Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT65MFKQ)

• DOT Name: Neural retina-specific leucine zipper protein (NRL)
• Synonyms: NRL
• Gene Name: NRL
• Related Disease:
  Breast cancer
  Breast carcinoma
  Retinitis pigmentosa 27
  Adenocarcinoma
  Medulloblastoma
  Neoplasm
  Night blindness
  Non-insulin dependent diabetes
  Refractive error
  Retinal degeneration
  Retinopathy
  Inherited retinal dystrophy
  Leber congenital amaurosis
  Oculopharyngeal muscular dystrophy
  Retinitis pigmentosa
  Chronic obstructive pulmonary disease
  Colorectal carcinoma
  Leber congenital amaurosis 1
• UniProt ID: NRL_HUMAN
• Pfam ID: PF03131 ; PF08383
• Sequence:
  MALPPSPLAMEYVNDFDLMKFEVKREPSEGRPGPPTASLGSTPYSSVPPSPTFSEPGMVG
  ATEGTRPGLEELYWLATLQQQLGAGEALGLSPEEAMELLQGQGPVPVDGPHGYYPGSPEE
  TGAQHVQLAERFSDAALVSMSVRELNRQLRGCGRDEALRLKQRRRTLKNRGYAQACRSKR
  LQQRRGLEAERARLAAQLDALRAEVARLARERDLYKARCDRLTSSGPGSGDPSHLFL
• Function: Acts as a transcriptional activator which regulates the expression of several rod-specific genes, including RHO and PDE6B. Functions also as a transcriptional coactivator, stimulating transcription mediated by the transcription factor CRX and NR2E3. Binds in a sequence-specific manner to the rhodopsin promoter.
• Tissue Specificity: Expressed in the brain and the retina . Expressed strongly in rod and cone cells (at protein level) .

Molecular Interaction Atlas (MIA) of This DOT

18 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Breast cancer	DIS7DPX1	Definitive	Biomarker	[1]
Breast carcinoma	DIS2UE88	Definitive	Biomarker	[1]
Retinitis pigmentosa 27	DISOZ4CR	Definitive	Autosomal dominant	[2]
Adenocarcinoma	DIS3IHTY	Strong	Biomarker	[3]
Medulloblastoma	DISZD2ZL	Strong	Biomarker	[4]
Neoplasm	DISZKGEW	Strong	Biomarker	[3]
Night blindness	DIS335K9	Strong	Biomarker	[5]
Non-insulin dependent diabetes	DISK1O5Z	Strong	Biomarker	[6]
Refractive error	DISWNEQ1	Strong	Genetic Variation	[7]
Retinal degeneration	DISM1JHQ	Strong	Biomarker	[5]
Retinopathy	DISB4B0F	Strong	Genetic Variation	[8]
Inherited retinal dystrophy	DISGGL77	moderate	Genetic Variation	[9]
Leber congenital amaurosis	DISMGH8F	moderate	Genetic Variation	[10]
Oculopharyngeal muscular dystrophy	DISF4G07	moderate	Genetic Variation	[9]
Retinitis pigmentosa	DISCGPY8	Supportive	Autosomal dominant	[11]
Chronic obstructive pulmonary disease	DISQCIRF	Limited	Biomarker	[12]
Colorectal carcinoma	DIS5PYL0	Limited	Biomarker	[13]
Leber congenital amaurosis 1	DISY2B33	Limited	Genetic Variation	[14]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Neural retina-specific leucine zipper protein (NRL).	[15]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Neural retina-specific leucine zipper protein (NRL).	[16]
Rifampicin	DM5DSFZ	Approved	Rifampicin increases the expression of Neural retina-specific leucine zipper protein (NRL).	[17]
Alitretinoin	DMME8LH	Approved	Alitretinoin increases the expression of Neural retina-specific leucine zipper protein (NRL).	[15]
Gefitinib	DM15F0X	Approved	Gefitinib decreases the expression of Neural retina-specific leucine zipper protein (NRL).	[18]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Neural retina-specific leucine zipper protein (NRL).	[19]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Neural retina-specific leucine zipper protein (NRL).	[20]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Neural retina-specific leucine zipper protein (NRL).	[21]
TTNPB	DMSABD0	Investigative	TTNPB increases the expression of Neural retina-specific leucine zipper protein (NRL).	[15]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the methylation of Neural retina-specific leucine zipper protein (NRL).	[22]

References

• [1] Modeling prolactin actions in breast cancer in vivo: insights from the NRL-PRL mouse.Adv Exp Med Biol. 2015;846:201-20. doi: 10.1007/978-3-319-12114-7_9.
• [2] Identification of a novel NRL mutation in a Chinese family with retinitis pigmentosa by whole-exome sequencing. Eye (Lond). 2017 May;31(5):815-817. doi: 10.1038/eye.2016.327. Epub 2017 Jan 20.
• [3] High collagen density augments mTOR-dependent cancer stem cells in ER+ mammary carcinomas, and increases mTOR-independent lung metastases.Cancer Lett. 2018 Oct 1;433:1-9. doi: 10.1016/j.canlet.2018.06.025. Epub 2018 Jun 20.
• [4] NRL and CRX Define Photoreceptor Identity and Reveal Subgroup-Specific Dependencies in Medulloblastoma.Cancer Cell. 2018 Mar 12;33(3):435-449.e6. doi: 10.1016/j.ccell.2018.02.006.
• [5] Recessive NRL mutations in patients with clumped pigmentary retinal degeneration and relative preservation of blue cone function.Proc Natl Acad Sci U S A. 2004 Dec 21;101(51):17819-24. doi: 10.1073/pnas.0408183101. Epub 2004 Dec 9.
• [6] Conformational analysis and invitro immunomodulatory and insulinotropic properties of the frog skin host-defense peptide rhinophrynin-27 and selected analogs.Biochimie. 2019 Dec;167:198-206. doi: 10.1016/j.biochi.2019.10.007. Epub 2019 Oct 19.
• [7] Novel mutations in the NRL gene and associated clinical findings in patients with dominant retinitis pigmentosa.Arch Ophthalmol. 2002 Mar;120(3):369-75. doi: 10.1001/archopht.120.3.369.
• [8] Retinopathy mutations in the bZIP protein NRL alter phosphorylation and transcriptional activity.Hum Mutat. 2007 Jun;28(6):589-98. doi: 10.1002/humu.20488.
• [9] Oculopharyngeal Muscular Dystrophy and Inherited Retinal Dystrophy in Bukhara Jews Due to Linked Mutations in the PABPN1 and NRL Genes.Genet Test Mol Biomarkers. 2017 Jul;21(7):450-453. doi: 10.1089/gtmb.2016.0429. Epub 2017 Jun 7.
• [10] Two novel CRX mutant proteins causing autosomal dominant Leber congenital amaurosis interact differently with NRL.Hum Mutat. 2010 Jun;31(6):E1472-83. doi: 10.1002/humu.21268.
• [11] Nonsyndromic Retinitis Pigmentosa Overview. 2000 Aug 4 [updated 2023 Apr 6]. In: Adam MP, Feldman J, Mirzaa GM, Pagon RA, Wallace SE, Bean LJH, Gripp KW, Amemiya A, editors. GeneReviews(?) [Internet]. Seattle (WA): University of Washington, Seattle; 1993C2024.
• [12] The relationship between chronic obstructive pulmonary disease and non-small cell lung cancer in the elderly.Cancer Med. 2019 Aug;8(9):4124-4134. doi: 10.1002/cam4.2333. Epub 2019 Jun 11.
• [13] Combined Diagnostic Efficacy of Neutrophil-to-Lymphocyte Ratio (NLR), Platelet-to-Lymphocyte Ratio (PLR), and Mean Platelet Volume (MPV) as Biomarkers of Systemic Inflammation in the Diagnosis of Colorectal Cancer.Dis Markers. 2019 Jan 17;2019:6036979. doi: 10.1155/2019/6036979. eCollection 2019.
• [14] Mutation screening of patients with Leber Congenital Amaurosis or the enhanced S-Cone Syndrome reveals a lack of sequence variations in the NRL gene.Mol Vis. 2003 Jan 24;9:14-7.
• [15] Retinoic acid regulates the expression of photoreceptor transcription factor NRL. J Biol Chem. 2006 Sep 15;281(37):27327-34. doi: 10.1074/jbc.M605500200. Epub 2006 Jul 19.
• [16] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [17] Integrated analysis of rifampicin-induced microRNA and gene expression changes in human hepatocytes. Drug Metab Pharmacokinet. 2014;29(4):333-40.
• [18] Identification of genes linked to gefitinib treatment in prostate cancer cell lines with or without resistance to androgen: a clue to application of gefitinib to hormone-resistant prostate cancer. Oncol Rep. 2006 Jun;15(6):1453-60.
• [19] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [20] Benzo[a]pyrene-induced changes in microRNA-mRNA networks. Chem Res Toxicol. 2012 Apr 16;25(4):838-49.
• [21] 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.
• [22] 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.