2. Epub 2021 Jun 20.
• [25] Survival of retinal pigment epithelium after exposure to prolonged oxidative injury: a detailed gene expression and cellular analysis. Invest Ophthalmol Vis Sci. 2004 Oct;45(10):3767-77.
• [26] In vitro and in vivo irinotecan-induced changes in expression profiles of cell cycle and apoptosis-associated genes in acute myeloid leukemia cells. Mol Cancer Ther. 2005 Jun;4(6):885-900.
• [27] 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.
• [28] Simvastatin potentiates TNF-alpha-induced apoptosis through the down-regulation of NF-kappaB-dependent antiapoptotic gene products: role of IkappaBalpha kinase and TGF-beta-activated kinase-1. J Immunol. 2007 Feb 15;178(4):2507-16. doi: 10.4049/jimmunol.178.4.2507.
• [29] Mangiferin has an additive effect on the apoptotic properties of hesperidin in Cyclopia sp. tea extracts. PLoS One. 2014 Mar 14;9(3):e92128. doi: 10.1371/journal.pone.0092128. eCollection 2014.
• [30] Definition of transcriptome-based indices for quantitative characterization of chemically disturbed stem cell development: introduction of the STOP-Toxukn and STOP-Toxukk tests. Arch Toxicol. 2017 Feb;91(2):839-864.
• [31] Gene expression profiling identifies activating transcription factor 3 as a novel contributor to the proapoptotic effect of curcumin. Mol Cancer Ther. 2005 Feb;4(2):233-41.
• [32] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [33] 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.
• [34] Molecular mechanism and inhibitory targets of dioscin in HepG2 cells. Food Chem Toxicol. 2018 Oct;120:143-154.
• [35] A synthetic coumarin derivative (4-flourophenylacetamide-acetyl coumarin) impedes cell cycle at G0/G1 stage, induces apoptosis, and inhibits metastasis via ROS-mediated p53 and AKT signaling pathways in A549 cells. J Biochem Mol Toxicol. 2020 Oct;34(10):e22553. doi: 10.1002/jbt.22553. Epub 2020 Jun 24.
• [36] 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.
• [37] Apoptotic effects of rhein through the mitochondrial pathways, two death receptor pathways, and reducing autophagy in human liver L02 cells. Environ Toxicol. 2019 Dec;34(12):1292-1302. doi: 10.1002/tox.22830. Epub 2019 Aug 21.
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