Details of Drug Off-Target (DOT)

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

• DOT Name: Insulin gene enhancer protein ISL-1 (ISL1)
• Synonyms: Islet-1
• Gene Name: ISL1
• Related Disease:
  Ventricular septal defect
  Adult lymphoma
  Anemia
  Arrhythmogenic right ventricular cardiomyopathy
  B-cell lymphoma
  Breast cancer
  Breast carcinoma
  Carcinoid tumor
  Classic Hodgkin lymphoma
  Congenital heart disease
  Dilated cardiomyopathy
  Dilated cardiomyopathy 1A
  Emery-Dreifuss muscular dystrophy
  Gastric cancer
  Lung neoplasm
  Lymphoma
  Lymphoma, non-Hodgkin, familial
  Maturity-onset diabetes of the young
  Myocardial infarction
  Neoplasm
  Non-hodgkin lymphoma
  Non-insulin dependent diabetes
  Pancreatic neuroendocrine tumor
  Pediatric lymphoma
  Persistent truncus arteriosus
  Pheochromocytoma
  Rheumatoid arthritis
  Schizophrenia
  Stomach cancer
  Advanced cancer
  Neuroblastoma
  Neuroendocrine cancer
  Type-1/2 diabetes
  Atrial septal defect
  Digestive system neoplasm
  Gastric adenocarcinoma
  Metastatic malignant neoplasm
  Triple negative breast cancer
  Urinary bladder cancer
  Urinary bladder neoplasm
• UniProt ID: ISL1_HUMAN
• Pfam ID: PF00046 ; PF00412
• Sequence:
  MGDMGDPPKKKRLISLCVGCGNQIHDQYILRVSPDLEWHAACLKCAECNQYLDESCTCFV
  RDGKTYCKRDYIRLYGIKCAKCSIGFSKNDFVMRARSKVYHIECFRCVACSRQLIPGDEF
  ALREDGLFCRADHDVVERASLGAGDPLSPLHPARPLQMAAEPISARQPALRPHVHKQPEK
  TTRVRTVLNEKQLHTLRTCYAANPRPDALMKEQLVEMTGLSPRVIRVWFQNKRCKDKKRS
  IMMKQLQQQQPNDKTNIQGMTGTPMVAASPERHDGGLQANPVEVQSYQPPWKVLSDFALQ
  SDIDQPAFQQLVNFSEGGPGSNSTGSEVASMSSQLPDTPNSMVASPIEA
• Function: DNA-binding transcriptional activator. Recognizes and binds to the consensus octamer binding site 5'-ATAATTAA-3' in promoter of target genes. Plays a fundamental role in the gene regulatory network essential for retinal ganglion cell (RGC) differentiation. Cooperates with the transcription factor POU4F2 to achieve maximal levels of expression of RGC target genes and RGC fate specification in the developing retina. Involved in the specification of motor neurons in cooperation with LHX3 and LDB1. Binds to insulin gene enhancer sequences. Essential for heart development. Marker of one progenitor cell population that give rise to the outflow tract, right ventricle, a subset of left ventricular cells, and a large number of atrial cells as well, its function is required for these progenitors to contribute to the heart. Controls the expression of FGF and BMP growth factors in this cell population and is required for proliferation and survival of cells within pharyngeal foregut endoderm and adjacent splanchnic mesoderm as well as for migration of cardiac progenitors into the heart.
• Tissue Specificity: Expressed in subsets of neurons of the adrenal medulla and dorsal root ganglion, inner nuclear and ganglion cell layers in the retina, the pineal and some regions of the brain.
• KEGG Pathway: Sig.ling pathways regulating pluripotency of stem cells (hsa04550)
• Reactome Pathway:
  Regulation of expression of SLITs and ROBOs (R-HSA-9010553)
  Cardiogenesis (R-HSA-9733709)
  Synthesis, secretion, and inactivation of Glucose-dependent Insulinotropic Polypeptide (GIP) (R-HSA-400511)

Molecular Interaction Atlas (MIA) of This DOT

40 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Ventricular septal defect	DISICO41	Definitive	Genetic Variation	[1]
Adult lymphoma	DISK8IZR	Strong	Altered Expression	[2]
Anemia	DISTVL0C	Strong	Altered Expression	[3]
Arrhythmogenic right ventricular cardiomyopathy	DIS3V2BE	Strong	Genetic Variation	[4]
B-cell lymphoma	DISIH1YQ	Strong	Biomarker	[5]
Breast cancer	DIS7DPX1	Strong	Biomarker	[6]
Breast carcinoma	DIS2UE88	Strong	Biomarker	[6]
Carcinoid tumor	DISMNRDC	Strong	Altered Expression	[7]
Classic Hodgkin lymphoma	DISV1LU6	Strong	Altered Expression	[2]
Congenital heart disease	DISQBA23	Strong	Biomarker	[8]
Dilated cardiomyopathy	DISX608J	Strong	Genetic Variation	[9]
Dilated cardiomyopathy 1A	DIS0RK9Z	Strong	Biomarker	[9]
Emery-Dreifuss muscular dystrophy	DISYTPR5	Strong	Genetic Variation	[4]
Gastric cancer	DISXGOUK	Strong	Biomarker	[10]
Lung neoplasm	DISVARNB	Strong	Biomarker	[6]
Lymphoma	DISN6V4S	Strong	Altered Expression	[2]
Lymphoma, non-Hodgkin, familial	DISCXYIZ	Strong	Altered Expression	[2]
Maturity-onset diabetes of the young	DISG75M5	Strong	Genetic Variation	[11]
Myocardial infarction	DIS655KI	Strong	Biomarker	[12]
Neoplasm	DISZKGEW	Strong	Biomarker	[13]
Non-hodgkin lymphoma	DISS2Y8A	Strong	Altered Expression	[2]
Non-insulin dependent diabetes	DISK1O5Z	Strong	Altered Expression	[14]
Pancreatic neuroendocrine tumor	DISDMPU0	Strong	Biomarker	[7]
Pediatric lymphoma	DIS51BK2	Strong	Altered Expression	[2]
Persistent truncus arteriosus	DISRZ8EA	Strong	Genetic Variation	[15]
Pheochromocytoma	DIS56IFV	Strong	Biomarker	[6]
Rheumatoid arthritis	DISTSB4J	Strong	Altered Expression	[16]
Schizophrenia	DISSRV2N	Strong	Biomarker	[17]
Stomach cancer	DISKIJSX	Strong	Biomarker	[10]
Advanced cancer	DISAT1Z9	moderate	Altered Expression	[18]
Neuroblastoma	DISVZBI4	moderate	Biomarker	[19]
Neuroendocrine cancer	DISVGJET	moderate	Biomarker	[20]
Type-1/2 diabetes	DISIUHAP	moderate	Genetic Variation	[21]
Atrial septal defect	DISJT76B	Limited	Biomarker	[22]
Digestive system neoplasm	DISPOJCT	Limited	Altered Expression	[23]
Gastric adenocarcinoma	DISWWLTC	Limited	Biomarker	[23]
Metastatic malignant neoplasm	DIS86UK6	Limited	Biomarker	[24]
Triple negative breast cancer	DISAMG6N	Limited	Altered Expression	[18]
Urinary bladder cancer	DISDV4T7	Limited	Biomarker	[25]
Urinary bladder neoplasm	DIS7HACE	Limited	Biomarker	[25]

12 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 Insulin gene enhancer protein ISL-1 (ISL1).	[26]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Insulin gene enhancer protein ISL-1 (ISL1).	[27]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Insulin gene enhancer protein ISL-1 (ISL1).	[28]
Vorinostat	DMWMPD4	Approved	Vorinostat increases the expression of Insulin gene enhancer protein ISL-1 (ISL1).	[30]
Triclosan	DMZUR4N	Approved	Triclosan decreases the expression of Insulin gene enhancer protein ISL-1 (ISL1).	[31]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of Insulin gene enhancer protein ISL-1 (ISL1).	[32]
Pioglitazone	DMKJ485	Approved	Pioglitazone increases the expression of Insulin gene enhancer protein ISL-1 (ISL1).	[33]
Ribavirin	DMEYLH9	Phase 1 Trial	Ribavirin decreases the expression of Insulin gene enhancer protein ISL-1 (ISL1).	[35]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Insulin gene enhancer protein ISL-1 (ISL1).	[36]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Insulin gene enhancer protein ISL-1 (ISL1).	[38]
Nitrobenzanthrone	DMN6L70	Investigative	Nitrobenzanthrone affects the expression of Insulin gene enhancer protein ISL-1 (ISL1).	[39]
Arachidonic acid	DMUOQZD	Investigative	Arachidonic acid decreases the expression of Insulin gene enhancer protein ISL-1 (ISL1).	[40]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of Insulin gene enhancer protein ISL-1 (ISL1).	[29]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the methylation of Insulin gene enhancer protein ISL-1 (ISL1).	[34]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the methylation of Insulin gene enhancer protein ISL-1 (ISL1).	[37]

References

• [1] A New ISL1 Loss-of-Function Mutation Predisposes to Congenital Double Outlet Right Ventricle.Int Heart J. 2019 Sep 27;60(5):1113-1122. doi: 10.1536/ihj.18-685. Epub 2019 Sep 4.
• [2] ISL-1 is overexpressed in non-Hodgkin lymphoma and promotes lymphoma cell proliferation by forming a p-STAT3/p-c-Jun/ISL-1 complex.Mol Cancer. 2014 Jul 29;13:181. doi: 10.1186/1476-4598-13-181.
• [3] Screening of LHX2 in patients presenting growth retardation with posterior pituitary and ocular abnormalities.Eur J Endocrinol. 2012 Jul;167(1):85-91. doi: 10.1530/EJE-12-0026. Epub 2012 Apr 24.
• [4] A novel genetic variant in the transcription factor Islet-1 exerts gain of function on myocyte enhancer factor 2C promoter activity.Eur J Heart Fail. 2013 Mar;15(3):267-76. doi: 10.1093/eurjhf/hfs178. Epub 2012 Nov 14.
• [5] A positive feedback regulation of ISL-1 in DLBCL but not in pancreatic -cells.Biochem Biophys Res Commun. 2014 Jul 4;449(3):295-300. doi: 10.1016/j.bbrc.2014.05.021. Epub 2014 May 15.
• [6] ISL1 is upregulated in breast cancer and promotes cell proliferation, invasion, and angiogenesis.Onco Targets Ther. 2018 Feb 14;11:781-789. doi: 10.2147/OTT.S144241. eCollection 2018.
• [7] Immunohistochemical Characterization of the Origins of Metastatic Well-differentiated Neuroendocrine Tumors to the Liver.Am J Surg Pathol. 2017 Jul;41(7):915-922. doi: 10.1097/PAS.0000000000000876.
• [8] Pediatric End-Stage Failing Hearts Demonstrate Increased Cardiac Stem Cells.Ann Thorac Surg. 2015 Aug;100(2):615-22. doi: 10.1016/j.athoracsur.2015.04.088. Epub 2015 Jun 30.
• [9] Identification and Functional Characterization of an ISL1 Mutation Predisposing to Dilated Cardiomyopathy.J Cardiovasc Transl Res. 2019 Jun;12(3):257-267. doi: 10.1007/s12265-018-9851-8. Epub 2018 Dec 10.
• [10] ISL1 predicts poor outcomes for patients with gastric cancer and drives tumor progression through binding to the ZEB1 promoter together with SETD7.Cell Death Dis. 2019 Jan 15;10(2):33. doi: 10.1038/s41419-018-1278-2.
• [11] The LIM-homeodomain protein ISL1 activates insulin gene promoter directly through synergy with BETA2.J Mol Biol. 2009 Sep 25;392(3):566-77. doi: 10.1016/j.jmb.2009.07.036. Epub 2009 Jul 17.
• [12] ISL1 overexpression enhances the survival of transplanted human mesenchymal stem cells in a murine myocardial infarction model.Stem Cell Res Ther. 2018 Feb 26;9(1):51. doi: 10.1186/s13287-018-0803-7.
• [13] ISL1, a novel regulator of CCNB1, CCNB2 and c-MYC genes, promotes gastric cancer cell proliferation and tumor growth.Oncotarget. 2016 Jun 14;7(24):36489-36500. doi: 10.18632/oncotarget.9269.
• [14] MiR-128-3p accelerates cardiovascular calcification and insulin resistance through ISL1-dependent Wnt pathway in type 2 diabetes mellitus rats.J Cell Physiol. 2019 Apr;234(4):4997-5010. doi: 10.1002/jcp.27300. Epub 2018 Oct 20.
• [15] New mutations in ZFPM2/FOG2 gene in tetralogy of Fallot and double outlet right ventricle.Clin Genet. 2011 Aug;80(2):184-90. doi: 10.1111/j.1399-0004.2010.01523.x. Epub 2010 Aug 2.
• [16] FHL2 regulates the resolution of tissue damage in chronic inflammatory arthritis.Ann Rheum Dis. 2015 Dec;74(12):2216-23. doi: 10.1136/annrheumdis-2013-205061. Epub 2014 Aug 14.
• [17] PDLIM5 and susceptibility to bipolar disorder: a family-based association study and meta-analysis.Psychiatr Genet. 2008 Jun;18(3):116-21. doi: 10.1097/YPG.0b013e3282fa184b.
• [18] ISL1 promotes cancer progression and inhibits cisplatin sensitivity in triple-negative breast cancer cells.Int J Mol Med. 2018 Nov;42(5):2343-2352. doi: 10.3892/ijmm.2018.3842. Epub 2018 Aug 27.
• [19] ASCL1 is a MYCN- and LMO1-dependent member of the adrenergic neuroblastoma core regulatory circuitry.Nat Commun. 2019 Dec 9;10(1):5622. doi: 10.1038/s41467-019-13515-5.
• [20] The expression of TTF1, CDX2 and ISL1 in 74 poorly differentiated neuroendocrine carcinomas.Ann Diagn Pathol. 2018 Dec;37:30-34. doi: 10.1016/j.anndiagpath.2018.09.005. Epub 2018 Sep 13.
• [21] Nonsense mutation of islet-1 gene (Q310X) found in a type 2 diabetic patient with a strong family history.Diabetes. 2000 Sep;49(9):1597-600. doi: 10.2337/diabetes.49.9.1597.
• [22] Genetic variations of ISL1 associated with human congenital heart disease in Chinese Han people.Genet Mol Res. 2014 Feb 28;13(1):1329-38. doi: 10.4238/2014.February.28.5.
• [23] An abnormally high expression of ISL-1 represents a potential prognostic factor in gastric cancer.Hum Pathol. 2015 Sep;46(9):1282-9. doi: 10.1016/j.humpath.2015.05.006. Epub 2015 May 27.
• [24] Screening pathogenic genes in oral squamous cell carcinoma based on the mRNA expression microarray data.Int J Mol Med. 2018 Jun;41(6):3597-3603. doi: 10.3892/ijmm.2018.3514. Epub 2018 Feb 27.
• [25] Methylation of HOXA9 and ISL1 Predicts Patient Outcome in High-Grade Non-Invasive Bladder Cancer.PLoS One. 2015 Sep 2;10(9):e0137003. doi: 10.1371/journal.pone.0137003. eCollection 2015.
• [26] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [27] 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.
• [28] Phenotypic characterization of retinoic acid differentiated SH-SY5Y cells by transcriptional profiling. PLoS One. 2013 May 28;8(5):e63862.
• [29] 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.
• [30] A transcriptome-based classifier to identify developmental toxicants by stem cell testing: design, validation and optimization for histone deacetylase inhibitors. Arch Toxicol. 2015 Sep;89(9):1599-618.
• [31] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [32] 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.
• [33] Peroxisome proliferator activated receptor gamma (PPAR-gama) ligand pioglitazone regulated gene networks in term human primary trophoblast cells. Reprod Toxicol. 2018 Oct;81:99-107.
• [34] 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.
• [35] Inhibition of cardiomyocyte differentiation of human induced pluripotent stem cells by Ribavirin: Implication for its cardiac developmental toxicity. Toxicology. 2020 Apr 15;435:152422. doi: 10.1016/j.tox.2020.152422. Epub 2020 Feb 26.
• [36] Cell-based two-dimensional morphological assessment system to predict cancer drug-induced cardiotoxicity using human induced pluripotent stem cell-derived cardiomyocytes. Toxicol Appl Pharmacol. 2019 Nov 15;383:114761. doi: 10.1016/j.taap.2019.114761. Epub 2019 Sep 15.
• [37] 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.
• [38] 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.
• [39] 3-Nitrobenzanthrone promotes malignant transformation in human lung epithelial cells through the epiregulin-signaling pathway. Cell Biol Toxicol. 2022 Oct;38(5):865-887. doi: 10.1007/s10565-021-09612-1. Epub 2021 May 25.
• [40] Arachidonic acid-induced gene expression in colon cancer cells. Carcinogenesis. 2006 Oct;27(10):1950-60.