Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT1FISGN)

• DOT Name: Tumor necrosis factor receptor superfamily member 11A (TNFRSF11A)
• Synonyms: Osteoclast differentiation factor receptor; ODFR; Receptor activator of NF-KB; CD antigen CD265
• Gene Name: TNFRSF11A
• Related Disease:
  Autosomal recessive osteopetrosis 7
  Paget disease of bone 2, early-onset
  Familial expansile osteolysis
  Dysosteosclerosis
  Osteosarcoma
• UniProt ID: TNR11_HUMAN
• PDB ID: 1LB5
• Pfam ID: PF18278 ; PF00020
• Sequence:
  MAPRARRRRPLFALLLLCALLARLQVALQIAPPCTSEKHYEHLGRCCNKCEPGKYMSSKC
  TTTSDSVCLPCGPDEYLDSWNEEDKCLLHKVCDTGKALVAVVAGNSTTPRRCACTAGYHW
  SQDCECCRRNTECAPGLGAQHPLQLNKDTVCKPCLAGYFSDAFSSTDKCRPWTNCTFLGK
  RVEHHGTEKSDAVCSSSLPARKPPNEPHVYLPGLIILLLFASVALVAAIIFGVCYRKKGK
  ALTANLWHWINEACGRLSGDKESSGDSCVSTHTANFGQQGACEGVLLLTLEEKTFPEDMC
  YPDQGGVCQGTCVGGGPYAQGEDARMLSLVSKTEIEEDSFRQMPTEDEYMDRPSQPTDQL
  LFLTEPGSKSTPPFSEPLEVGENDSLSQCFTGTQSTVGSESCNCTEPLCRTDWTPMSSEN
  YLQKEVDSGHCPHWAASPSPNWADVCTGCRNPPGEDCEPLVGSPKRGPLPQCAYGMGLPP
  EEEASRTEARDQPEDGADGRLPSSARAGAGSGSSPGGQSPASGNVTGNSNSTFISSGQVM
  NFKGDIIVVYVSQTSQEGAAAAAEPMGRPVQEETLARRDSFAGNGPRFPDPCGGPEGLRE
  PEKASRPVQEQGGAKA
• Function: Receptor for TNFSF11/RANKL/TRANCE/OPGL; essential for RANKL-mediated osteoclastogenesis. Its interaction with EEIG1 promotes osteoclastogenesis via facilitating the transcription of NFATC1 and activation of PLCG2. Involved in the regulation of interactions between T-cells and dendritic cells.
• Tissue Specificity: Ubiquitous expression with high levels in skeletal muscle, thymus, liver, colon, small intestine and adrenal gland.
• KEGG Pathway:
  Cytokine-cytokine receptor interaction (hsa04060)
  NF-kappa B sig.ling pathway (hsa04064)
  Osteoclast differentiation (hsa04380)
  Prolactin sig.ling pathway (hsa04917)
  Rheumatoid arthritis (hsa05323)
• Reactome Pathway:
  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

5 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Autosomal recessive osteopetrosis 7	DISPJ64W	Strong	Autosomal recessive	[1]
Paget disease of bone 2, early-onset	DISFBRFO	Strong	Autosomal dominant	[2]
Familial expansile osteolysis	DISZR6ZN	Moderate	Autosomal dominant	[3]
Dysosteosclerosis	DISYAE0Y	Supportive	Autosomal recessive	[4]
Osteosarcoma	DISLQ7E2	Limited	Autosomal dominant	[5]

13 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 superfamily member 11A (TNFRSF11A).	[6]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Tumor necrosis factor receptor superfamily member 11A (TNFRSF11A).	[7]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Tumor necrosis factor receptor superfamily member 11A (TNFRSF11A).	[8]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Tumor necrosis factor receptor superfamily member 11A (TNFRSF11A).	[9]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Tumor necrosis factor receptor superfamily member 11A (TNFRSF11A).	[10]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Tumor necrosis factor receptor superfamily member 11A (TNFRSF11A).	[11]
Arsenic	DMTL2Y1	Approved	Arsenic affects the expression of Tumor necrosis factor receptor superfamily member 11A (TNFRSF11A).	[12]
Quercetin	DM3NC4M	Approved	Quercetin increases the expression of Tumor necrosis factor receptor superfamily member 11A (TNFRSF11A).	[13]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide decreases the expression of Tumor necrosis factor receptor superfamily member 11A (TNFRSF11A).	[14]
Menthol	DMG2KW7	Approved	Menthol decreases the expression of Tumor necrosis factor receptor superfamily member 11A (TNFRSF11A).	[15]
Diphenylpyraline	DMW4X37	Approved	Diphenylpyraline increases the expression of Tumor necrosis factor receptor superfamily member 11A (TNFRSF11A).	[16]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the mutagenesis of Tumor necrosis factor receptor superfamily member 11A (TNFRSF11A).	[17]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of Tumor necrosis factor receptor superfamily member 11A (TNFRSF11A).	[18]

References

• [1] 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.
• [2] Mutations in TNFRSF11A, affecting the signal peptide of RANK, cause familial expansile osteolysis. Nat Genet. 2000 Jan;24(1):45-8. doi: 10.1038/71667.
• [3] Classification of Genes: Standardized Clinical Validity Assessment of Gene-Disease Associations Aids Diagnostic Exome Analysis and Reclassifications. Hum Mutat. 2017 May;38(5):600-608. doi: 10.1002/humu.23183. Epub 2017 Feb 13.
• [4] Dysosteosclerosis is also caused by TNFRSF11A mutation. J Hum Genet. 2018 Jun;63(6):769-774. doi: 10.1038/s10038-018-0447-6. Epub 2018 Mar 22.
• [5] Genetic and molecular aspects of osteosarcoma. J Musculoskelet Neuronal Interact. 2002 Dec;2(6):554-60.
• [6] The neuroprotective action of the mood stabilizing drugs lithium chloride and sodium valproate is mediated through the up-regulation of the homeodomain protein Six1. Toxicol Appl Pharmacol. 2009 Feb 15;235(1):124-34.
• [7] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [8] Development of a neural teratogenicity test based on human embryonic stem cells: response to retinoic acid exposure. Toxicol Sci. 2011 Dec;124(2):370-7.
• [9] 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.
• [10] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [11] 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.
• [12] Prenatal arsenic exposure and shifts in the newborn proteome: interindividual differences in tumor necrosis factor (TNF)-responsive signaling. Toxicol Sci. 2014 Jun;139(2):328-37. doi: 10.1093/toxsci/kfu053. Epub 2014 Mar 27.
• [13] 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.
• [14] Arsenic trioxide and cisplatin synergism increase cytotoxicity in human ovarian cancer cells: therapeutic potential for ovarian cancer. Cancer Sci. 2009 Dec;100(12):2459-64.
• [15] 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.
• [16] Controlled diesel exhaust and allergen coexposure modulates microRNA and gene expression in humans: Effects on inflammatory lung markers. J Allergy Clin Immunol. 2016 Dec;138(6):1690-1700. doi: 10.1016/j.jaci.2016.02.038. Epub 2016 Apr 24.
• [17] Exome-wide mutation profile in benzo[a]pyrene-derived post-stasis and immortal human mammary epithelial cells. Mutat Res Genet Toxicol Environ Mutagen. 2014 Dec;775-776:48-54. doi: 10.1016/j.mrgentox.2014.10.011. Epub 2014 Nov 4.
• [18] 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.