Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT6FQ02V)

• DOT Name: Tumor necrosis factor ligand superfamily member 12 (TNFSF12)
• Synonyms: APO3 ligand; TNF-related weak inducer of apoptosis; TWEAK
• Gene Name: TNFSF12
• Related Disease: Common variable immunodeficiency
• UniProt ID: TNF12_HUMAN
• PDB ID: 4HT1
• Pfam ID: PF00229
• Sequence:
  MAARRSQRRRGRRGEPGTALLVPLALGLGLALACLGLLLAVVSLGSRASLSAQEPAQEEL
  VAEEDQDPSELNPQTEESQDPAPFLNRLVRPRRSAPKGRKTRARRAIAAHYEVHPRPGQD
  GAQAGVDGTVSGWEEARINSSSPLRYNRQIGEFIVTRAGLYYLYCQVHFDEGKAVYLKLD
  LLVDGVLALRCLEEFSATAASSLGPQLRLCQVSGLLALRPGSSLRIRTLPWAHLKAAPFL
  TYFGLFQVH
• Function: Binds to FN14 and possibly also to TNRFSF12/APO3. Weak inducer of apoptosis in some cell types. Mediates NF-kappa-B activation. Promotes angiogenesis and the proliferation of endothelial cells. Also involved in induction of inflammatory cytokines. Promotes IL8 secretion.
• Tissue Specificity: Highly expressed in adult heart, pancreas, skeletal muscle, brain, colon, small intestine, lung, ovary, prostate, spleen, lymph node, appendix and peripheral blood lymphocytes. Low expression in kidney, testis, liver, placenta, thymus and bone marrow. Also detected in fetal kidney, liver, lung and brain.
• 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

1 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Common variable immunodeficiency	DISHE7JQ	Supportive	Autosomal dominant	[1]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the expression of Tumor necrosis factor ligand superfamily member 12 (TNFSF12).	[2]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Tumor necrosis factor ligand superfamily member 12 (TNFSF12).	[3]
Arsenic	DMTL2Y1	Approved	Arsenic affects the expression of Tumor necrosis factor ligand superfamily member 12 (TNFSF12).	[4]
Temozolomide	DMKECZD	Approved	Temozolomide increases the expression of Tumor necrosis factor ligand superfamily member 12 (TNFSF12).	[5]
Hydroquinone	DM6AVR4	Approved	Hydroquinone decreases the expression of Tumor necrosis factor ligand superfamily member 12 (TNFSF12).	[7]
Rosiglitazone	DMILWZR	Approved	Rosiglitazone decreases the expression of Tumor necrosis factor ligand superfamily member 12 (TNFSF12).	[8]
Menthol	DMG2KW7	Approved	Menthol decreases the expression of Tumor necrosis factor ligand superfamily member 12 (TNFSF12).	[9]
Diphenylpyraline	DMW4X37	Approved	Diphenylpyraline increases the expression of Tumor necrosis factor ligand superfamily member 12 (TNFSF12).	[10]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Tumor necrosis factor ligand superfamily member 12 (TNFSF12).	[11]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Tumor necrosis factor ligand superfamily member 12 (TNFSF12).	[12]
PMID27336223-Compound-5	DM6E50A	Patented	PMID27336223-Compound-5 decreases the expression of Tumor necrosis factor ligand superfamily member 12 (TNFSF12).	[8]
Nitrobenzanthrone	DMN6L70	Investigative	Nitrobenzanthrone decreases the expression of Tumor necrosis factor ligand superfamily member 12 (TNFSF12).	[13]

1 Drug(s) Affected the Post-Translational Modifications of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Marinol	DM70IK5	Approved	Marinol increases the methylation of Tumor necrosis factor ligand superfamily member 12 (TNFSF12).	[6]

References

• [1] Antibody deficiency associated with an inherited autosomal dominant mutation in TWEAK. Proc Natl Acad Sci U S A. 2013 Mar 26;110(13):5127-32. doi: 10.1073/pnas.1221211110. Epub 2013 Mar 14.
• [2] Integrative omics data analyses of repeated dose toxicity of valproic acid in vitro reveal new mechanisms of steatosis induction. Toxicology. 2018 Jan 15;393:160-170.
• [3] 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.
• [4] 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.
• [5] 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.
• [6] Epigenetic activation of O-linked -N-acetylglucosamine transferase overrides the differentiation blockage in acute leukemia. EBioMedicine. 2020 Apr;54:102678. doi: 10.1016/j.ebiom.2020.102678. Epub 2020 Apr 6.
• [7] 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.
• [8] PPARgamma controls CD1d expression by turning on retinoic acid synthesis in developing human dendritic cells. J Exp Med. 2006 Oct 2;203(10):2351-62.
• [9] 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.
• [10] 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.
• [11] New insights into BaP-induced toxicity: role of major metabolites in transcriptomics and contribution to hepatocarcinogenesis. Arch Toxicol. 2016 Jun;90(6):1449-58.
• [12] CCAT1 is an enhancer-templated RNA that predicts BET sensitivity in colorectal cancer. J Clin Invest. 2016 Feb;126(2):639-52.
• [13] 3-Nitrobenzanthrone promotes malignant transformation in human lung epithelial cells through the epiregulin-signaling pathway. Cell Biol Toxicol. 2022 Oct;38(5):865-887. doi: 10.1007/s10565-021-09612-1. Epub 2021 May 25.