Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTF96IC2)

• DOT Name: F-box only protein 31 (FBXO31)
• Gene Name: FBXO31
• Related Disease:
  Advanced cancer
  Breast cancer
  Breast carcinoma
  Breast neoplasm
  Carcinoma of esophagus
  Esophageal cancer
  Esophageal squamous cell carcinoma
  Hepatocellular carcinoma
  Intellectual disability
  Neoplasm
  Neoplasm of esophagus
  Prostate cancer
  Systemic lupus erythematosus
  Autosomal recessive non-syndromic intellectual disability
  Autism spectrum disorder
  Intellectual disability, autosomal recessive 45
• UniProt ID: FBX31_HUMAN
• PDB ID: 5VZT; 5VZU
• Pfam ID: PF12014 ; PF12937
• Sequence:
  MAVCARLCGVGPSRGCRRRQQRRGPAETAAADSEPDTDPEEERIEASAGVGGGLCAGPSP
  PPPRCSLLELPPELLVEIFASLPGTDLPSLAQVCTKFRRILHTDTIWRRRCREEYGVCEN
  LRKLEITGVSCRDVYAKLLHRYRHILGLWQPDIGPYGGLLNVVVDGLFIIGWMYLPPHDP
  HVDDPMRFKPLFRIHLMERKAATVECMYGHKGPHHGHIQIVKKDEFSTKCNQTDHHRMSG
  GRQEEFRTWLREEWGRTLEDIFHEHMQELILMKFIYTSQYDNCLTYRRIYLPPSRPDDLI
  KPGLFKGTYGSHGLEIVMLSFHGRRARGTKITGDPNIPAGQQTVEIDLRHRIQLPDLENQ
  RNFNELSRIVLEVRERVRQEQQEGGHEAGEGRGRQGPRESQPSPAQPRAEAPSKGPDGTP
  GEDGGEPGDAVAAAEQPAQCGQGQPFVLPVGVSSRNEDYPRTCRMCFYGTGLIAGHGFTS
  PERTPGVFILFDEDRFGFVWLELKSFSLYSRVQATFRNADAPSPQAFDEMLKNIQSLTS
• Function: Component of some SCF (SKP1-cullin-F-box) protein ligase complex that plays a central role in G1 arrest following DNA damage. Specifically recognizes phosphorylated cyclin-D1 (CCND1), promoting its ubiquitination and degradation by the proteasome, resulting in G1 arrest. May act as a tumor suppressor.
• Tissue Specificity: Highly expressed in brain. Expressed at moderate levels in most tissues, except bone marrow.
• Reactome Pathway:
  Antigen processing (R-HSA-983168)
  Neddylation (R-HSA-8951664)

Molecular Interaction Atlas (MIA) of This DOT

16 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Advanced cancer	DISAT1Z9	Strong	Biomarker	[1]
Breast cancer	DIS7DPX1	Strong	Altered Expression	[2]
Breast carcinoma	DIS2UE88	Strong	Altered Expression	[2]
Breast neoplasm	DISNGJLM	Strong	Altered Expression	[2]
Carcinoma of esophagus	DISS6G4D	Strong	Biomarker	[3]
Esophageal cancer	DISGB2VN	Strong	Biomarker	[3]
Esophageal squamous cell carcinoma	DIS5N2GV	Strong	Biomarker	[3]
Hepatocellular carcinoma	DIS0J828	Strong	Altered Expression	[4]
Intellectual disability	DISMBNXP	Strong	Genetic Variation	[5]
Neoplasm	DISZKGEW	Strong	Biomarker	[6]
Neoplasm of esophagus	DISOLKAQ	Strong	Biomarker	[3]
Prostate cancer	DISF190Y	Strong	Biomarker	[7]
Systemic lupus erythematosus	DISI1SZ7	Strong	Genetic Variation	[8]
Autosomal recessive non-syndromic intellectual disability	DISJWRZZ	Supportive	Autosomal recessive	[5]
Autism spectrum disorder	DISXK8NV	Limited	Genetic Variation	[9]
Intellectual disability, autosomal recessive 45	DIS2CLTL	Limited	Autosomal recessive	[10]

9 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 F-box only protein 31 (FBXO31).	[11]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of F-box only protein 31 (FBXO31).	[12]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of F-box only protein 31 (FBXO31).	[13]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of F-box only protein 31 (FBXO31).	[14]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of F-box only protein 31 (FBXO31).	[16]
Tocopherol	DMBIJZ6	Phase 2	Tocopherol increases the expression of F-box only protein 31 (FBXO31).	[17]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of F-box only protein 31 (FBXO31).	[18]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of F-box only protein 31 (FBXO31).	[19]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of F-box only protein 31 (FBXO31).	[20]

1 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 F-box only protein 31 (FBXO31).	[15]

References

• [1] The role of F-box only protein 31 in cancer.Oncol Lett. 2018 Apr;15(4):4047-4052. doi: 10.3892/ol.2018.7816. Epub 2018 Jan 17.
• [2] FBXO31 is the chromosome 16q24.3 senescence gene, a candidate breast tumor suppressor, and a component of an SCF complex.Cancer Res. 2005 Dec 15;65(24):11304-13. doi: 10.1158/0008-5472.CAN-05-0936.
• [3] Identification of miR-29c and its Target FBXO31 as a Key Regulatory Mechanism in Esophageal Cancer Chemoresistance: Functional Validation and Clinical Significance.Theranostics. 2019 Feb 28;9(6):1599-1613. doi: 10.7150/thno.30372. eCollection 2019.
• [4] FBXO31 is down-regulated and may function as a tumor suppressor in hepatocellular carcinoma.Oncol Rep. 2010 Sep;24(3):715-20. doi: 10.3892/or_00000912.
• [5] Truncation of the E3 ubiquitin ligase component FBXO31 causes non-syndromic autosomal recessive intellectual disability in a Pakistani family. Hum Genet. 2014 Aug;133(8):975-84. doi: 10.1007/s00439-014-1438-0. Epub 2014 Mar 13.
• [6] The tumor suppressor FBXO31 preserves genomic integrity by regulating DNA replication and segregation through precise control of cyclin A levels.J Biol Chem. 2019 Oct 11;294(41):14879-14895. doi: 10.1074/jbc.RA118.007055. Epub 2019 Aug 14.
• [7] F-box protein FBXO31 mediates cyclin D1 degradation to induce G1 arrest after DNA damage.Nature. 2009 Jun 4;459(7247):722-5. doi: 10.1038/nature08011. Epub 2009 May 3.
• [8] A Rare Variant (rs933717) at FBXO31-MAP1LC3B in Chinese Is Associated With Systemic Lupus Erythematosus.Arthritis Rheumatol. 2018 Feb;70(2):287-297. doi: 10.1002/art.40353. Epub 2018 Jan 9.
• [9] Deletions in 16q24.2 are associated with autism spectrum disorder, intellectual disability and congenital renal malformation.J Med Genet. 2013 Mar;50(3):163-73. doi: 10.1136/jmedgenet-2012-101288. Epub 2013 Jan 18.
• [10] 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.
• [11] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [12] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [13] 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.
• [14] 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.
• [15] 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.
• [16] Comparison of phenotypic and transcriptomic effects of false-positive genotoxins, true genotoxins and non-genotoxins using HepG2 cells. Mutagenesis. 2011 Sep;26(5):593-604.
• [17] 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.
• [18] 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.
• [19] 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.
• [20] Gene expression changes in primary human nasal epithelial cells exposed to formaldehyde in vitro. Toxicol Lett. 2010 Oct 5;198(2):289-95.