Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTND26XR)

• DOT Name: Tumor necrosis factor ligand superfamily member 13B (TNFSF13B)
• Synonyms: B lymphocyte stimulator; BLyS; B-cell-activating factor; BAFF; Dendritic cell-derived TNF-like molecule; TNF- and APOL-related leukocyte expressed ligand 1; TALL-1; CD antigen CD257
• Gene Name: TNFSF13B
• UniProt ID: TN13B_HUMAN
• PDB ID: 1JH5; 1KD7; 1KXG; 1OQD; 1OQE; 1OSG; 3V56; 4V46; 4ZCH; 5Y9J; 6FXN
• Pfam ID: PF00229
• Sequence:
  MDDSTEREQSRLTSCLKKREEMKLKECVSILPRKESPSVRSSKDGKLLAATLLLALLSCC
  LTVVSFYQVAALQGDLASLRAELQGHHAEKLPAGAGAPKAGLEEAPAVTAGLKIFEPPAP
  GEGNSSQNSRNKRAVQGPEETVTQDCLQLIADSETPTIQKGSYTFVPWLLSFKRGSALEE
  KENKILVKETGYFFIYGQVLYTDKTYAMGHLIQRKKVHVFGDELSLVTLFRCIQNMPETL
  PNNSCYSAGIAKLEEGDELQLAIPRENAQISLDGDVTFFGALKLL
• Function: Cytokine that binds to TNFRSF13B/TACI and TNFRSF17/BCMA. TNFSF13/APRIL binds to the same 2 receptors. Together, they form a 2 ligands -2 receptors pathway involved in the stimulation of B- and T-cell function and the regulation of humoral immunity. A third B-cell specific BAFF-receptor (BAFFR/BR3) promotes the survival of mature B-cells and the B-cell response; Isoform 2 seems to inhibit isoform 1 secretion and bioactivity; [Isoform 3]: Acts as a transcription factor for its own parent gene, in association with NF-kappa-B p50 subunit, at least in autoimmune and proliferative B-cell diseases. The presence of Delta4BAFF is essential for soluble BAFF release by IFNG/IFN-gamma-stimulated monocytes and for B-cell survival. It can directly or indirectly regulate the differential expression of a large number of genes involved in the innate immune response and the regulation of apoptosis.
• Tissue Specificity: Abundantly expressed in peripheral blood Leukocytes and is specifically expressed in monocytes and macrophages. Also found in the spleen, lymph node, bone marrow, T-cells and dendritic cells. A lower expression seen in placenta, heart, lung, fetal liver, thymus, and pancreas. Isoform 2 is expressed in many myeloid cell lines.
• KEGG Pathway:
  Cytokine-cytokine receptor interaction (hsa04060)
  NF-kappa B sig.ling pathway (hsa04064)
  Intesti.l immune network for IgA production (hsa04672)
  Rheumatoid arthritis (hsa05323)
• Reactome Pathway:
  TNFs bind their physiological receptors (R-HSA-5669034)
  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

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 13B (TNFSF13B).	[1]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Tumor necrosis factor ligand superfamily member 13B (TNFSF13B).	[2]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Tumor necrosis factor ligand superfamily member 13B (TNFSF13B).	[3]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Tumor necrosis factor ligand superfamily member 13B (TNFSF13B).	[4]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide affects the expression of Tumor necrosis factor ligand superfamily member 13B (TNFSF13B).	[6]
Progesterone	DMUY35B	Approved	Progesterone increases the expression of Tumor necrosis factor ligand superfamily member 13B (TNFSF13B).	[8]
Demecolcine	DMCZQGK	Approved	Demecolcine increases the expression of Tumor necrosis factor ligand superfamily member 13B (TNFSF13B).	[9]
Paclitaxel	DMLB81S	Approved	Paclitaxel increases the expression of Tumor necrosis factor ligand superfamily member 13B (TNFSF13B).	[10]
Fenretinide	DMRD5SP	Phase 3	Fenretinide increases the expression of Tumor necrosis factor ligand superfamily member 13B (TNFSF13B).	[11]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Tumor necrosis factor ligand superfamily member 13B (TNFSF13B).	[13]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Tumor necrosis factor ligand superfamily member 13B (TNFSF13B).	[15]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde increases the expression of Tumor necrosis factor ligand superfamily member 13B (TNFSF13B).	[9]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of Tumor necrosis factor ligand superfamily member 13B (TNFSF13B).	[5]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Tumor necrosis factor ligand superfamily member 13B (TNFSF13B).	[12]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Tumor necrosis factor ligand superfamily member 13B (TNFSF13B).	[14]

1 Drug(s) Affected the Protein Interaction/Cellular Processes of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide increases the secretion of Tumor necrosis factor ligand superfamily member 13B (TNFSF13B).	[7]

References

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• [2] 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.
• [3] Human 3D multicellular microtissues: an upgraded model for the in vitro mechanistic investigation of inflammation-associated drug toxicity. Toxicol Lett. 2019 Sep 15;312:34-44.
• [4] 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.
• [5] Prenatal arsenic exposure and the epigenome: identifying sites of 5-methylcytosine alterations that predict functional changes in gene expression in newborn cord blood and subsequent birth outcomes. Toxicol Sci. 2015 Jan;143(1):97-106. doi: 10.1093/toxsci/kfu210. Epub 2014 Oct 10.
• [6] 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.
• [7] Chronic senescent human mesenchymal stem cells as possible contributor to the wound healing disorder after exposure to the alkylating agent sulfur mustard. Arch Toxicol. 2021 Feb;95(2):727-747. doi: 10.1007/s00204-020-02946-5. Epub 2021 Jan 25.
• [8] Progesterone promotes differentiation of human cord blood fetal T cells into T regulatory cells but suppresses their differentiation into Th17 cells. J Immunol. 2011 Aug 15;187(4):1778-87. doi: 10.4049/jimmunol.1003919. Epub 2011 Jul 18.
• [9] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [10] Marked regression of liver metastasis by combined therapy of ultrasound-mediated NF kappaB-decoy transfer and transportal injection of paclitaxel, in mouse. Int J Cancer. 2008 Apr 1;122(7):1645-56. doi: 10.1002/ijc.23280.
• [11] 4-HPR modulates gene expression in ovarian cells. Int J Cancer. 2006 Sep 1;119(5):1005-13. doi: 10.1002/ijc.21797.
• [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] Inhibition of Super-Enhancer Activity in Autoinflammatory Site-Derived T Cells Reduces Disease-Associated Gene Expression. Cell Rep. 2015 Sep 29;12(12):1986-96. doi: 10.1016/j.celrep.2015.08.046. Epub 2015 Sep 17.
• [14] DNA methylome-wide alterations associated with estrogen receptor-dependent effects of bisphenols in breast cancer. Clin Epigenetics. 2019 Oct 10;11(1):138. doi: 10.1186/s13148-019-0725-y.
• [15] 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.