Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTW6FR32)

• DOT Name: Transcription factor E2-alpha (TCF3)
• Synonyms: Class B basic helix-loop-helix protein 21; bHLHb21; Immunoglobulin enhancer-binding factor E12/E47; Immunoglobulin transcription factor 1; Kappa-E2-binding factor; Transcription factor 3; TCF-3; Transcription factor ITF-1
• Gene Name: TCF3
• Related Disease:
  Autosomal agammaglobulinemia
  Agammaglobulinemia 8, autosomal dominant
• UniProt ID: TFE2_HUMAN
• PDB ID: 2MH0; 2YPA; 2YPB; 3U5V; 6MGN
• Pfam ID: PF00010
• Sequence:
  MNQPQRMAPVGTDKELSDLLDFSMMFPLPVTNGKGRPASLAGAQFGGSGLEDRPSSGSWG
  SGDQSSSSFDPSRTFSEGTHFTESHSSLSSSTFLGPGLGGKSGERGAYASFGRDAGVGGL
  TQAGFLSGELALNSPGPLSPSGMKGTSQYYPSYSGSSRRRAADGSLDTQPKKVRKVPPGL
  PSSVYPPSSGEDYGRDATAYPSAKTPSSTYPAPFYVADGSLHPSAELWSPPGQAGFGPML
  GGGSSPLPLPPGSGPVGSSGSSSTFGGLHQHERMGYQLHGAEVNGGLPSASSFSSAPGAT
  YGGVSSHTPPVSGADSLLGSRGTTAGSSGDALGKALASIYSPDHSSNNFSSSPSTPVGSP
  QGLAGTSQWPRAGAPGALSPSYDGGLHGLQSKIEDHLDEAIHVLRSHAVGTAGDMHTLLP
  GHGALASGFTGPMSLGGRHAGLVGGSHPEDGLAGSTSLMHNHAALPSQPGTLPDLSRPPD
  SYSGLGRAGATAAASEIKREEKEDEENTSAADHSEEEKKELKAPRARTSPDEDEDDLLPP
  EQKAEREKERRVANNARERLRVRDINEAFKELGRMCQLHLNSEKPQTKLLILHQAVSVIL
  NLEQQVRERNLNPKAACLKRREEEKVSGVVGDPQMVLSAPHPGLSEAHNPAGHM
• Function: Transcriptional regulator involved in the initiation of neuronal differentiation and mesenchymal to epithelial transition. Heterodimers between TCF3 and tissue-specific basic helix-loop-helix (bHLH) proteins play major roles in determining tissue-specific cell fate during embryogenesis, like muscle or early B-cell differentiation. Together with TCF15, required for the mesenchymal to epithelial transition. Dimers bind DNA on E-box motifs: 5'-CANNTG-3'. Binds to the kappa-E2 site in the kappa immunoglobulin gene enhancer. Binds to IEB1 and IEB2, which are short DNA sequences in the insulin gene transcription control region; [Isoform E47]: Facilitates ATOH7 binding to DNA at the consensus sequence 5'-CAGGTG-3', and positively regulates transcriptional activity.
• KEGG Pathway:
  Sig.ling pathways regulating pluripotency of stem cells (hsa04550)
  Human T-cell leukemia virus 1 infection (hsa05166)
  Transcriptio.l misregulation in cancer (hsa05202)
• Reactome Pathway:
  RUNX1 regulates transcription of genes involved in differentiation of HSCs (R-HSA-8939236)
  Myogenesis (R-HSA-525793)

Molecular Interaction Atlas (MIA) of This DOT

2 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Autosomal agammaglobulinemia	DISRW8BT	Definitive	Semidominant	[1]
Agammaglobulinemia 8, autosomal dominant	DISGS5A3	Strong	Autosomal dominant	[2]

This DOT Affected the Drug Response of 2 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Doxorubicin	DMVP5YE	Approved	Transcription factor E2-alpha (TCF3) decreases the response to substance of Doxorubicin.	[20]
Topotecan	DMP6G8T	Approved	Transcription factor E2-alpha (TCF3) affects the response to substance of Topotecan.	[21]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the methylation of Transcription factor E2-alpha (TCF3).	[3]
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of Transcription factor E2-alpha (TCF3).	[7]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Transcription factor E2-alpha (TCF3).	[12]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 affects the phosphorylation of Transcription factor E2-alpha (TCF3).	[14]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Transcription factor E2-alpha (TCF3).	[15]
Coumarin	DM0N8ZM	Investigative	Coumarin decreases the phosphorylation of Transcription factor E2-alpha (TCF3).	[14]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Transcription factor E2-alpha (TCF3).	[4]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Transcription factor E2-alpha (TCF3).	[5]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Transcription factor E2-alpha (TCF3).	[6]
Vorinostat	DMWMPD4	Approved	Vorinostat decreases the expression of Transcription factor E2-alpha (TCF3).	[8]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of Transcription factor E2-alpha (TCF3).	[9]
Fluorouracil	DMUM7HZ	Approved	Fluorouracil affects the expression of Transcription factor E2-alpha (TCF3).	[10]
Diclofenac	DMPIHLS	Approved	Diclofenac affects the expression of Transcription factor E2-alpha (TCF3).	[9]
Piroxicam	DMTK234	Approved	Piroxicam decreases the expression of Transcription factor E2-alpha (TCF3).	[11]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Transcription factor E2-alpha (TCF3).	[13]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of Transcription factor E2-alpha (TCF3).	[16]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of Transcription factor E2-alpha (TCF3).	[17]
4-hydroxy-2-nonenal	DM2LJFZ	Investigative	4-hydroxy-2-nonenal decreases the expression of Transcription factor E2-alpha (TCF3).	[18]
Rutin	DMEHRAJ	Investigative	Rutin decreases the expression of Transcription factor E2-alpha (TCF3).	[19]

References

• [1] Technical standards for the interpretation and reporting of constitutional copy-number variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics (ACMG) and the Clinical Genome Resource (ClinGen). Genet Med. 2020 Feb;22(2):245-257. doi: 10.1038/s41436-019-0686-8. Epub 2019 Nov 6.
• [2] Agammaglobulinemia associated with BCR? B cells and enhanced expression of CD19. Blood. 2011 Aug 18;118(7):1828-37. doi: 10.1182/blood-2011-01-330472. Epub 2011 Jun 21.
• [3] Nuclear and Mitochondrial DNA Methylation Patterns Induced by Valproic Acid in Human Hepatocytes. Chem Res Toxicol. 2017 Oct 16;30(10):1847-1854. doi: 10.1021/acs.chemrestox.7b00171. Epub 2017 Sep 13.
• [4] 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.
• [5] 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.
• [6] Predictive toxicology using systemic biology and liver microfluidic "on chip" approaches: application to acetaminophen injury. Toxicol Appl Pharmacol. 2012 Mar 15;259(3):270-80.
• [7] 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.
• [8] 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.
• [9] Drug-induced endoplasmic reticulum and oxidative stress responses independently sensitize toward TNF-mediated hepatotoxicity. Toxicol Sci. 2014 Jul;140(1):144-59. doi: 10.1093/toxsci/kfu072. Epub 2014 Apr 20.
• [10] New insights into the mechanisms underlying 5-fluorouracil-induced intestinal toxicity based on transcriptomic and metabolomic responses in human intestinal organoids. Arch Toxicol. 2021 Aug;95(8):2691-2718. doi: 10.1007/s00204-021-03092-2. Epub 2021 Jun 20.
• [11] Apoptosis induced by piroxicam plus cisplatin combined treatment is triggered by p21 in mesothelioma. PLoS One. 2011;6(8):e23569.
• [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] Bromodomain-containing protein 4 (BRD4) regulates RNA polymerase II serine 2 phosphorylation in human CD4+ T cells. J Biol Chem. 2012 Dec 14;287(51):43137-55.
• [14] 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.
• [15] 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.
• [16] 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.
• [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] Microarray analysis of H2O2-, HNE-, or tBH-treated ARPE-19 cells. Free Radic Biol Med. 2002 Nov 15;33(10):1419-32.
• [19] Epicatechin and a cocoa polyphenolic extract modulate gene expression in human Caco-2 cells. J Nutr. 2004 Oct;134(10):2509-16.
• [20] Comparative promoter analysis of doxorubicin resistance-associated genes suggests E47 as a key regulatory element. Anticancer Res. 2006 Jul-Aug;26(4B):2971-6.
• [21] Gene expression profiling of 30 cancer cell lines predicts resistance towards 11 anticancer drugs at clinically achieved concentrations. Int J Cancer. 2006 Apr 1;118(7):1699-712. doi: 10.1002/ijc.21570.