Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTJEL7WT)

• DOT Name: Nuclear receptor subfamily 2 group C member 1 (NR2C1)
• Synonyms: Orphan nuclear receptor TR2; Testicular receptor 2
• Gene Name: NR2C1
• Related Disease:
  Endometriosis
  Parkinson disease
  Prostate cancer
  Prostate carcinoma
  Prostate neoplasm
• UniProt ID: NR2C1_HUMAN
• Pfam ID: PF00104 ; PF00105
• Sequence:
  MATIEEIAHQIIEQQMGEIVTEQQTGQKIQIVTALDHNTQGKQFILTNHDGSTPSKVILA
  RQDSTPGKVFLTTPDAAGVNQLFFTTPDLSAQHLQLLTDNSPDQGPNKVFDLCVVCGDKA
  SGRHYGAVTCEGCKGFFKRSIRKNLVYSCRGSKDCIINKHHRNRCQYCRLQRCIAFGMKQ
  DSVQCERKPIEVSREKSSNCAASTEKIYIRKDLRSPLTATPTFVTDSESTRSTGLLDSGM
  FMNIHPSGVKTESAVLMTSDKAESCQGDLSTLANVVTSLANLGKTKDLSQNSNEMSMIES
  LSNDDTSLCEFQEMQTNGDVSRAFDTLAKALNPGESTACQSSVAGMEGSVHLITGDSSIN
  YTEKEGPLLSDSHVAFRLTMPSPMPEYLNVHYIGESASRLLFLSMHWALSIPSFQALGQE
  NSISLVKAYWNELFTLGLAQCWQVMNVATILATFVNCLHNSLQQDKMSTERRKLLMEHIF
  KLQEFCNSMVKLCIDGYEYAYLKAIVLFSPDHPSLENMEQIEKFQEKAYVEFQDYITKTY
  PDDTYRLSRLLLRLPALRLMNATITEELFFKGLIGNIRIDSVIPHILKMEPADYNSQIIG
  HSI
• Function: Orphan nuclear receptor. Binds the IR7 element in the promoter of its own gene in an autoregulatory negative feedback mechanism. Primarily repressor of a broad range of genes. Binds to hormone response elements (HREs) consisting of two 5'-AGGTCA-3' half site direct repeat consensus sequences. Together with NR2C2, forms the core of the DRED (direct repeat erythroid-definitive) complex that represses embryonic and fetal globin transcription. Also activator of OCT4 gene expression. May be involved in stem cell proliferation and differentiation. Mediator of retinoic acid-regulated preadipocyte proliferation.
• Reactome Pathway:
  SUMOylation of intracellular receptors (R-HSA-4090294)
  Nuclear Receptor transcription pathway (R-HSA-383280)

Molecular Interaction Atlas (MIA) of This DOT

5 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Endometriosis	DISX1AG8	Strong	Biomarker	[1]
Parkinson disease	DISQVHKL	Strong	Genetic Variation	[2]
Prostate cancer	DISF190Y	Strong	Biomarker	[3]
Prostate carcinoma	DISMJPLE	Strong	Biomarker	[3]
Prostate neoplasm	DISHDKGQ	Strong	Biomarker	[3]

12 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 C member 1 (NR2C1).	[4]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Nuclear receptor subfamily 2 group C member 1 (NR2C1).	[5]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Nuclear receptor subfamily 2 group C member 1 (NR2C1).	[6]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Nuclear receptor subfamily 2 group C member 1 (NR2C1).	[7]
Temozolomide	DMKECZD	Approved	Temozolomide increases the expression of Nuclear receptor subfamily 2 group C member 1 (NR2C1).	[8]
Selenium	DM25CGV	Approved	Selenium decreases the expression of Nuclear receptor subfamily 2 group C member 1 (NR2C1).	[9]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 decreases the expression of Nuclear receptor subfamily 2 group C member 1 (NR2C1).	[11]
Tocopherol	DMBIJZ6	Phase 2	Tocopherol decreases the expression of Nuclear receptor subfamily 2 group C member 1 (NR2C1).	[9]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Nuclear receptor subfamily 2 group C member 1 (NR2C1).	[13]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Nuclear receptor subfamily 2 group C member 1 (NR2C1).	[14]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of Nuclear receptor subfamily 2 group C member 1 (NR2C1).	[11]
Coumestrol	DM40TBU	Investigative	Coumestrol decreases the expression of Nuclear receptor subfamily 2 group C member 1 (NR2C1).	[15]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Fulvestrant	DM0YZC6	Approved	Fulvestrant increases the methylation of Nuclear receptor subfamily 2 group C member 1 (NR2C1).	[10]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene affects the methylation of Nuclear receptor subfamily 2 group C member 1 (NR2C1).	[12]

References

• [1] Nuclear receptor, coregulator signaling, and chromatin remodeling pathways suggest involvement of the epigenome in the steroid hormone response of endometrium and abnormalities in endometriosis.Reprod Sci. 2012 Feb;19(2):152-62. doi: 10.1177/1933719111415546. Epub 2011 Dec 2.
• [2] Tomoregulin-2 is found extensively in plaques in Alzheimer's disease brain.J Neurochem. 2006 Jul;98(1):34-44. doi: 10.1111/j.1471-4159.2006.03801.x.
• [3] TR2 orphan receptor functions as negative modulator for androgen receptor in prostate cancer cells PC-3.Prostate. 2003 Oct 1;57(2):129-33. doi: 10.1002/pros.10282.
• [4] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [5] Transcriptional and Metabolic Dissection of ATRA-Induced Granulocytic Differentiation in NB4 Acute Promyelocytic Leukemia Cells. Cells. 2020 Nov 5;9(11):2423. doi: 10.3390/cells9112423.
• [6] Gene expression analysis of precision-cut human liver slices indicates stable expression of ADME-Tox related genes. Toxicol Appl Pharmacol. 2011 May 15;253(1):57-69.
• [7] 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.
• [8] 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.
• [9] Selenium and vitamin E: cell type- and intervention-specific tissue effects in prostate cancer. J Natl Cancer Inst. 2009 Mar 4;101(5):306-20.
• [10] 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.
• [11] 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.
• [12] Effect of aflatoxin B(1), benzo[a]pyrene, and methapyrilene on transcriptomic and epigenetic alterations in human liver HepaRG cells. Food Chem Toxicol. 2018 Nov;121:214-223. doi: 10.1016/j.fct.2018.08.034. Epub 2018 Aug 26.
• [13] 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.
• [14] Bisphenol A Exposure Changes the Transcriptomic and Proteomic Dynamics of Human Retinoblastoma Y79 Cells. Genes (Basel). 2021 Feb 11;12(2):264. doi: 10.3390/genes12020264.
• [15] Pleiotropic combinatorial transcriptomes of human breast cancer cells exposed to mixtures of dietary phytoestrogens. Food Chem Toxicol. 2009 Apr;47(4):787-95.