Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT5NHOO3)

• DOT Name: Transformer-2 protein homolog alpha (TRA2A)
• Synonyms: TRA-2 alpha; TRA2-alpha; Transformer-2 protein homolog A
• Gene Name: TRA2A
• Related Disease:
  Breast cancer
  Breast carcinoma
  Fragile X-associated tremor/ataxia syndrome
  Glioma
  Hepatocellular carcinoma
  Neoplasm
  Skin disease
  Triple negative breast cancer
• UniProt ID: TRA2A_HUMAN
• Pfam ID: PF00076
• Sequence:
  MSDVEENNFEGRESRSQSKSPTGTPARVKSESRSGSRSPSRVSKHSESHSRSRSKSRSRS
  RRHSHRRYTRSRSHSHSHRRRSRSRSYTPEYRRRRSRSHSPMSNRRRHTGSRANPDPNTC
  LGVFGLSLYTTERDLREVFSRYGPLSGVNVVYDQRTGRSRGFAFVYFERIDDSKEAMERA
  NGMELDGRRIRVDYSITKRAHTPTPGIYMGRPTHSGGGGGGGGGGGGGGGGRRRDSYYDR
  GYDRGYDRYEDYDYRYRRRSPSPYYSRYRSRSRSRSYSPRRY
• Function: Sequence-specific RNA-binding protein which participates in the control of pre-mRNA splicing.
• KEGG Pathway:
  Spliceosome (hsa03040)
  Alcoholic liver disease (hsa04936)

Molecular Interaction Atlas (MIA) of This DOT

8 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Breast cancer	DIS7DPX1	Strong	Biomarker	[1]
Breast carcinoma	DIS2UE88	Strong	Biomarker	[1]
Fragile X-associated tremor/ataxia syndrome	DISKB25R	Strong	Biomarker	[2]
Glioma	DIS5RPEH	Strong	Biomarker	[1]
Hepatocellular carcinoma	DIS0J828	Strong	Altered Expression	[3]
Neoplasm	DISZKGEW	Strong	Biomarker	[1]
Skin disease	DISDW8R6	Strong	Biomarker	[4]
Triple negative breast cancer	DISAMG6N	Strong	Biomarker	[5]

27 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 alpha (TRA2A).	[6]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Transformer-2 protein homolog alpha (TRA2A).	[7]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Transformer-2 protein homolog alpha (TRA2A).	[8]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Transformer-2 protein homolog alpha (TRA2A).	[9]
Arsenic	DMTL2Y1	Approved	Arsenic decreases the expression of Transformer-2 protein homolog alpha (TRA2A).	[4]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of Transformer-2 protein homolog alpha (TRA2A).	[11]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide decreases the expression of Transformer-2 protein homolog alpha (TRA2A).	[12]
Testosterone	DM7HUNW	Approved	Testosterone decreases the expression of Transformer-2 protein homolog alpha (TRA2A).	[13]
Marinol	DM70IK5	Approved	Marinol increases the expression of Transformer-2 protein homolog alpha (TRA2A).	[14]
Selenium	DM25CGV	Approved	Selenium decreases the expression of Transformer-2 protein homolog alpha (TRA2A).	[15]
Progesterone	DMUY35B	Approved	Progesterone decreases the expression of Transformer-2 protein homolog alpha (TRA2A).	[16]
Demecolcine	DMCZQGK	Approved	Demecolcine increases the expression of Transformer-2 protein homolog alpha (TRA2A).	[17]
Cannabidiol	DM0659E	Approved	Cannabidiol increases the expression of Transformer-2 protein homolog alpha (TRA2A).	[18]
Bortezomib	DMNO38U	Approved	Bortezomib decreases the expression of Transformer-2 protein homolog alpha (TRA2A).	[19]
Diethylstilbestrol	DMN3UXQ	Approved	Diethylstilbestrol increases the expression of Transformer-2 protein homolog alpha (TRA2A).	[20]
Azathioprine	DMMZSXQ	Approved	Azathioprine decreases the expression of Transformer-2 protein homolog alpha (TRA2A).	[21]
Testosterone enanthate	DMB6871	Approved	Testosterone enanthate affects the expression of Transformer-2 protein homolog alpha (TRA2A).	[22]
Nicotine	DMWX5CO	Approved	Nicotine increases the expression of Transformer-2 protein homolog alpha (TRA2A).	[23]
Sodium phenylbutyrate	DMXLBCQ	Approved	Sodium phenylbutyrate decreases the expression of Transformer-2 protein homolog alpha (TRA2A).	[24]
Testosterone Undecanoate	DMZO10Y	Approved	Testosterone Undecanoate decreases the expression of Transformer-2 protein homolog alpha (TRA2A).	[25]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Transformer-2 protein homolog alpha (TRA2A).	[26]
Tocopherol	DMBIJZ6	Phase 2	Tocopherol decreases the expression of Transformer-2 protein homolog alpha (TRA2A).	[15]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide decreases the expression of Transformer-2 protein homolog alpha (TRA2A).	[27]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Transformer-2 protein homolog alpha (TRA2A).	[29]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Transformer-2 protein homolog alpha (TRA2A).	[30]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Transformer-2 protein homolog alpha (TRA2A).	[31]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde increases the expression of Transformer-2 protein homolog alpha (TRA2A).	[32]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
TAK-243	DM4GKV2	Phase 1	TAK-243 decreases the sumoylation of Transformer-2 protein homolog alpha (TRA2A).	[28]
Coumarin	DM0N8ZM	Investigative	Coumarin increases the phosphorylation of Transformer-2 protein homolog alpha (TRA2A).	[33]

References

• [1] TRA2A promotes proliferation, migration, invasion and epithelial mesenchymal transition of glioma cells.Brain Res Bull. 2018 Oct;143:138-144. doi: 10.1016/j.brainresbull.2018.10.006. Epub 2018 Oct 24.
• [2] An Integrative Study of Protein-RNA Condensates Identifies Scaffolding RNAs and Reveals Players in Fragile X-Associated Tremor/Ataxia Syndrome.Cell Rep. 2018 Dec 18;25(12):3422-3434.e7. doi: 10.1016/j.celrep.2018.11.076.
• [3] Meta-analysis of gene expression profiles indicates genes in spliceosome pathway are up-regulated in hepatocellular carcinoma (HCC).Med Oncol. 2015 Apr;32(4):96. doi: 10.1007/s12032-014-0425-6. Epub 2015 Mar 3.
• [4] Gene expression profiles in peripheral lymphocytes by arsenic exposure and skin lesion status in a Bangladeshi population. Cancer Epidemiol Biomarkers Prev. 2006 Jul;15(7):1367-75. doi: 10.1158/1055-9965.EPI-06-0106.
• [5] TRA2A Promoted Paclitaxel Resistance and Tumor Progression in Triple-Negative Breast Cancers via Regulating Alternative Splicing.Mol Cancer Ther. 2017 Jul;16(7):1377-1388. doi: 10.1158/1535-7163.MCT-17-0026. Epub 2017 Apr 17.
• [6] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [7] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [8] Gene expression analysis of precision-cut human liver slices indicates stable expression of ADME-Tox related genes. Toxicol Appl Pharmacol. 2011 May 15;253(1):57-69.
• [9] 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.
• [10] Gene expression profiles in peripheral lymphocytes by arsenic exposure and skin lesion status in a Bangladeshi population. Cancer Epidemiol Biomarkers Prev. 2006 Jul;15(7):1367-75. doi: 10.1158/1055-9965.EPI-06-0106.
• [11] 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.
• [12] Arsenic suppresses gene expression in promyelocytic leukemia cells partly through Sp1 oxidation. Blood. 2005 Jul 1;106(1):304-10.
• [13] The exosome-like vesicles derived from androgen exposed-prostate stromal cells promote epithelial cells proliferation and epithelial-mesenchymal transition. Toxicol Appl Pharmacol. 2021 Jan 15;411:115384. doi: 10.1016/j.taap.2020.115384. Epub 2020 Dec 25.
• [14] Delta9-tetrahydrocannabinol inhibits cytotrophoblast cell proliferation and modulates gene transcription. Mol Hum Reprod. 2006 May;12(5):321-33. doi: 10.1093/molehr/gal036. Epub 2006 Apr 5.
• [15] Selenium and vitamin E: cell type- and intervention-specific tissue effects in prostate cancer. J Natl Cancer Inst. 2009 Mar 4;101(5):306-20.
• [16] Coordinate up-regulation of TMEM97 and cholesterol biosynthesis genes in normal ovarian surface epithelial cells treated with progesterone: implications for pathogenesis of ovarian cancer. BMC Cancer. 2007 Dec 11;7:223.
• [17] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [18] 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.
• [19] The proapoptotic effect of zoledronic acid is independent of either the bone microenvironment or the intrinsic resistance to bortezomib of myeloma cells and is enhanced by the combination with arsenic trioxide. Exp Hematol. 2011 Jan;39(1):55-65.
• [20] Identification of biomarkers and outcomes of endocrine disruption in human ovarian cortex using In Vitro Models. Toxicology. 2023 Feb;485:153425. doi: 10.1016/j.tox.2023.153425. Epub 2023 Jan 5.
• [21] A transcriptomics-based in vitro assay for predicting chemical genotoxicity in vivo. Carcinogenesis. 2012 Jul;33(7):1421-9.
• [22] Transcriptional profiling of testosterone-regulated genes in the skeletal muscle of human immunodeficiency virus-infected men experiencing weight loss. J Clin Endocrinol Metab. 2007 Jul;92(7):2793-802. doi: 10.1210/jc.2006-2722. Epub 2007 Apr 17.
• [23] Nicotinic modulation of gene expression in SH-SY5Y neuroblastoma cells. Brain Res. 2006 Oct 20;1116(1):39-49.
• [24] Gene expression profile analysis of 4-phenylbutyrate treatment of IB3-1 bronchial epithelial cell line demonstrates a major influence on heat-shock proteins. Physiol Genomics. 2004 Jan 15;16(2):204-11.
• [25] Levonorgestrel enhances spermatogenesis suppression by testosterone with greater alteration in testicular gene expression in men. Biol Reprod. 2009 Mar;80(3):484-92.
• [26] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [27] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [28] Inhibiting ubiquitination causes an accumulation of SUMOylated newly synthesized nuclear proteins at PML bodies. J Biol Chem. 2019 Oct 18;294(42):15218-15234. doi: 10.1074/jbc.RA119.009147. Epub 2019 Jul 8.
• [29] 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.
• [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] A transcriptome-based classifier to identify developmental toxicants by stem cell testing: design, validation and optimization for histone deacetylase inhibitors. Arch Toxicol. 2015 Sep;89(9):1599-618.
• [32] Gene expression changes in primary human nasal epithelial cells exposed to formaldehyde in vitro. Toxicol Lett. 2010 Oct 5;198(2):289-95.
• [33] 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.