Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTW47GKM)

• DOT Name: Nuclear receptor subfamily 2 group E member 1 (NR2E1)
• Synonyms: Nuclear receptor TLX; Protein tailless homolog; Tll; hTll
• Gene Name: NR2E1
• Related Disease:
  Childhood acute lymphoblastic leukemia
  Glioblastoma multiforme
  Advanced cancer
  Amoebiasis
  Bipolar disorder
  Bipolar I disorder
  Brain neoplasm
  Breast cancer
  Breast carcinoma
  Castration-resistant prostate carcinoma
  Fatty liver disease
  Fibrosarcoma
  Glioma
  Intestinal amebiasis
  Leukemia
  Mental disorder
  Microphthalmia
  Neoplasm
  Nervous system disease
  Nervous system neoplasm
  Non-alcoholic fatty liver disease
  Prostate cancer
  Prostate carcinoma
  T-cell acute lymphoblastic leukaemia
  Adult glioblastoma
  Isolated congenital microcephaly
  Squamous cell carcinoma
  Nephropathy
  Lymphoid leukemia
  Male infertility
  Non-insulin dependent diabetes
  Schizophrenia
  Spermatogenic failure 16
• UniProt ID: NR2E1_HUMAN
• PDB ID: 4XAJ
• Pfam ID: PF00104 ; PF00105
• Sequence:
  MSKPAGSTSRILDIPCKVCGDRSSGKHYGVYACDGCSGFFKRSIRRNRTYVCKSGNQGGC
  PVDKTHRNQCRACRLKKCLEVNMNKDAVQHERGPRTSTIRKQVALYFRGHKEENGAAAHF
  PSAALPAPAFFTAVTQLEPHGLELAAVSTTPERQTLVSLAQPTPKYPHEVNGTPMYLYEV
  ATESVCESAARLLFMSIKWAKSVPAFSTLSLQDQLMLLEDAWRELFVLGIAQWAIPVDAN
  TLLAVSGMNGDNTDSQKLNKIISEIQALQEVVARFRQLRLDATEFACLKCIVTFKAVPTH
  SGSELRSFRNAAAIAALQDEAQLTLNSYIHTRYPTQPCRFGKLLLLLPALRSISPSTIEE
  VFFKKTIGNVPITRLLSDMYKSSDI
• Function: Orphan receptor that binds DNA as a monomer to hormone response elements (HRE) containing an extended core motif half-site sequence 5'-AAGGTCA-3' in which the 5' flanking nucleotides participate in determining receptor specificity. May be required to pattern anterior brain differentiation. Involved in the regulation of retinal development and essential for vision. During retinogenesis, regulates PTEN-Cyclin D expression via binding to the promoter region of PTEN and suppressing its activity. May be involved in retinoic acid receptor (RAR) regulation in retinal cells.
• Tissue Specificity: Brain specific. Present in all brain sections tested, highest levels in the caudate nucleus and hippocampus, weakest levels in the thalamus.
• Reactome Pathway:
  Regulation of PTEN gene transcription (R-HSA-8943724)
  Nuclear Receptor transcription pathway (R-HSA-383280)

Molecular Interaction Atlas (MIA) of This DOT

33 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Childhood acute lymphoblastic leukemia	DISJ5D6U	Definitive	Biomarker	[1]
Glioblastoma multiforme	DISK8246	Definitive	Biomarker	[2]
Advanced cancer	DISAT1Z9	Strong	Altered Expression	[3]
Amoebiasis	DISAJWJL	Strong	Genetic Variation	[4]
Bipolar disorder	DISAM7J2	Strong	Biomarker	[5]
Bipolar I disorder	DISD09EH	Strong	Biomarker	[5]
Brain neoplasm	DISY3EKS	Strong	Biomarker	[6]
Breast cancer	DIS7DPX1	Strong	Biomarker	[6]
Breast carcinoma	DIS2UE88	Strong	Biomarker	[6]
Castration-resistant prostate carcinoma	DISVGAE6	Strong	Biomarker	[7]
Fatty liver disease	DIS485QZ	Strong	Biomarker	[8]
Fibrosarcoma	DISWX7MU	Strong	Altered Expression	[9]
Glioma	DIS5RPEH	Strong	Altered Expression	[10]
Intestinal amebiasis	DIS0IHMD	Strong	Genetic Variation	[4]
Leukemia	DISNAKFL	Strong	Biomarker	[11]
Mental disorder	DIS3J5R8	Strong	Biomarker	[12]
Microphthalmia	DISGEBES	Strong	Genetic Variation	[13]
Neoplasm	DISZKGEW	Strong	Biomarker	[2]
Nervous system disease	DISJ7GGT	Strong	Biomarker	[14]
Nervous system neoplasm	DIS141UP	Strong	Altered Expression	[14]
Non-alcoholic fatty liver disease	DISDG1NL	Strong	Biomarker	[8]
Prostate cancer	DISF190Y	Strong	Altered Expression	[7]
Prostate carcinoma	DISMJPLE	Strong	Altered Expression	[7]
T-cell acute lymphoblastic leukaemia	DIS17AI2	Strong	Biomarker	[1]
Adult glioblastoma	DISVP4LU	moderate	Biomarker	[2]
Isolated congenital microcephaly	DISUXHZ6	moderate	Genetic Variation	[15]
Squamous cell carcinoma	DISQVIFL	moderate	Biomarker	[16]
Nephropathy	DISXWP4P	Disputed	Genetic Variation	[17]
Lymphoid leukemia	DIS65TYQ	Limited	Genetic Variation	[18]
Male infertility	DISY3YZZ	Limited	Biomarker	[19]
Non-insulin dependent diabetes	DISK1O5Z	Limited	Altered Expression	[20]
Schizophrenia	DISSRV2N	Limited	Biomarker	[21]
Spermatogenic failure 16	DISJT1VL	Limited	Biomarker	[19]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the expression of Nuclear receptor subfamily 2 group E member 1 (NR2E1).	[22]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of Nuclear receptor subfamily 2 group E member 1 (NR2E1).	[23]
Temozolomide	DMKECZD	Approved	Temozolomide increases the expression of Nuclear receptor subfamily 2 group E member 1 (NR2E1).	[25]
Vorinostat	DMWMPD4	Approved	Vorinostat decreases the expression of Nuclear receptor subfamily 2 group E member 1 (NR2E1).	[26]
Amphotericin B	DMTAJQE	Approved	Amphotericin B increases the expression of Nuclear receptor subfamily 2 group E member 1 (NR2E1).	[27]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of Nuclear receptor subfamily 2 group E member 1 (NR2E1).	[30]

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 Nuclear receptor subfamily 2 group E member 1 (NR2E1).	[24]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the methylation of Nuclear receptor subfamily 2 group E member 1 (NR2E1).	[28]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Nuclear receptor subfamily 2 group E member 1 (NR2E1).	[29]

References

• [1] IL-7 Receptor Mutations and Steroid Resistance in Pediatric T cell Acute Lymphoblastic Leukemia: A Genome Sequencing Study.PLoS Med. 2016 Dec 20;13(12):e1002200. doi: 10.1371/journal.pmed.1002200. eCollection 2016 Dec.
• [2] Downregulation of TLX induces TET3 expression and inhibits glioblastoma stem cell self-renewal and tumorigenesis.Nat Commun. 2016 Feb 3;7:10637. doi: 10.1038/ncomms10637.
• [3] Nuclear receptor profiling in prostatospheroids and castration-resistant prostate cancer.Endocr Relat Cancer. 2018 Jan;25(1):35-50. doi: 10.1530/ERC-17-0280. Epub 2017 Oct 17.
• [4] Molecular mechanisms underlying gliomas and glioblastoma pathogenesis revealed by bioinformatics analysis of microarray data.Med Oncol. 2017 Sep 26;34(11):182. doi: 10.1007/s12032-017-1043-x.
• [5] Hyperactivity, startle reactivity and cell-proliferation deficits are resistant to chronic lithium treatment in adult Nr2e1(frc/frc) mice.Genes Brain Behav. 2010 Oct;9(7):681-94. doi: 10.1111/j.1601-183X.2010.00602.x. Epub 2010 Jun 21.
• [6] Computer-Aided Discovery of Small Molecule Inhibitors of Transcriptional Activity of TLX (NR2E1) Nuclear Receptor.Molecules. 2018 Nov 14;23(11):2967. doi: 10.3390/molecules23112967.
• [7] Orphan nuclear receptor TLX contributes to androgen insensitivity in castration-resistant prostate cancer via its repression of androgen receptor transcription.Oncogene. 2018 Jun;37(25):3340-3355. doi: 10.1038/s41388-018-0198-z. Epub 2018 Mar 20.
• [8] Nr2e1 ablation impairs liver glucolipid metabolism and induces inflammation, high-fat diets amplify the damage.Biomed Pharmacother. 2019 Dec;120:109503. doi: 10.1016/j.biopha.2019.109503. Epub 2019 Oct 4.
• [9] Tumor cells expressing tissue factor influence the migration of smooth muscle cells in a catalytic activity-dependent way.Can J Physiol Pharmacol. 2009 Sep;87(9):694-701. doi: 10.1139/y09-063.
• [10] Monitoring in real time the effect of TLX overexpression on proliferation and migration of C6 cells.Neoplasma. 2017;64(1):48-55. doi: 10.4149/neo_2017_106.
• [11] TLX homeodomain oncogenes mediate T cell maturation arrest in T-ALL via interaction with ETS1 and suppression of TCR gene expression.Cancer Cell. 2012 Apr 17;21(4):563-76. doi: 10.1016/j.ccr.2012.02.013.
• [12] Initial association of NR2E1 with bipolar disorder and identification of candidate mutations in bipolar disorder, schizophrenia, and aggression through resequencing.Am J Med Genet B Neuropsychiatr Genet. 2008 Sep 5;147B(6):880-9. doi: 10.1002/ajmg.b.30696.
• [13] Absence of NR2E1 mutations in patients with aniridia.Mol Vis. 2012;18:2770-82. Epub 2012 Nov 22.
• [14] TLX-Its Emerging Role for Neurogenesis in Health and Disease.Mol Neurobiol. 2017 Jan;54(1):272-280. doi: 10.1007/s12035-015-9608-1. Epub 2016 Jan 6.
• [15] Mutation and evolutionary analyses identify NR2E1-candidate-regulatory mutations in humans with severe cortical malformations.Genes Brain Behav. 2007 Aug;6(6):503-16. doi: 10.1111/j.1601-183X.2006.00277.x. Epub 2006 Nov 29.
• [16] DNA methylation biomarkers for lung cancer.Tumour Biol. 2012 Apr;33(2):287-96. doi: 10.1007/s13277-011-0282-2. Epub 2011 Dec 6.
• [17] Novel vertebrate genes and putative regulatory elements identified at kidney disease and NR2E1/fierce loci.Genomics. 2002 Jul;80(1):45-53. doi: 10.1006/geno.2002.6795.
• [18] The human homologue of the Drosophila tailless gene (TLX): characterization and mapping to a region of common deletion in human lymphoid leukemia on chromosome 6q21.Genomics. 1998 May 15;50(1):34-43. doi: 10.1006/geno.1998.5270.
• [19] Mechanistic insights into acephalic spermatozoa syndrome-associated mutations in the human SUN5 gene.J Biol Chem. 2018 Feb 16;293(7):2395-2407. doi: 10.1074/jbc.RA117.000861. Epub 2018 Jan 3.
• [20] The relationship between NR2E1 and subclinical inflammation in newly diagnosed type 2 diabetic patients.J Diabetes Complications. 2015 May-Jun;29(4):589-94. doi: 10.1016/j.jdiacomp.2014.12.018. Epub 2014 Dec 31.
• [21] The TLX-miR-219 cascade regulates neural stem cell proliferation in neurodevelopment and schizophrenia iPSC model.Nat Commun. 2016 Mar 11;7:10965. doi: 10.1038/ncomms10965.
• [22] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [23] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [24] 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.
• [25] 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.
• [26] 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.
• [27] Differential expression of microRNAs and their predicted targets in renal cells exposed to amphotericin B and its complex with copper (II) ions. Toxicol Mech Methods. 2017 Sep;27(7):537-543. doi: 10.1080/15376516.2017.1333554. Epub 2017 Jun 8.
• [28] 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.
• [29] 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.
• [30] 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.