Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTEMQ1SR)

• DOT Name: RNA-binding protein FXR1 (FXR1)
• Synonyms: FMR1 autosomal homolog 1; hFXR1p
• Gene Name: FXR1
• Related Disease:
  facioscapulohumeral muscular dystrophy
  Advanced cancer
  Amyloidosis
  Anxiety
  Anxiety disorder
  Bipolar disorder
  Cardiac disease
  Colorectal carcinoma
  Congenital multicore myopathy with external ophthalmoplegia
  Depression
  Dilated cardiomyopathy
  Dilated cardiomyopathy 1A
  Eating disorder
  Fragile X syndrome
  Lung squamous cell carcinoma
  Mental disorder
  Myopathy
  Myopathy, congenital, with respiratory insufficiency and bone fractures
  Neoplasm
  Non-small-cell lung cancer
  Prostate cancer
  Prostate carcinoma
  Squamous cell carcinoma
  Ventricular tachycardia
  Head-neck squamous cell carcinoma
  Childhood kidney Wilms tumor
  Wilms tumor
  Acute myelogenous leukaemia
  Adenocarcinoma
  Intellectual disability
  Melanoma
  Mood disorder
  Myopathy, congenital proximal, with minicore lesions
  Schizophrenia
• UniProt ID: FXR1_HUMAN
• PDB ID: 2CPQ; 3KUF; 3O8V
• Pfam ID: PF05641 ; PF12235 ; PF16096 ; PF16097 ; PF00013 ; PF17904 ; PF18336
• Sequence:
  MAELTVEVRGSNGAFYKGFIKDVHEDSLTVVFENNWQPERQVPFNEVRLPPPPDIKKEIS
  EGDEVEVYSRANDQEPCGWWLAKVRMMKGEFYVIEYAACDATYNEIVTFERLRPVNQNKT
  VKKNTFFKCTVDVPEDLREACANENAHKDFKKAVGACRIFYHPETTQLMILSASEATVKR
  VNILSDMHLRSIRTKLMLMSRNEEATKHLECTKQLAAAFHEEFVVREDLMGLAIGTHGSN
  IQQARKVPGVTAIELDEDTGTFRIYGESADAVKKARGFLEFVEDFIQVPRNLVGKVIGKN
  GKVIQEIVDKSGVVRVRIEGDNENKLPREDGMVPFVFVGTKESIGNVQVLLEYHIAYLKE
  VEQLRMERLQIDEQLRQIGSRSYSGRGRGRRGPNYTSGYGTNSELSNPSETESERKDELS
  DWSLAGEDDRDSRHQRDSRRRPGGRGRSVSGGRGRGGPRGGKSSISSVLKDPDSNPYSLL
  DNTESDQTADTDASESHHSTNRRRRSRRRRTDEDAVLMDGMTESDTASVNENGLVTVADY
  ISRAESQSRQRNLPRETLAKNKKEMAKDVIEEHGPSEKAINGPTSASGDDISKLQRTPGE
  EKINTLKEENTQEAAVLNGVS
• Function: mRNA-binding protein that acts as a regulator of mRNAs translation and/or stability, and which is required for various processes, such as neurogenesis, muscle development and spermatogenesis. Specifically binds to AU-rich elements (AREs) in the 3'-UTR of target mRNAs. Promotes formation of some phase-separated membraneless compartment by undergoing liquid-liquid phase separation upon binding to AREs-containing mRNAs, leading to assemble mRNAs into cytoplasmic ribonucleoprotein granules that concentrate mRNAs with associated regulatory factors. Required to activate translation of stored mRNAs during late spermatogenesis: acts by undergoing liquid-liquid phase separation to assemble target mRNAs into cytoplasmic ribonucleoprotein granules that recruit translation initiation factor EIF4G3 to activate translation of stored mRNAs in late spermatids. Promotes translation of MYC transcripts by recruiting the eIF4F complex to the translation start site. Acts as a negative regulator of inflammation in response to IL19 by promoting destabilization of pro-inflammatory transcripts. Also acts as an inhibitor of inflammation by binding to TNF mRNA, decreasing TNF protein production. Acts as a negative regulator of AMPA receptor GRIA2/GluA2 synthesis during long-lasting synaptic potentiation of hippocampal neurons by binding to GRIA2/GluA2 mRNA, thereby inhibiting its translation. Regulates proliferation of adult neural stem cells by binding to CDKN1A mRNA and promoting its expression. Acts as a regulator of sleep and synaptic homeostasis by regulating translation of transcripts in neurons. Required for embryonic and postnatal development of muscle tissue by undergoing liquid-liquid phase separation to assemble target mRNAs into cytoplasmic ribonucleoprotein granules. Involved in the nuclear pore complex localization to the nuclear envelope by preventing cytoplasmic aggregation of nucleoporins: acts by preventing ectopic phase separation of nucleoporins in the cytoplasm via a microtubule-dependent mechanism.
• Tissue Specificity: Expressed in all tissues examined including heart, brain, kidney and testis . In brain, present at high level in neurons and especially in the Purkinje cells at the interface between the granular layer and the molecular layer (at protein level) .
• Reactome Pathway: Signaling by BRAF and RAF1 fusions (R-HSA-6802952)

Molecular Interaction Atlas (MIA) of This DOT

34 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
facioscapulohumeral muscular dystrophy	DISSE0H0	Definitive	Altered Expression	[1]
Advanced cancer	DISAT1Z9	Strong	Biomarker	[2]
Amyloidosis	DISHTAI2	Strong	Biomarker	[3]
Anxiety	DISIJDBA	Strong	Biomarker	[4]
Anxiety disorder	DISBI2BT	Strong	Biomarker	[4]
Bipolar disorder	DISAM7J2	Strong	Biomarker	[4]
Cardiac disease	DISVO1I5	Strong	Altered Expression	[5]
Colorectal carcinoma	DIS5PYL0	Strong	Biomarker	[6]
Congenital multicore myopathy with external ophthalmoplegia	DIS39ELI	Strong	Genetic Variation	[7]
Depression	DIS3XJ69	Strong	Genetic Variation	[8]
Dilated cardiomyopathy	DISX608J	Strong	Altered Expression	[5]
Dilated cardiomyopathy 1A	DIS0RK9Z	Strong	Altered Expression	[5]
Eating disorder	DISVGXN0	Strong	Genetic Variation	[9]
Fragile X syndrome	DISE8W3A	Strong	Biomarker	[10]
Lung squamous cell carcinoma	DISXPIBD	Strong	Biomarker	[11]
Mental disorder	DIS3J5R8	Strong	Biomarker	[12]
Myopathy	DISOWG27	Strong	Genetic Variation	[7]
Myopathy, congenital, with respiratory insufficiency and bone fractures	DISBA0K2	Strong	Autosomal recessive	[13]
Neoplasm	DISZKGEW	Strong	Biomarker	[14]
Non-small-cell lung cancer	DIS5Y6R9	Strong	Biomarker	[15]
Prostate cancer	DISF190Y	Strong	Biomarker	[14]
Prostate carcinoma	DISMJPLE	Strong	Biomarker	[14]
Squamous cell carcinoma	DISQVIFL	Strong	Biomarker	[16]
Ventricular tachycardia	DISIBXJ3	Strong	Biomarker	[5]
Head-neck squamous cell carcinoma	DISF7P24	moderate	Biomarker	[17]
Childhood kidney Wilms tumor	DIS0NMK3	Disputed	Biomarker	[2]
Wilms tumor	DISB6T16	Disputed	Biomarker	[2]
Acute myelogenous leukaemia	DISCSPTN	Limited	Genetic Variation	[18]
Adenocarcinoma	DIS3IHTY	Limited	Altered Expression	[19]
Intellectual disability	DISMBNXP	Limited	Genetic Variation	[1]
Melanoma	DIS1RRCY	Limited	Altered Expression	[20]
Mood disorder	DISLVMWO	Limited	Biomarker	[4]
Myopathy, congenital proximal, with minicore lesions	DISNUCGV	Limited	Autosomal recessive	[21]
Schizophrenia	DISSRV2N	Limited	Genetic Variation	[22]

14 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 RNA-binding protein FXR1 (FXR1).	[23]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of RNA-binding protein FXR1 (FXR1).	[24]
Doxorubicin	DMVP5YE	Approved	Doxorubicin increases the expression of RNA-binding protein FXR1 (FXR1).	[25]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of RNA-binding protein FXR1 (FXR1).	[26]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of RNA-binding protein FXR1 (FXR1).	[27]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of RNA-binding protein FXR1 (FXR1).	[30]
Selenium	DM25CGV	Approved	Selenium decreases the expression of RNA-binding protein FXR1 (FXR1).	[31]
Testosterone enanthate	DMB6871	Approved	Testosterone enanthate affects the expression of RNA-binding protein FXR1 (FXR1).	[32]
Amphotericin B	DMTAJQE	Approved	Amphotericin B decreases the expression of RNA-binding protein FXR1 (FXR1).	[33]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of RNA-binding protein FXR1 (FXR1).	[34]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 decreases the expression of RNA-binding protein FXR1 (FXR1).	[35]
Tocopherol	DMBIJZ6	Phase 2	Tocopherol decreases the expression of RNA-binding protein FXR1 (FXR1).	[31]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of RNA-binding protein FXR1 (FXR1).	[36]
Milchsaure	DM462BT	Investigative	Milchsaure increases the expression of RNA-binding protein FXR1 (FXR1).	[37]

4 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 RNA-binding protein FXR1 (FXR1).	[28]
Quercetin	DM3NC4M	Approved	Quercetin increases the phosphorylation of RNA-binding protein FXR1 (FXR1).	[29]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 increases the phosphorylation of RNA-binding protein FXR1 (FXR1).	[29]
Coumarin	DM0N8ZM	Investigative	Coumarin increases the phosphorylation of RNA-binding protein FXR1 (FXR1).	[29]

References

• [1] A novel role for the RNA-binding protein FXR1P in myoblasts cell-cycle progression by modulating p21/Cdkn1a/Cip1/Waf1 mRNA stability.PLoS Genet. 2013 Mar;9(3):e1003367. doi: 10.1371/journal.pgen.1003367. Epub 2013 Mar 21.
• [2] FXR1 expression domain in Wilms tumor.J Pediatr Surg. 2019 Jun;54(6):1198-1205. doi: 10.1016/j.jpedsurg.2019.02.030. Epub 2019 Feb 28.
• [3] RNA-binding protein FXR1 is presented in rat brain in amyloid form.Sci Rep. 2019 Dec 12;9(1):18983. doi: 10.1038/s41598-019-55528-6.
• [4] Mental Illnesses-Associated Fxr1 and Its Negative Regulator Gsk3 Are Modulators of Anxiety and Glutamatergic Neurotransmission.Front Mol Neurosci. 2018 Apr 12;11:119. doi: 10.3389/fnmol.2018.00119. eCollection 2018.
• [5] Increased Cardiac Arrhythmogenesis Associated With Gap Junction Remodeling With Upregulation of RNA-Binding Protein FXR1.Circulation. 2018 Feb 6;137(6):605-618. doi: 10.1161/CIRCULATIONAHA.117.028976. Epub 2017 Nov 3.
• [6] FXR1 is elevated in colorectal cancer and acts as an oncogene.Tumour Biol. 2016 Feb;37(2):2683-90. doi: 10.1007/s13277-015-4068-9. Epub 2015 Sep 24.
• [7] Recessive mutations in muscle-specific isoforms of FXR1 cause congenital multi-minicore myopathy.Nat Commun. 2019 Feb 15;10(1):797. doi: 10.1038/s41467-019-08548-9.
• [8] The interaction of GSK3B and FXR1 genotypes may influence the mania and depression dimensions in mood disorders.J Affect Disord. 2017 Apr 15;213:172-177. doi: 10.1016/j.jad.2017.02.023. Epub 2017 Feb 16.
• [9] A genome-wide association study of bipolar disorder with comorbid eating disorder replicates the SOX2-OT region.J Affect Disord. 2016 Jan 1;189:141-9. doi: 10.1016/j.jad.2015.09.029. Epub 2015 Sep 25.
• [10] Comparative Behavioral Phenotypes of Fmr1 KO, Fxr2 Het, and Fmr1 KO/Fxr2 Het Mice.Brain Sci. 2019 Jan 16;9(1):13. doi: 10.3390/brainsci9010013.
• [11] The RNA binding protein FXR1 is a new driver in the 3q26-29 amplicon and predicts poor prognosis in human cancers.Proc Natl Acad Sci U S A. 2015 Mar 17;112(11):3469-74. doi: 10.1073/pnas.1421975112. Epub 2015 Mar 2.
• [12] Fragile X related protein 1 (FXR1P) regulates proliferation of adult neural stem cells.Hum Mol Genet. 2017 Apr 1;26(7):1340-1352. doi: 10.1093/hmg/ddx034.
• [13] [Anatomic-radiographic study of the maxillary sinus in adults]. Rev Odontol Concepcion. 1967 Oct-Dec;12(2):61-72.
• [14] The RNA-binding protein FXR1 modulates prostate cancer progression by regulating FBXO4.Funct Integr Genomics. 2019 May;19(3):487-496. doi: 10.1007/s10142-019-00661-8. Epub 2019 Feb 11.
• [15] Significance of miR-15a-5p and CNKSR3 as Novel Prognostic Biomarkers in Non-Small Cell Lung Cancer.Anticancer Agents Med Chem. 2018;18(12):1695-1701. doi: 10.2174/1871520618666180718100656.
• [16] Muscle-Specific FXR1 Isoforms in Squamous Cell Cancer.Trends Cancer. 2019 Feb;5(2):82-84. doi: 10.1016/j.trecan.2018.12.001. Epub 2018 Dec 21.
• [17] Fbxo4-mediated degradation of Fxr1 suppresses tumorigenesis in head and neck squamous cell carcinoma.Nat Commun. 2017 Nov 16;8(1):1534. doi: 10.1038/s41467-017-01199-8.
• [18] Genome-wide haplotype association study identify the FGFR2 gene as a risk gene for acute myeloid leukemia.Oncotarget. 2017 Jan 31;8(5):7891-7899. doi: 10.18632/oncotarget.13631.
• [19] Overexpression of Dicer in precursor lesions of lung adenocarcinoma.Cancer Res. 2007 Mar 1;67(5):2345-50. doi: 10.1158/0008-5472.CAN-06-3533.
• [20] Immunohistochemical Expression of FXR1 in Canine Normal Tissues and Melanomas.J Histochem Cytochem. 2018 Aug;66(8):585-593. doi: 10.1369/0022155418766292. Epub 2018 Apr 2.
• [21] Classification of Genes: Standardized Clinical Validity Assessment of Gene-Disease Associations Aids Diagnostic Exome Analysis and Reclassifications. Hum Mutat. 2017 May;38(5):600-608. doi: 10.1002/humu.23183. Epub 2017 Feb 13.
• [22] Genome-Wide Association Study Detected Novel Susceptibility Genes for Schizophrenia and Shared Trans-Populations/Diseases Genetic Effect.Schizophr Bull. 2019 Jun 18;45(4):824-834. doi: 10.1093/schbul/sby140.
• [23] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [24] 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.
• [25] 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.
• [26] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [27] Quantitative proteomics reveals a broad-spectrum antiviral property of ivermectin, benefiting for COVID-19 treatment. J Cell Physiol. 2021 Apr;236(4):2959-2975. doi: 10.1002/jcp.30055. Epub 2020 Sep 22.
• [28] 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.
• [29] Quantitative phosphoproteomics reveal cellular responses from caffeine, coumarin and quercetin in treated HepG2 cells. Toxicol Appl Pharmacol. 2022 Aug 15;449:116110. doi: 10.1016/j.taap.2022.116110. Epub 2022 Jun 7.
• [30] Global gene expression analysis reveals differences in cellular responses to hydroxyl- and superoxide anion radical-induced oxidative stress in caco-2 cells. Toxicol Sci. 2010 Apr;114(2):193-203. doi: 10.1093/toxsci/kfp309. Epub 2009 Dec 31.
• [31] 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.
• [32] Transcriptional profiling of testosterone-regulated genes in the skeletal muscle of human immunodeficiency virus-infected men experiencing weight loss. J Clin Endocrinol Metab. 2007 Jul;92(7):2793-802. doi: 10.1210/jc.2006-2722. Epub 2007 Apr 17.
• [33] 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.
• [34] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [35] 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.
• [36] 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.
• [37] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.