Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTZYQW52)

• DOT Name: Transformer-2 protein homolog beta (TRA2B)
• Synonyms: TRA-2 beta; TRA2-beta; hTRA2-beta; Splicing factor, arginine/serine-rich 10; Transformer-2 protein homolog B
• Gene Name: TRA2B
• Related Disease:
  Adenocarcinoma
  Colon cancer
  Colon carcinoma
  Advanced cancer
  Alcoholic hepatitis
  Alzheimer disease
  Breast cancer
  Breast carcinoma
  Endometrial cancer
  Endometrial carcinoma
  Glioma
  Lung squamous cell carcinoma
  Neoplasm
  Non-small-cell lung cancer
  Obesity
  Progressive supranuclear palsy
  Prostate cancer
  Prostate carcinoma
  Spinal muscular atrophy
  Supranuclear palsy, progressive, 1
  Age-related macular degeneration
  Complex neurodevelopmental disorder
  Laryngeal squamous cell carcinoma
  Tauopathy
• UniProt ID: TRA2B_HUMAN
• PDB ID: 2CQC; 2KXN; 2RRA; 2RRB
• Pfam ID: PF00076
• Sequence:
  MSDSGEQNYGERESRSASRSGSAHGSGKSARHTPARSRSKEDSRRSRSKSRSRSESRSRS
  RRSSRRHYTRSRSRSRSHRRSRSRSYSRDYRRRHSHSHSPMSTRRRHVGNRANPDPNCCL
  GVFGLSLYTTERDLREVFSKYGPIADVSIVYDQQSRRSRGFAFVYFENVDDAKEAKERAN
  GMELDGRRIRVDFSITKRPHTPTPGIYMGRPTYGSSRRRDYYDRGYDRGYDDRDYYSRSY
  RGGGGGGGGWRAAQDRDQIYRRRSPSPYYSRGGYRSRSRSRSYSPRRY
• Function: Sequence-specific RNA-binding protein which participates in the control of pre-mRNA splicing. Can either activate or suppress exon inclusion. Acts additively with RBMX to promote exon 7 inclusion of the survival motor neuron SMN2. Activates the splicing of MAPT/Tau exon 10. Alters pre-mRNA splicing patterns by antagonizing the effects of splicing regulators, like RBMX. Binds to the AG-rich SE2 domain in the SMN exon 7 RNA. Binds to pre-mRNA.
• Tissue Specificity: Highest expression in heart, skeletal muscle and pancreas. Less abundant in kidney, placenta and brain. Lowest expression in kidney and liver.
• KEGG Pathway:
  Spliceosome (hsa03040)
  Alcoholic liver disease (hsa04936)
• Reactome Pathway:
  Processing of Capped Intron-Containing Pre-mRNA (R-HSA-72203)
  RHOBTB2 GTPase cycle (R-HSA-9013418)
  RHOBTB1 GTPase cycle (R-HSA-9013422)
  mRNA Splicing - Major Pathway (R-HSA-72163)

Molecular Interaction Atlas (MIA) of This DOT

24 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Adenocarcinoma	DIS3IHTY	Definitive	Altered Expression	[1]
Colon cancer	DISVC52G	Definitive	Biomarker	[1]
Colon carcinoma	DISJYKUO	Definitive	Biomarker	[1]
Advanced cancer	DISAT1Z9	Strong	Biomarker	[2]
Alcoholic hepatitis	DISA7SH0	Strong	Altered Expression	[3]
Alzheimer disease	DISF8S70	Strong	Altered Expression	[4]
Breast cancer	DIS7DPX1	Strong	Altered Expression	[5]
Breast carcinoma	DIS2UE88	Strong	Altered Expression	[5]
Endometrial cancer	DISW0LMR	Strong	Biomarker	[6]
Endometrial carcinoma	DISXR5CY	Strong	Biomarker	[6]
Glioma	DIS5RPEH	Strong	Altered Expression	[7]
Lung squamous cell carcinoma	DISXPIBD	Strong	Biomarker	[8]
Neoplasm	DISZKGEW	Strong	Altered Expression	[9]
Non-small-cell lung cancer	DIS5Y6R9	Strong	Altered Expression	[9]
Obesity	DIS47Y1K	Strong	Altered Expression	[10]
Progressive supranuclear palsy	DISO5KRQ	Strong	Biomarker	[11]
Prostate cancer	DISF190Y	Strong	Altered Expression	[12]
Prostate carcinoma	DISMJPLE	Strong	Altered Expression	[12]
Spinal muscular atrophy	DISTLKOB	Strong	Altered Expression	[13]
Supranuclear palsy, progressive, 1	DIS47BVM	Strong	Biomarker	[11]
Age-related macular degeneration	DIS0XS2C	moderate	Biomarker	[14]
Complex neurodevelopmental disorder	DISB9AFI	Moderate	Autosomal dominant	[15]
Laryngeal squamous cell carcinoma	DIS9UUVF	moderate	Altered Expression	[2]
Tauopathy	DISY2IPA	Limited	Biomarker	[16]

15 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 Transformer-2 protein homolog beta (TRA2B).	[17]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Transformer-2 protein homolog beta (TRA2B).	[18]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Transformer-2 protein homolog beta (TRA2B).	[19]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate affects the expression of Transformer-2 protein homolog beta (TRA2B).	[20]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide decreases the expression of Transformer-2 protein homolog beta (TRA2B).	[22]
Aspirin	DM672AH	Approved	Aspirin increases the expression of Transformer-2 protein homolog beta (TRA2B).	[23]
Clozapine	DMFC71L	Approved	Clozapine decreases the expression of Transformer-2 protein homolog beta (TRA2B).	[24]
Ethinyl estradiol	DMODJ40	Approved	Ethinyl estradiol increases the expression of Transformer-2 protein homolog beta (TRA2B).	[25]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Transformer-2 protein homolog beta (TRA2B).	[26]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide decreases the expression of Transformer-2 protein homolog beta (TRA2B).	[27]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Transformer-2 protein homolog beta (TRA2B).	[28]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Transformer-2 protein homolog beta (TRA2B).	[30]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of Transformer-2 protein homolog beta (TRA2B).	[31]
Coumestrol	DM40TBU	Investigative	Coumestrol increases the expression of Transformer-2 protein homolog beta (TRA2B).	[32]
chloropicrin	DMSGBQA	Investigative	chloropicrin increases the expression of Transformer-2 protein homolog beta (TRA2B).	[33]

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 Transformer-2 protein homolog beta (TRA2B).	[21]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 decreases the phosphorylation of Transformer-2 protein homolog beta (TRA2B).	[29]
Coumarin	DM0N8ZM	Investigative	Coumarin affects the phosphorylation of Transformer-2 protein homolog beta (TRA2B).	[29]

References

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• [2] Tra2 silencing suppresses cell proliferation in laryngeal squamous cell carcinoma via inhibiting PI3K/AKT signaling.Laryngoscope. 2019 Sep;129(9):E318-E328. doi: 10.1002/lary.27716. Epub 2018 Dec 31.
• [3] Deletion of SIRT1 from hepatocytes in mice disrupts lipin-1 signaling and aggravates alcoholic fatty liver.Gastroenterology. 2014 Mar;146(3):801-11. doi: 10.1053/j.gastro.2013.11.008. Epub 2013 Nov 18.
• [4] Regulation of RAGE splicing by hnRNP A1 and Tra2-1 and its potential role in AD pathogenesis.J Neurochem. 2015 Apr;133(2):187-98. doi: 10.1111/jnc.13069. Epub 2015 Mar 2.
• [5] Differential Functions of Splicing Factors in Mammary Transformation and Breast Cancer Metastasis.Cell Rep. 2019 Nov 26;29(9):2672-2688.e7. doi: 10.1016/j.celrep.2019.10.110.
• [6] Expression of TRA2B in endometrial carcinoma and its regulatory roles in endometrial carcinoma cells.Oncol Lett. 2019 Sep;18(3):2455-2463. doi: 10.3892/ol.2019.10553. Epub 2019 Jul 3.
• [7] Knocking down the expression of TRA2 inhibits the proliferation and migration of human glioma cells.Pathol Res Pract. 2015 Oct;211(10):731-9. doi: 10.1016/j.prp.2015.04.014. Epub 2015 May 21.
• [8] Identification of TRA2B-DNAH5 fusion as a novel oncogenic driver in human lung squamous cell carcinoma.Cell Res. 2016 Oct;26(10):1149-1164. doi: 10.1038/cr.2016.111. Epub 2016 Sep 27.
• [9] miR-335 inhibited cell proliferation of lung cancer cells by target Tra2.Cancer Sci. 2018 Feb;109(2):289-296. doi: 10.1111/cas.13452. Epub 2017 Dec 15.
• [10] Expression of the splicing factor gene SFRS10 is reduced in human obesity and contributes to enhanced lipogenesis.Cell Metab. 2011 Aug 3;14(2):208-18. doi: 10.1016/j.cmet.2011.06.007.
• [11] Mitochondrial complex 1 inhibition increases 4-repeat isoform tau by SRSF2 upregulation.PLoS One. 2014 Nov 17;9(11):e113070. doi: 10.1371/journal.pone.0113070. eCollection 2014.
• [12] RNA splicing and splicing regulator changes in prostate cancer pathology.Hum Genet. 2017 Sep;136(9):1143-1154. doi: 10.1007/s00439-017-1792-9. Epub 2017 Apr 5.
• [13] Evidence for a modifying pathway in SMA discordant families: reduced SMN level decreases the amount of its interacting partners and Htra2-beta1.Hum Genet. 2003 Dec;114(1):11-21. doi: 10.1007/s00439-003-1025-2. Epub 2003 Oct 1.
• [14] Expression analysis of an evolutionarily conserved alternative splicing factor, Sfrs10, in age-related macular degeneration.PLoS One. 2013 Sep 30;8(9):e75964. doi: 10.1371/journal.pone.0075964. eCollection 2013.
• [15] 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.
• [16] Mutations in tau gene exon 10 associated with FTDP-17 alter the activity of an exonic splicing enhancer to interact with Tra2 beta.J Biol Chem. 2003 May 23;278(21):18997-9007. doi: 10.1074/jbc.M301800200. Epub 2003 Mar 20.
• [17] 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.
• [18] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [19] 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.
• [20] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [21] 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.
• [22] Chronic occupational exposure to arsenic induces carcinogenic gene signaling networks and neoplastic transformation in human lung epithelial cells. Toxicol Appl Pharmacol. 2012 Jun 1;261(2):204-16.
• [23] Expression profile analysis of human peripheral blood mononuclear cells in response to aspirin. Arch Immunol Ther Exp (Warsz). 2005 Mar-Apr;53(2):151-8.
• [24] Cannabidiol Displays Proteomic Similarities to Antipsychotics in Cuprizone-Exposed Human Oligodendrocytic Cell Line MO3.13. Front Mol Neurosci. 2021 May 28;14:673144. doi: 10.3389/fnmol.2021.673144. eCollection 2021.
• [25] Regulation of alternative splicing of liver scavenger receptor class B gene by estrogen and the involved regulatory splicing factors. Endocrinology. 2007 Nov;148(11):5295-304. doi: 10.1210/en.2007-0376. Epub 2007 Aug 2.
• [26] Benzo[a]pyrene-induced changes in microRNA-mRNA networks. Chem Res Toxicol. 2012 Apr 16;25(4):838-49.
• [27] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [28] Cell-based two-dimensional morphological assessment system to predict cancer drug-induced cardiotoxicity using human induced pluripotent stem cell-derived cardiomyocytes. Toxicol Appl Pharmacol. 2019 Nov 15;383:114761. doi: 10.1016/j.taap.2019.114761. Epub 2019 Sep 15.
• [29] 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.
• [30] 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.
• [31] Cystathionine metabolic enzymes play a role in the inflammation resolution of human keratinocytes in response to sub-cytotoxic formaldehyde exposure. Toxicol Appl Pharmacol. 2016 Nov 1;310:185-194.
• [32] Pleiotropic combinatorial transcriptomes of human breast cancer cells exposed to mixtures of dietary phytoestrogens. Food Chem Toxicol. 2009 Apr;47(4):787-95.
• [33] Transcriptomic analysis of human primary bronchial epithelial cells after chloropicrin treatment. Chem Res Toxicol. 2015 Oct 19;28(10):1926-35.