Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTJG15EO)

• DOT Name: F-box/WD repeat-containing protein 8 (FBXW8)
• Synonyms: F-box and WD-40 domain-containing protein 8; F-box only protein 29
• Gene Name: FBXW8
• Related Disease:
  Choriocarcinoma
  Fetal growth restriction
  Marginal zone lymphoma
  Rheumatoid arthritis
  Breast cancer
  Breast carcinoma
  Dementia
  Urinary bladder cancer
  Urinary bladder neoplasm
  Wilms tumor
• UniProt ID: FBXW8_HUMAN
• PDB ID: 7Z8B
• Pfam ID: PF12937
• Sequence:
  MDDYSLDEFRRRWQEELAQAQAPKKRRRPEAAERRARRPEVGSGRGEQASGDPALAQRLL
  EGAGRPPAARATRAEGQDVASRSRSPLAREGAGGGEQLVDQLIRDLNEMNDVPFFDIQLP
  YELAINIFQYLDRKELGRCAQVSKTWKVIAEDEVLWYRLCQQEGHLPDSSISDYSCWKLI
  FQECRAKEHMLRTNWKNRKGAVSELEHVPDTVLCDVHSHDGVVIAGYTSGDVRVWDTRTW
  DYVAPFLESEDEEDEPGMQPNVSFVRINSSLAVAAYEDGFLNIWDLRTGKYPVHRFEHDA
  RIQALALSQDDATVATASAFDVVMLSPNEEGYWQIAAEFEVPKLVQYLEIVPETRRYPVA
  VAAAGDLMYLLKAEDSARTLLYAHGPPVTCLDVSANQVAFGVQGLGWVYEGSKILVYSLE
  AGRRLLKLGNVLRDFTCVNLSDSPPNLMVSGNMDGRVRIHDLRSGNIALSLSAHQLRVSA
  VQMDDWKIVSGGEEGLVSVWDYRMNQKLWEVYSGHPVQHISFSSHSLITANVPYQTVMRN
  ADLDSFTTHRRHRGLIRAYEFAVDQLAFQSPLPVCRSSCDAMATHYYDLALAFPYNHV
• Function: Substrate-recognition component of a Cul7-RING ubiquitin-protein ligase complex, which mediates the ubiquitination and subsequent proteasomal degradation of target proteins. The Cul7-RING(FBXW8) complex mediates ubiquitination and consequent degradation of GORASP1, acting as a component of the ubiquitin ligase pathway that regulates Golgi morphogenesis and dendrite patterning in brain. Mediates ubiquitination and degradation of IRS1 in a mTOR-dependent manner: the Cul7-RING(FBXW8) complex recognizes and binds IRS1 previously phosphorylated by S6 kinase (RPS6KB1 or RPS6KB2). The Cul7-RING(FBXW8) complex also mediates ubiquitination of MAP4K1/HPK1: recognizes and binds autophosphorylated MAP4K1/HPK1, leading to its degradation, thereby affecting cell proliferation and differentiation. Associated component of the 3M complex, suggesting that it mediates some of 3M complex functions.
• KEGG Pathway: Ubiquitin mediated proteolysis (hsa04120)
• Reactome Pathway:
  Antigen processing (R-HSA-983168)
  Neddylation (R-HSA-8951664)

Molecular Interaction Atlas (MIA) of This DOT

10 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Choriocarcinoma	DISDBVNL	Definitive	Biomarker	[1]
Fetal growth restriction	DIS5WEJ5	Definitive	Altered Expression	[2]
Marginal zone lymphoma	DISLZ4AO	Definitive	Genetic Variation	[3]
Rheumatoid arthritis	DISTSB4J	Definitive	Genetic Variation	[3]
Breast cancer	DIS7DPX1	Strong	Genetic Variation	[4]
Breast carcinoma	DIS2UE88	Strong	Genetic Variation	[4]
Dementia	DISXL1WY	Strong	Biomarker	[5]
Urinary bladder cancer	DISDV4T7	Strong	Biomarker	[6]
Urinary bladder neoplasm	DIS7HACE	Strong	Biomarker	[6]
Wilms tumor	DISB6T16	Strong	Biomarker	[7]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of F-box/WD repeat-containing protein 8 (FBXW8).	[8]
Testosterone	DM7HUNW	Approved	Testosterone decreases the expression of F-box/WD repeat-containing protein 8 (FBXW8).	[10]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of F-box/WD repeat-containing protein 8 (FBXW8).	[11]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of F-box/WD repeat-containing protein 8 (FBXW8).	[13]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Arsenic	DMTL2Y1	Approved	Arsenic increases the methylation of F-box/WD repeat-containing protein 8 (FBXW8).	[6]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of F-box/WD repeat-containing protein 8 (FBXW8).	[12]

References

• [1] The long non-coding RNA MALAT1 interacted with miR-218 modulates choriocarcinoma growth by targeting Fbxw8.Biomed Pharmacother. 2018 Jan;97:543-550. doi: 10.1016/j.biopha.2017.10.083. Epub 2017 Nov 6.
• [2] Cullin 7 and Fbxw 8 expression in trophoblastic cells is regulated via oxygen tension: implications for intrauterine growth restriction?.J Matern Fetal Neonatal Med. 2012 Nov;25(11):2209-15. doi: 10.3109/14767058.2012.684166. Epub 2012 May 14.
• [3] Genetic overlap between autoimmune diseases and non-Hodgkin lymphoma subtypes.Genet Epidemiol. 2019 Oct;43(7):844-863. doi: 10.1002/gepi.22242. Epub 2019 Aug 13.
• [4] Assessment of a FBXW8 frameshift mutation, c.1312_1313delGT, in breast cancer patients and controls from Central Europe.Cancer Genet. 2018 Jan;220:38-43. doi: 10.1016/j.cancergen.2017.11.006. Epub 2017 Nov 28.
• [5] Common variants at 12q14 and 12q24 are associated with hippocampal volume.Nat Genet. 2012 Apr 15;44(5):545-51. doi: 10.1038/ng.2237.
• [6] Identification of novel gene targets and putative regulators of arsenic-associated DNA methylation in human urothelial cells and bladder cancer. Chem Res Toxicol. 2015 Jun 15;28(6):1144-55. doi: 10.1021/tx500393y. Epub 2015 Jun 3.
• [7] The CUG-translated WT1, not AUG-WT1, is an oncogene.Carcinogenesis. 2017 Dec 7;38(12):1228-1240. doi: 10.1093/carcin/bgx108.
• [8] 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.
• [9] Identification of novel gene targets and putative regulators of arsenic-associated DNA methylation in human urothelial cells and bladder cancer. Chem Res Toxicol. 2015 Jun 15;28(6):1144-55. doi: 10.1021/tx500393y. Epub 2015 Jun 3.
• [10] The exosome-like vesicles derived from androgen exposed-prostate stromal cells promote epithelial cells proliferation and epithelial-mesenchymal transition. Toxicol Appl Pharmacol. 2021 Jan 15;411:115384. doi: 10.1016/j.taap.2020.115384. Epub 2020 Dec 25.
• [11] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [12] 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.
• [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.