Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTNUK1DJ)

• DOT Name: F-box/LRR-repeat protein 7 (FBXL7)
• Synonyms: F-box and leucine-rich repeat protein 7; F-box protein FBL6/FBL7
• Gene Name: FBXL7
• Related Disease:
  Alzheimer disease
  Breast cancer
  Breast carcinoma
  Chronic obstructive pulmonary disease
  Lung adenocarcinoma
  Non-insulin dependent diabetes
  Asthma
  Gastric cancer
  Stomach cancer
• UniProt ID: FBXL7_HUMAN
• Pfam ID: PF12937 ; PF13516
• Sequence:
  MGANNGKQYGSEGKGSSSISSDVSSSTDHTPTKAQKNVATSEDSDLSMRTLSTPSPALIC
  PPNLPGFQNGRGSSTSSSSITGETVAMVHSPPPTRLTHPLIRLASRPQKEQASIDRLPDH
  SMVQIFSFLPTNQLCRCARVCRRWYNLAWDPRLWRTIRLTGETINVDRALKVLTRRLCQD
  TPNVCLMLETVTVSGCRRLTDRGLYTIAQCCPELRRLEVSGCYNISNEAVFDVVSLCPNL
  EHLDVSGCSKVTCISLTREASIKLSPLHGKQISIRYLDMTDCFVLEDEGLHTIAAHCTQL
  THLYLRRCVRLTDEGLRYLVIYCASIKELSVSDCRFVSDFGLREIAKLESRLRYLSIAHC
  GRVTDVGIRYVAKYCSKLRYLNARGCEGITDHGVEYLAKNCTKLKSLDIGKCPLVSDTGL
  ECLALNCFNLKRLSLKSCESITGQGLQIVAANCFDLQTLNVQDCEVSVEALRFVKRHCKR
  CVIEHTNPAFF
• Function: Substrate recognition component of a SCF (SKP1-CUL1-F-box protein) E3 ubiquitin-protein ligase complex. During mitosis, it mediates the ubiquitination and subsequent proteasomal degradation of AURKA, causing mitotic arrest. It also regulates mitochondrial function by mediating the ubiquitination and proteasomal degradation of the apoptosis inhibitor BIRC5.
• Reactome Pathway:
  Neddylation (R-HSA-8951664)
  Antigen processing (R-HSA-983168)
  FBXL7 down-regulates AURKA during mitotic entry and in early mitosis (R-HSA-8854050)

Molecular Interaction Atlas (MIA) of This DOT

9 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Alzheimer disease	DISF8S70	Strong	Genetic Variation	[1]
Breast cancer	DIS7DPX1	Strong	Biomarker	[2]
Breast carcinoma	DIS2UE88	Strong	Biomarker	[2]
Chronic obstructive pulmonary disease	DISQCIRF	Strong	Genetic Variation	[3]
Lung adenocarcinoma	DISD51WR	Strong	Biomarker	[4]
Non-insulin dependent diabetes	DISK1O5Z	Strong	Genetic Variation	[5]
Asthma	DISW9QNS	moderate	Biomarker	[6]
Gastric cancer	DISXGOUK	moderate	Biomarker	[7]
Stomach cancer	DISKIJSX	moderate	Biomarker	[7]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the methylation of F-box/LRR-repeat protein 7 (FBXL7).	[8]
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of F-box/LRR-repeat protein 7 (FBXL7).	[12]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the methylation of F-box/LRR-repeat protein 7 (FBXL7).	[17]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of F-box/LRR-repeat protein 7 (FBXL7).	[18]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of F-box/LRR-repeat protein 7 (FBXL7).	[9]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of F-box/LRR-repeat protein 7 (FBXL7).	[10]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of F-box/LRR-repeat protein 7 (FBXL7).	[11]
Temozolomide	DMKECZD	Approved	Temozolomide decreases the expression of F-box/LRR-repeat protein 7 (FBXL7).	[13]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide decreases the expression of F-box/LRR-repeat protein 7 (FBXL7).	[14]
Isotretinoin	DM4QTBN	Approved	Isotretinoin increases the expression of F-box/LRR-repeat protein 7 (FBXL7).	[15]
Tocopherol	DMBIJZ6	Phase 2	Tocopherol increases the expression of F-box/LRR-repeat protein 7 (FBXL7).	[16]

References

• [1] F-box/LRR-repeat protein 7 is genetically associated with Alzheimer's disease.Ann Clin Transl Neurol. 2015 Aug;2(8):810-20. doi: 10.1002/acn3.223. Epub 2015 Jun 18.
• [2] Pathway-based classification of cancer subtypes.Biol Direct. 2012 Jul 3;7:21. doi: 10.1186/1745-6150-7-21.
• [3] A genome-wide association study identifies risk loci for spirometric measures among smokers of European and African ancestry.BMC Genet. 2015 Dec 3;16:138. doi: 10.1186/s12863-015-0299-4.
• [4] Identification of transcription factors that may reprogram lung adenocarcinoma.Artif Intell Med. 2017 Nov;83:52-57. doi: 10.1016/j.artmed.2017.03.010. Epub 2017 Apr 1.
• [5] Genetic Variants in HSD17B3, SMAD3, and IPO11 Impact Circulating Lipids in Response to Fenofibrate in Individuals With Type 2 Diabetes.Clin Pharmacol Ther. 2018 Apr;103(4):712-721. doi: 10.1002/cpt.798. Epub 2017 Nov 3.
• [6] Genome-wide analysis revealed sex-specific gene expression in asthmatics.Hum Mol Genet. 2019 Aug 1;28(15):2600-2614. doi: 10.1093/hmg/ddz074.
• [7] Aurora kinase A regulates Survivin stability through targeting FBXL7 in gastric cancer drug resistance and prognosis.Oncogenesis. 2017 Feb 20;6(2):e298. doi: 10.1038/oncsis.2016.80.
• [8] Integrative omics data analyses of repeated dose toxicity of valproic acid in vitro reveal new mechanisms of steatosis induction. Toxicology. 2018 Jan 15;393:160-170.
• [9] Integrative "-Omics" analysis in primary human hepatocytes unravels persistent mechanisms of cyclosporine A-induced cholestasis. Chem Res Toxicol. 2016 Dec 19;29(12):2164-2174.
• [10] Multiple microRNAs function as self-protective modules in acetaminophen-induced hepatotoxicity in humans. Arch Toxicol. 2018 Feb;92(2):845-858.
• [11] 17-Estradiol Activates HSF1 via MAPK Signaling in ER-Positive Breast Cancer Cells. Cancers (Basel). 2019 Oct 11;11(10):1533. doi: 10.3390/cancers11101533.
• [12] 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.
• [13] 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.
• [14] Changes in gene expression profiles of multiple myeloma cells induced by arsenic trioxide (ATO): possible mechanisms to explain ATO resistance in vivo. Br J Haematol. 2005 Mar;128(5):636-44.
• [15] Temporal changes in gene expression in the skin of patients treated with isotretinoin provide insight into its mechanism of action. Dermatoendocrinol. 2009 May;1(3):177-87.
• [16] 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.
• [17] 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.
• [18] 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.