Details of Drug Off-Target (DOT)

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

DOT Name	T-box transcription factor TBX1 (TBX1)
Synonyms	T-box protein 1; Testis-specific T-box protein
Gene Name	TBX1
Related Disease	Acute undifferentiated leukemia ( ) Conotruncal heart malformations ( ) DiGeorge syndrome ( ) Lung neoplasm ( ) Schizophrenia ( ) Advanced cancer ( ) Anemia ( ) Autism spectrum disorder ( ) Carcinoma ( ) Chromosomal disorder ( ) Cleft palate ( ) Colorectal carcinoma ( ) Congenital heart disease ( ) Diabetic kidney disease ( ) High blood pressure ( ) Isolated cleft palate ( ) Lung carcinoma ( ) Mental disorder ( ) Metastatic malignant neoplasm ( ) Neural tube defect ( ) Obesity ( ) Otitis media ( ) Persistent truncus arteriosus ( ) Polycystic ovarian syndrome ( ) Psychotic disorder ( ) Transposition of the great arteries ( ) Trichohepatoenteric syndrome ( ) Triple negative breast cancer ( ) Velocardiofacial syndrome ( ) Ventricular septal defect ( ) Asthma ( ) Lung cancer ( ) Severe combined immunodeficiency ( ) 22q11.2 deletion syndrome ( ) Hypoparathyroidism ( ) Intellectual disability ( ) Breast cancer ( ) Breast carcinoma ( ) Essential hypertension ( ) Non-small-cell lung cancer ( ) Pervasive developmental disorder ( ) Prostate carcinoma ( )
UniProt ID	TBX1_HUMAN
3D Structure	Download 2D Sequence (FASTA) Download 3D Structure (PDB) Download
PDB ID	4A04
Pfam ID	PF00907
Sequence	MHFSTVTRDMEAFTASSLSSLGAAGGFPGAASPGADPYGPREPPPPPPRYDPCAAAAPGA PGPPPPPHAYPFAPAAGAATSAAAEPEGPGASCAAAAKAPVKKNAKVAGVSVQLEMKALW DEFNQLGTEMIVTKAGRRMFPTFQVKLFGMDPMADYMLLMDFVPVDDKRYRYAFHSSSWL VAGKADPATPGRVHYHPDSPAKGAQWMKQIVSFDKLKLTNNLLDDNGHIILNSMHRYQPR FHVVYVDPRKDSEKYAEENFKTFVFEETRFTAVTAYQNHRITQLKIASNPFAKGFRDCDP EDWPRNHRPGALPLMSAFARSRNPVASPTQPSGTEKGGHVLKDKEVKAETSRNTPEREVE LLRDAGGCVNLGLPCPAECQPFNTQGLVAGRTAGDRLC
Function	Transcription factor that plays a key role in cardiovascular development by promoting pharyngeal arch segmentation during embryonic development. Also involved in craniofacial muscle development. Together with NKX2-5, acts as a regulator of asymmetric cardiac morphogenesis by promoting expression of PITX2. Acts upstream of TBX1 for the formation of the thymus and parathyroid glands from the third pharyngeal pouch. Required for hair follicle stem cell self-renewal. Binds to the palindromic T site 5'-TTCACACCTAGGTGTGAA-3' DNA sequence.
Reactome Pathway	Cardiogenesis (R-HSA-9733709 )

Molecular Interaction Atlas (MIA) of This DOT

42 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance
Acute undifferentiated leukemia	DISJ4SSG	Definitive	Biomarker	[1]
Conotruncal heart malformations	DIS7FMIG	Definitive	Autosomal dominant	[2]
DiGeorge syndrome	DIST1RKO	Definitive	Autosomal dominant	[3]
Lung neoplasm	DISVARNB	Definitive	Altered Expression	[4]
Schizophrenia	DISSRV2N	Definitive	Biomarker	[5]
Advanced cancer	DISAT1Z9	Strong	Biomarker	[6]
Anemia	DISTVL0C	Strong	Biomarker	[7]
Autism spectrum disorder	DISXK8NV	Strong	Biomarker	[8]
Carcinoma	DISH9F1N	Strong	Biomarker	[9]
Chromosomal disorder	DISM5BB5	Strong	Biomarker	[10]
Cleft palate	DIS6G5TF	Strong	Biomarker	[11]
Colorectal carcinoma	DIS5PYL0	Strong	Biomarker	[12]
Congenital heart disease	DISQBA23	Strong	Biomarker	[13]
Diabetic kidney disease	DISJMWEY	Strong	Biomarker	[14]
High blood pressure	DISY2OHH	Strong	Biomarker	[15]
Isolated cleft palate	DISV80CD	Strong	Biomarker	[11]
Lung carcinoma	DISTR26C	Strong	Genetic Variation	[16]
Mental disorder	DIS3J5R8	Strong	Genetic Variation	[8]
Metastatic malignant neoplasm	DIS86UK6	Strong	Biomarker	[17]
Neural tube defect	DIS5J95E	Strong	Biomarker	[18]
Obesity	DIS47Y1K	Strong	Genetic Variation	[19]
Otitis media	DISGZDUO	Strong	Biomarker	[20]
Persistent truncus arteriosus	DISRZ8EA	Strong	Biomarker	[21]
Polycystic ovarian syndrome	DISZ2BNG	Strong	Biomarker	[22]
Psychotic disorder	DIS4UQOT	Strong	Biomarker	[23]
Transposition of the great arteries	DISPXJ8X	Strong	Biomarker	[24]
Trichohepatoenteric syndrome	DISL3ODF	Strong	Biomarker	[25]
Triple negative breast cancer	DISAMG6N	Strong	Altered Expression	[17]
Velocardiofacial syndrome	DISOSBTY	Strong	Autosomal dominant	[2]
Ventricular septal defect	DISICO41	Strong	Genetic Variation	[26]
Asthma	DISW9QNS	moderate	Biomarker	[27]
Lung cancer	DISCM4YA	moderate	Genetic Variation	[16]
Severe combined immunodeficiency	DIS6MF4Q	moderate	Biomarker	[28]
22q11.2 deletion syndrome	DISMOPYM	Supportive	Autosomal dominant	[3]
Hypoparathyroidism	DISICS0V	Disputed	Genetic Variation	[29]
Intellectual disability	DISMBNXP	Disputed	Biomarker	[30]
Breast cancer	DIS7DPX1	Limited	Biomarker	[31]
Breast carcinoma	DIS2UE88	Limited	Biomarker	[31]
Essential hypertension	DIS7WI98	Limited	Genetic Variation	[32]
Non-small-cell lung cancer	DIS5Y6R9	Limited	Altered Expression	[33]
Pervasive developmental disorder	DIS51975	Limited	Genetic Variation	[34]
Prostate carcinoma	DISMJPLE	Limited	Genetic Variation	[35]
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⏷ Show the Full List of 42 Disease(s)

Molecular Interaction Atlas (MIA)

MIA Detail

Jump to Detail Molecular Interaction Atlas of This DOT

3 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 T-box transcription factor TBX1 (TBX1).	[36]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the methylation of T-box transcription factor TBX1 (TBX1).	[40]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of T-box transcription factor TBX1 (TBX1).	[41]
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4 Drug(s) Affected the Gene/Protein Processing of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of T-box transcription factor TBX1 (TBX1).	[37]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of T-box transcription factor TBX1 (TBX1).	[38]
Testosterone enanthate	DMB6871	Approved	Testosterone enanthate affects the expression of T-box transcription factor TBX1 (TBX1).	[39]
Sulforaphane	DMQY3L0	Investigative	Sulforaphane decreases the expression of T-box transcription factor TBX1 (TBX1).	[42]
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References

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3	Role of TBX1 in human del22q11.2 syndrome. Lancet. 2003 Oct 25;362(9393):1366-73. doi: 10.1016/s0140-6736(03)14632-6.
4	T-box transcription factor Brachyury in lung cancer cells inhibits macrophage infiltration by suppressing CCL2 and CCL4 chemokines.Tumour Biol. 2015 Aug;36(8):5881-90. doi: 10.1007/s13277-015-3260-2. Epub 2015 Mar 6.
5	Cortical Development Requires Mesodermal Expression of Tbx1, a Gene Haploinsufficient in 22q11.2 Deletion Syndrome.Cereb Cortex. 2017 Mar 1;27(3):2210-2225. doi: 10.1093/cercor/bhw076.
6	Deep gene selection method to select genes from microarray datasets for cancer classification.BMC Bioinformatics. 2019 Nov 27;20(1):608. doi: 10.1186/s12859-019-3161-2.
7	Anemia and hematinic deficiencies in anti-gastric parietal cell antibody-positive and -negative recurrent aphthous stomatitis patients with anti-thyroid antibody positivity.J Formos Med Assoc. 2017 Mar;116(3):145-152. doi: 10.1016/j.jfma.2016.10.008. Epub 2016 Nov 5.
8	Association between autism spectrum disorder in individuals with velocardiofacial (22q11.2 deletion) syndrome and PRODH and COMT genotypes.Psychiatr Genet. 2014 Dec;24(6):269-72. doi: 10.1097/YPG.0000000000000062.
9	Loss of the Cyclin-Dependent Kinase Inhibitor 1 in the Context of Brachyury-Mediated Phenotypic Plasticity Drives Tumor Resistance to Immune Attack.Front Oncol. 2018 May 3;8:143. doi: 10.3389/fonc.2018.00143. eCollection 2018.
10	De novo copy number variants are associated with congenital diaphragmatic hernia. J Med Genet. 2012 Oct;49(10):650-9. doi: 10.1136/jmedgenet-2012-101135.
11	Deletion of the T-box transcription factor gene, Tbx1, in mice induces differential expression of genes associated with cleft palate in humans.Arch Oral Biol. 2018 Nov;95:149-155. doi: 10.1016/j.archoralbio.2018.08.001. Epub 2018 Aug 9.
12	BRACHYURY confers cancer stem cell characteristics on colorectal cancer cells.Int J Cancer. 2012 Jan 15;130(2):328-37. doi: 10.1002/ijc.26029. Epub 2011 May 28.
13	Dysregulation of TBX1 dosage in the anterior heart field results in congenital heart disease resembling the 22q11.2 duplication syndrome.Hum Mol Genet. 2018 Jun 1;27(11):1847-1857. doi: 10.1093/hmg/ddy078.
14	A Novel Type 2 Diabetes Mouse Model of Combined Diabetic Kidney Disease and Atherosclerosis.Am J Pathol. 2018 Feb;188(2):343-352. doi: 10.1016/j.ajpath.2017.10.012. Epub 2017 Dec 15.
15	Late-onset pulmonary arterial hypertension in repaired D-transposition of great arteries: an uncommon complication.Pulm Circ. 2017 Apr-Jun;7(2):547-550. doi: 10.1177/2045893217699228. Epub 2017 May 30.
16	Single nucleotide polymorphisms, haplotype association and tumour expression of the vascular endothelial growth factor (VEGF) gene with lung carcinoma.Gene. 2017 Apr 15;608:95-102. doi: 10.1016/j.gene.2017.01.007. Epub 2017 Jan 23.
17	Prognostic significance of expression of epithelial-mesenchymal transition driver brachyury in breast cancer and its association with subtype and characteristics.Oncol Lett. 2018 Jan;15(1):1037-1045. doi: 10.3892/ol.2017.7402. Epub 2017 Nov 14.
18	The effect of folic acid deficiency on FGF pathway via Brachyury regulation in neural tube defects.FASEB J. 2019 Apr;33(4):4688-4702. doi: 10.1096/fj.201801536R. Epub 2018 Dec 28.
19	Resting Energy Expenditure, Insulin Resistance and UCP1 Expression in Human Subcutaneous and Visceral Adipose Tissue of Patients With Obesity.Front Endocrinol (Lausanne). 2019 Aug 7;10:548. doi: 10.3389/fendo.2019.00548. eCollection 2019.
20	Full spectrum of malformations in velo-cardio-facial syndrome/DiGeorge syndrome mouse models by altering Tbx1 dosage.Hum Mol Genet. 2004 Aug 1;13(15):1577-85. doi: 10.1093/hmg/ddh176. Epub 2004 Jun 9.
21	Inositol 1,4,5-trisphosphate receptor 2 as a novel marker of vasculature to delineate processes of cardiopulmonary development.Dev Biol. 2020 Feb 15;458(2):237-245. doi: 10.1016/j.ydbio.2019.11.011. Epub 2019 Nov 20.
22	Progesterone resistance in PCOS endometrium: a microarray analysis in clomiphene citrate-treated and artificial menstrual cycles.J Clin Endocrinol Metab. 2011 Jun;96(6):1737-46. doi: 10.1210/jc.2010-2600. Epub 2011 Mar 16.
23	Mapping cortical morphology in youth with velocardiofacial (22q11.2 deletion) syndrome.J Am Acad Child Adolesc Psychiatry. 2011 Mar;50(3):272-282.e2. doi: 10.1016/j.jaac.2010.12.002. Epub 2011 Jan 14.
24	Adult Congenital Heart Disease with Pregnancy.Korean Circ J. 2018 Apr;48(4):251-276. doi: 10.4070/kcj.2018.0070.
25	Detecting 22q11.2 deletion in Chinese children with conotruncal heart defects and single nucleotide polymorphisms in the haploid TBX1 locus.BMC Med Genet. 2011 Dec 21;12:169. doi: 10.1186/1471-2350-12-169.
26	TBX1 loss-of-function mutation contributes to congenital conotruncal defects.Exp Ther Med. 2018 Jan;15(1):447-453. doi: 10.3892/etm.2017.5362. Epub 2017 Oct 24.
27	Intercellular adhesion molecule-1 and childhood asthma.Hum Genet. 2005 Sep;117(5):476-84. doi: 10.1007/s00439-005-1319-7. Epub 2005 Jul 14.
28	DiGeorge syndrome phenotype in mice mutant for the T-box gene, Tbx1.Nat Genet. 2001 Mar;27(3):286-91. doi: 10.1038/85845.
29	Heterozygous Mutations in TBX1 as a Cause of Isolated Hypoparathyroidism.J Clin Endocrinol Metab. 2018 Nov 1;103(11):4023-4032. doi: 10.1210/jc.2018-01260.
30	Mutations in TBX1 genocopy the 22q11.2 deletion and duplication syndromes: a new susceptibility factor for mental retardation.Eur J Hum Genet. 2007 Jun;15(6):658-63. doi: 10.1038/sj.ejhg.5201819. Epub 2007 Mar 21.
31	Transactivation of SOX5 by Brachyury promotes breast cancer bone metastasis.Carcinogenesis. 2020 Jul 10;41(5):551-560. doi: 10.1093/carcin/bgz142.
32	Genetic association of rs1800780 (AG) polymorphism of the eNOS gene with susceptibility to essential hypertension in a Chinese Han population.Biochem Genet. 2014 Feb;52(1-2):71-8. doi: 10.1007/s10528-013-9628-3. Epub 2013 Nov 29.
33	T-boxtranscription factor brachyury promotes tumor cell invasion and metastasis in non-small cell lung cancer via upregulation of matrix metalloproteinase 12.Oncol Rep. 2016 Jul;36(1):306-14. doi: 10.3892/or.2016.4792. Epub 2016 May 9.
34	Tbx1: identification of a 22q11.2 gene as a risk factor for autism spectrum disorder in a mouse model.Hum Mol Genet. 2011 Dec 15;20(24):4775-85. doi: 10.1093/hmg/ddr404. Epub 2011 Sep 9.
35	A meta-analysis of 87,040 individuals identifies 23 new susceptibility loci for prostate cancer.Nat Genet. 2014 Oct;46(10):1103-9. doi: 10.1038/ng.3094. Epub 2014 Sep 14.
36	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.
37	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.
38	Global gene expression analysis reveals differences in cellular responses to hydroxyl- and superoxide anion radical-induced oxidative stress in caco-2 cells. Toxicol Sci. 2010 Apr;114(2):193-203. doi: 10.1093/toxsci/kfp309. Epub 2009 Dec 31.
39	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.
40	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.
41	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.
42	Transcriptome and DNA methylation changes modulated by sulforaphane induce cell cycle arrest, apoptosis, DNA damage, and suppression of proliferation in human liver cancer cells. Food Chem Toxicol. 2020 Feb;136:111047. doi: 10.1016/j.fct.2019.111047. Epub 2019 Dec 12.