Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTPFAUM8)

• DOT Name: T-cell leukemia homeobox protein 2 (TLX2)
• Synonyms: Homeobox protein Hox-11L1; Neural crest homeobox protein
• Gene Name: TLX2
• Related Disease:
  Sinoatrial node disorder
  Adult lymphoma
  Adult T-cell leukemia/lymphoma
  Advanced cancer
  Cardiac disease
  Cardiac failure
  Central hypoventilation syndrome, congenital
  Congestive heart failure
  Herpes simplex infection
  High blood pressure
  Hyperglycemia
  Lymphoma
  Neoplasm
  Neuroblastoma
  Pediatric lymphoma
  Periodontal disease
  T-cell leukaemia
  Gastrointestinal stromal tumour
  Stroke
  Chronic intestinal pseudoobstruction
  Glaucoma/ocular hypertension
  Ocular hypertension
  Parkinson disease
• UniProt ID: TLX2_HUMAN
• PDB ID: 3A03
• Pfam ID: PF00046
• Sequence:
  MEPGMLGPHNLPHHEPISFGIDQILSGPETPGGGLGLGRGGQGHGENGAFSGGYHGASGY
  GPAGSLAPLPGSSGVGPGGVIRVPAHRPLPVPPPAGGAPAVPGPSGLGGAGGLAGLTFPW
  MDSGRRFAKDRLTAALSPFSGTRRIGHPYQNRTPPKRKKPRTSFSRSQVLELERRFLRQK
  YLASAERAALAKALRMTDAQVKTWFQNRRTKWRRQTAEEREAERHRAGRLLLHLQQDALP
  RPLRPPLPPDPLCLHNSSLFALQNLQPWAEDNKVASVSGLASVV
• Function: Transcription activator that binds DNA elements with the consensus sequence 5'-CGGTAATTGG-3'. Binds DNA via its homeobox. Required for normal cell death of enteric neurons in the gastrointestinal tract. Required for normal development of the enteric nervous system, and for proper development of normal motility of the gastrointestinal tract.

Molecular Interaction Atlas (MIA) of This DOT

23 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Sinoatrial node disorder	DISYJI6J	Definitive	Biomarker	[1]
Adult lymphoma	DISK8IZR	Strong	Biomarker	[2]
Adult T-cell leukemia/lymphoma	DIS882XU	Strong	Biomarker	[3]
Advanced cancer	DISAT1Z9	Strong	Biomarker	[4]
Cardiac disease	DISVO1I5	Strong	Biomarker	[4]
Cardiac failure	DISDC067	Strong	Biomarker	[5]
Central hypoventilation syndrome, congenital	DISQRK53	Strong	Genetic Variation	[6]
Congestive heart failure	DIS32MEA	Strong	Biomarker	[5]
Herpes simplex infection	DISL1SAV	Strong	Genetic Variation	[7]
High blood pressure	DISY2OHH	Strong	Altered Expression	[8]
Hyperglycemia	DIS0BZB5	Strong	Biomarker	[9]
Lymphoma	DISN6V4S	Strong	Biomarker	[2]
Neoplasm	DISZKGEW	Strong	Biomarker	[10]
Neuroblastoma	DISVZBI4	Strong	Genetic Variation	[7]
Pediatric lymphoma	DIS51BK2	Strong	Biomarker	[2]
Periodontal disease	DISJQHVN	Strong	Biomarker	[11]
T-cell leukaemia	DISJ6YIF	Strong	Biomarker	[3]
Gastrointestinal stromal tumour	DIS6TJYS	moderate	Genetic Variation	[12]
Stroke	DISX6UHX	moderate	Biomarker	[13]
Chronic intestinal pseudoobstruction	DISR68AN	Limited	Biomarker	[14]
Glaucoma/ocular hypertension	DISLBXBY	Limited	Biomarker	[15]
Ocular hypertension	DISC2BT9	Limited	Biomarker	[15]
Parkinson disease	DISQVHKL	Limited	Biomarker	[16]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the expression of T-cell leukemia homeobox protein 2 (TLX2).	[17]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of T-cell leukemia homeobox protein 2 (TLX2).	[18]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of T-cell leukemia homeobox protein 2 (TLX2).	[19]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of T-cell leukemia homeobox protein 2 (TLX2).	[20]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of T-cell leukemia homeobox protein 2 (TLX2).	[19]
Acetaldehyde	DMJFKG4	Investigative	Acetaldehyde increases the expression of T-cell leukemia homeobox protein 2 (TLX2).	[22]

1 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-cell leukemia homeobox protein 2 (TLX2).	[21]

References

• [1] Heterogeneity of transverse-axial tubule system in mouse atria: Remodeling in atrial-specific Na(+)-Ca(2+) exchanger knockout mice.J Mol Cell Cardiol. 2017 Jul;108:50-60. doi: 10.1016/j.yjmcc.2017.05.008. Epub 2017 May 19.
• [2] Pro-death and pro-survival properties of ouabain in U937 lymphoma derived cells.J Exp Clin Cancer Res. 2012 Nov 15;31(1):95. doi: 10.1186/1756-9966-31-95.
• [3] Genetic mapping of two mouse homeobox genes Tlx-1 and Tlx-2 to murine chromosomes 19 and 6.Genomics. 1994 Nov 15;24(2):388-90. doi: 10.1006/geno.1994.1634.
• [4] Na(+)/Ca(2+) exchangers: Unexploited opportunities for cancer therapy?.Biochem Pharmacol. 2019 May;163:357-361. doi: 10.1016/j.bcp.2019.02.032. Epub 2019 Feb 28.
• [5] Sensitivity analysis revealing the effect of modulating ionic mechanisms on calcium dynamics in simulated human heart failure.PLoS One. 2017 Nov 8;12(11):e0187739. doi: 10.1371/journal.pone.0187739. eCollection 2017.
• [6] The TLX2 homeobox gene is a transcriptional target of PHOX2B in neural-crest-derived cells.Biochem J. 2006 Apr 15;395(2):355-61. doi: 10.1042/BJ20051386.
• [7] Tissue-specific expression of a suicide gene for selective killing of neuroblastoma cells using a promoter region of the NCX gene.Cancer Gene Ther. 2001 Dec;8(12):997-1002. doi: 10.1038/sj.cgt.7700408.
• [8] Influence of Long-Term Salt Diets on Cardiac Ca2+ Handling and Contractility Proteins in Hypertensive Rats.Am J Hypertens. 2018 May 7;31(6):726-734. doi: 10.1093/ajh/hpy023.
• [9] Hyperglycemia Enhances Constriction of Retinal Venules via Activation of the Reverse-Mode Sodium-Calcium Exchanger.Diabetes. 2019 Aug;68(8):1624-1634. doi: 10.2337/db19-0069. Epub 2019 May 14.
• [10] NCX-4040, a nitric oxide-releasing aspirin, sensitizes drug-resistant human ovarian xenograft tumors to cisplatin by depletion of cellular thiols.J Transl Med. 2008 Feb 26;6:9. doi: 10.1186/1479-5876-6-9.
• [11] Effect of nitric oxide-releasing derivative of indomethacin on Prevotella intermedia lipopolysaccharide-induced production of proinflammatory mediators in murine macrophages.Biochem Biophys Res Commun. 2017 Oct 14;492(2):224-230. doi: 10.1016/j.bbrc.2017.08.055. Epub 2017 Aug 16.
• [12] Allelic loss of Hox11L1 gene locus predicts outcome of gastrointestinal stromal tumors.Oncol Rep. 2006 Oct;16(4):915-9.
• [13] Does Na?Ca?exchanger, NCX, represent a new druggable target in stroke intervention?.Transl Stroke Res. 2014 Feb;5(1):145-55. doi: 10.1007/s12975-013-0308-8. Epub 2013 Nov 19.
• [14] Evaluation of Hox11L1 in the fmc/fmc rat model of chronic intestinal pseudo-obstruction.J Pediatr Surg. 2005 Nov;40(11):1760-5. doi: 10.1016/j.jpedsurg.2005.07.010.
• [15] Prostaglandin analogues and nitric oxide contribution in the treatment of ocular hypertension and glaucoma.Br J Pharmacol. 2019 Apr;176(8):1079-1089. doi: 10.1111/bph.14328. Epub 2018 May 24.
• [16] The role of the mitochondrial NCX in the mechanism of neurodegeneration in Parkinson's disease.Adv Exp Med Biol. 2013;961:241-9. doi: 10.1007/978-1-4614-4756-6_20.
• [17] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [18] Phenotypic characterization of retinoic acid differentiated SH-SY5Y cells by transcriptional profiling. PLoS One. 2013 May 28;8(5):e63862.
• [19] Bisphenol-A and estradiol exert novel gene regulation in human MCF-7 derived breast cancer cells. Mol Cell Endocrinol. 2004 Jun 30;221(1-2):47-55. doi: 10.1016/j.mce.2004.04.010.
• [20] Gene Expression Regulation and Pathway Analysis After Valproic Acid and Carbamazepine Exposure in a Human Embryonic Stem Cell-Based Neurodevelopmental Toxicity Assay. Toxicol Sci. 2015 Aug;146(2):311-20. doi: 10.1093/toxsci/kfv094. Epub 2015 May 15.
• [21] 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.
• [22] Transcriptome profile analysis of saturated aliphatic aldehydes reveals carbon number-specific molecules involved in pulmonary toxicity. Chem Res Toxicol. 2014 Aug 18;27(8):1362-70.