Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT3BEBLN)

• DOT Name: T-box transcription factor TBX18 (TBX18)
• Synonyms: T-box protein 18
• Gene Name: TBX18
• Related Disease:
  Bone osteosarcoma
  Congenital anomalies of kidney and urinary tract 2
  Neoplasm
  Nephropathy
  Osteosarcoma
  Sick sinus syndrome
  Ventricular septal defect
  Ventricular fibrillation
• UniProt ID: TBX18_HUMAN
• Pfam ID: PF00907
• Sequence:
  MAEKRRGSPCSMLSLKAHAFSVEALIGAEKQQQLQKKRRKLGAEEAAGAVDDGGCSRGGG
  AGEKGSSEGDEGAALPPPAGATSGPARSGADLERGAAGGCEDGFQQGASPLASPGGSPKG
  SPARSLARPGTPLPSPQAPRVDLQGAELWKRFHEIGTEMIITKAGRRMFPAMRVKISGLD
  PHQQYYIAMDIVPVDNKRYRYVYHSSKWMVAGNADSPVPPRVYIHPDSPASGETWMRQVI
  SFDKLKLTNNELDDQGHIILHSMHKYQPRVHVIRKDCGDDLSPIKPVPSGEGVKAFSFPE
  TVFTTVTAYQNQQITRLKIDRNPFAKGFRDSGRNRMGLEALVESYAFWRPSLRTLTFEDI
  PGIPKQGNASSSTLLQGTGNGVPATHPHLLSGSSCSSPAFHLGPNTSQLCSLAPADYSAC
  ARSGLTLNRYSTSLAETYNRLTNQAGETFAPPRTPSYVGVSSSTSVNMSMGGTDGDTFSC
  PQTSLSMQISGMSPQLQYIMPSPSSNAFATNQTHQGSYNTFRLHSPCALYGYNFSTSPKL
  AASPEKIVSSQGSFLGSSPSGTMTDRQMLPPVEGVHLLSSGGQQSFFDSRTLGSLTLSSS
  QVSAHMV
• Function: Acts as a transcriptional repressor involved in developmental processes of a variety of tissues and organs, including the heart and coronary vessels, the ureter and the vertebral column. Required for embryonic development of the sino atrial node (SAN) head area.

Molecular Interaction Atlas (MIA) of This DOT

8 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Bone osteosarcoma	DIST1004	Strong	Biomarker	[1]
Congenital anomalies of kidney and urinary tract 2	DISF9QYE	Strong	Autosomal dominant	[2]
Neoplasm	DISZKGEW	Strong	Biomarker	[3]
Nephropathy	DISXWP4P	Strong	Altered Expression	[4]
Osteosarcoma	DISLQ7E2	Strong	Biomarker	[1]
Sick sinus syndrome	DIS5AOLK	Strong	Biomarker	[5]
Ventricular septal defect	DISICO41	Strong	Genetic Variation	[6]
Ventricular fibrillation	DIS7IN76	moderate	Biomarker	[7]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of T-box transcription factor TBX18 (TBX18).	[8]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of T-box transcription factor TBX18 (TBX18).	[9]
Temozolomide	DMKECZD	Approved	Temozolomide decreases the expression of T-box transcription factor TBX18 (TBX18).	[10]
methyl p-hydroxybenzoate	DMO58UW	Investigative	methyl p-hydroxybenzoate decreases the expression of T-box transcription factor TBX18 (TBX18).	[13]
Manganese	DMKT129	Investigative	Manganese increases the expression of T-box transcription factor TBX18 (TBX18).	[14]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of T-box transcription factor TBX18 (TBX18).	[11]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A affects the methylation of T-box transcription factor TBX18 (TBX18).	[12]

References

• [1] Allelic imbalance at intragenic markers of Tbx18 is a hallmark of murine osteosarcoma.Carcinogenesis. 2003 Mar;24(3):371-6. doi: 10.1093/carcin/24.3.371.
• [2] Mutations in TBX18 Cause Dominant Urinary Tract Malformations via Transcriptional Dysregulation of Ureter Development. Am J Hum Genet. 2015 Aug 6;97(2):291-301. doi: 10.1016/j.ajhg.2015.07.001. Epub 2015 Jul 30.
• [3] HOXB13, a target of DNMT3B, is methylated at an upstream CpG island, and functions as a tumor suppressor in primary colorectal tumors.PLoS One. 2010 Apr 29;5(4):e10338. doi: 10.1371/journal.pone.0010338.
• [4] Proteomic analysis identifies transcriptional cofactors and homeobox transcription factors as TBX18 binding proteins.PLoS One. 2018 Aug 2;13(8):e0200964. doi: 10.1371/journal.pone.0200964. eCollection 2018.
• [5] TBX18 overexpression enhances pacemaker function in a rat subsidiary atrial pacemaker model of sick sinus syndrome.J Physiol. 2018 Dec;596(24):6141-6155. doi: 10.1113/JP276508. Epub 2018 Oct 13.
• [6] Novel and functional variants within the TBX18 gene promoter in ventricular septal defects.Mol Cell Biochem. 2013 Oct;382(1-2):121-6. doi: 10.1007/s11010-013-1725-4. Epub 2013 Jun 8.
• [7] Functional biological pacemaker generation by T-Box18 protein expression via stem cell and viral delivery approaches in a murine model of complete heart block.Pharmacol Res. 2019 Mar;141:443-450. doi: 10.1016/j.phrs.2019.01.034. Epub 2019 Jan 21.
• [8] 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.
• [9] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [10] Temozolomide induces activation of Wnt/-catenin signaling in glioma cells via PI3K/Akt pathway: implications in glioma therapy. Cell Biol Toxicol. 2020 Jun;36(3):273-278. doi: 10.1007/s10565-019-09502-7. Epub 2019 Nov 22.
• [11] 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.
• [12] 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.
• [13] Transcriptome dynamics of alternative splicing events revealed early phase of apoptosis induced by methylparaben in H1299 human lung carcinoma cells. Arch Toxicol. 2020 Jan;94(1):127-140. doi: 10.1007/s00204-019-02629-w. Epub 2019 Nov 20.
• [14] Gene expression profiling of human primary astrocytes exposed to manganese chloride indicates selective effects on several functions of the cells. Neurotoxicology. 2007 May;28(3):478-89.