Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT3RX4QF)

• DOT Name: Left-right determination factor 2 (LEFTY2)
• Synonyms: Endometrial bleeding-associated factor; Left-right determination factor A; Protein lefty-2; Protein lefty-A; Transforming growth factor beta-4; TGF-beta-4
• Gene Name: LEFTY2
• Related Disease:
  Adenocarcinoma
  Endometrial cancer
  Endometrial carcinoma
  Endometriosis
  Proteus syndrome
  Ventricular septal defect
  Right atrial isomerism
  Visceral heterotaxy
  Congenital heart disease
  Neoplasm
• UniProt ID: LFTY2_HUMAN
• Pfam ID: PF00019 ; PF00688
• Sequence:
  MWPLWLCWALWVLPLAGPGAALTEEQLLGSLLRQLQLSEVPVLDRADMEKLVIPAHVRAQ
  YVVLLRRSHGDRSRGKRFSQSFREVAGRFLASEASTHLLVFGMEQRLPPNSELVQAVLRL
  FQEPVPKAALHRHGRLSPRSAQARVTVEWLRVRDDGSNRTSLIDSRLVSVHESGWKAFDV
  TEAVNFWQQLSRPRQPLLLQVSVQREHLGPLASGAHKLVRFASQGAPAGLGEPQLELHTL
  DLRDYGAQGDCDPEAPMTEGTRCCRQEMYIDLQGMKWAKNWVLEPPGFLAYECVGTCQQP
  PEALAFNWPFLGPRQCIASETASLPMIVSIKEGGRTRPQVVSLPNMRVQKCSCASDGALV
  PRRLQP
• Function: Required for left-right (L-R) asymmetry determination of organ systems in mammals. May play a role in endometrial bleeding.
• Tissue Specificity: Mesenchymal cells of the endometrial stroma.
• KEGG Pathway:
  TGF-beta sig.ling pathway (hsa04350)
  Sig.ling pathways regulating pluripotency of stem cells (hsa04550)
• Reactome Pathway:
  Signaling by NODAL (R-HSA-1181150)
  Regulation of signaling by NODAL (R-HSA-1433617)
  Platelet degranulation (R-HSA-114608)

Molecular Interaction Atlas (MIA) of This DOT

10 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Adenocarcinoma	DIS3IHTY	Strong	Altered Expression	[1]
Endometrial cancer	DISW0LMR	Strong	Altered Expression	[2]
Endometrial carcinoma	DISXR5CY	Strong	Altered Expression	[2]
Endometriosis	DISX1AG8	Strong	Biomarker	[3]
Proteus syndrome	DISJ3VXH	Strong	Biomarker	[4]
Ventricular septal defect	DISICO41	Strong	Altered Expression	[5]
Right atrial isomerism	DIS2SZ2Q	moderate	Biomarker	[6]
Visceral heterotaxy	DIS1DV90	moderate	Biomarker	[6]
Congenital heart disease	DISQBA23	Disputed	Autosomal dominant	[7]
Neoplasm	DISZKGEW	Limited	Biomarker	[2]

1 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 Left-right determination factor 2 (LEFTY2).	[8]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Left-right determination factor 2 (LEFTY2).	[9]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Left-right determination factor 2 (LEFTY2).	[10]
Triclosan	DMZUR4N	Approved	Triclosan decreases the expression of Left-right determination factor 2 (LEFTY2).	[11]
Fluorouracil	DMUM7HZ	Approved	Fluorouracil decreases the expression of Left-right determination factor 2 (LEFTY2).	[12]
Ethanol	DMDRQZU	Approved	Ethanol increases the expression of Left-right determination factor 2 (LEFTY2).	[13]
Resveratrol	DM3RWXL	Phase 3	Resveratrol decreases the expression of Left-right determination factor 2 (LEFTY2).	[14]
Genistein	DM0JETC	Phase 2/3	Genistein decreases the expression of Left-right determination factor 2 (LEFTY2).	[14]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the mutagenesis of Left-right determination factor 2 (LEFTY2).	[15]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Left-right determination factor 2 (LEFTY2).	[16]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Left-right determination factor 2 (LEFTY2).	[14]
Manganese	DMKT129	Investigative	Manganese decreases the expression of Left-right determination factor 2 (LEFTY2).	[17]

References

• [1] Distinct tumor specific expression of TGFB4 (ebaf)*, a novel human gene of the TGF-beta superfamily.Front Biosci. 1997 Jul 15;2:a18-25. doi: 10.2741/a158.
• [2] miR?15 promotes epithelial to mesenchymal transition and proliferation by regulating LEFTY2 in endometrial cancer.Int J Mol Med. 2018 Sep;42(3):1229-1236. doi: 10.3892/ijmm.2018.3703. Epub 2018 May 22.
• [3] Dysregulated expression of ebaf, a novel molecular defect in the endometria of patients with infertility.J Clin Endocrinol Metab. 2000 Jul;85(7):2526-36. doi: 10.1210/jcem.85.7.6674.
• [4] Asymmetry: molecular, biologic, embryopathic, and clinical perspectives.Am J Med Genet. 2001 Jul 15;101(4):292-314. doi: 10.1002/ajmg.1217.
• [5] Down-regulation of EBAF in the heart with ventricular septal defects and its regulation by histone acetyltransferase p300 and transcription factors smad2 and cited2.Biochim Biophys Acta. 2013 Dec;1832(12):2145-52. doi: 10.1016/j.bbadis.2013.07.013. Epub 2013 Jul 27.
• [6] Characterization and mutation analysis of human LEFTY A and LEFTY B, homologues of murine genes implicated in left-right axis development.Am J Hum Genet. 1999 Mar;64(3):712-21. doi: 10.1086/302289.
• [7] 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.
• [8] 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.
• [9] Evaluation of a human iPSC-derived BBB model for repeated dose toxicity testing with cyclosporine A as model compound. Toxicol In Vitro. 2021 Jun;73:105112. doi: 10.1016/j.tiv.2021.105112. Epub 2021 Feb 22.
• [10] RNA sequence analysis of inducible pluripotent stem cell-derived cardiomyocytes reveals altered expression of DNA damage and cell cycle genes in response to doxorubicin. Toxicol Appl Pharmacol. 2018 Oct 1;356:44-53.
• [11] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [12] Evaluation of developmental toxicity using undifferentiated human embryonic stem cells. J Appl Toxicol. 2015 Feb;35(2):205-18.
• [13] Chronic ethanol exposure increases goosecoid (GSC) expression in human embryonic carcinoma cell differentiation. J Appl Toxicol. 2014 Jan;34(1):66-75.
• [14] Gene expression profiling in Ishikawa cells: a fingerprint for estrogen active compounds. Toxicol Appl Pharmacol. 2009 Apr 1;236(1):85-96.
• [15] Exome-wide mutation profile in benzo[a]pyrene-derived post-stasis and immortal human mammary epithelial cells. Mutat Res Genet Toxicol Environ Mutagen. 2014 Dec;775-776:48-54. doi: 10.1016/j.mrgentox.2014.10.011. Epub 2014 Nov 4.
• [16] BET bromodomain inhibition of MYC-amplified medulloblastoma. Clin Cancer Res. 2014 Feb 15;20(4):912-25.
• [17] 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.