Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTJXE4OT)

• DOT Name: F-box/WD repeat-containing protein 7 (FBXW7)
• Synonyms: Archipelago homolog; hAgo; F-box and WD-40 domain-containing protein 7; F-box protein FBX30; SEL-10; hCdc4
• Gene Name: FBXW7
• Related Disease: Developmental delay, hypotonia, and impaired language
• UniProt ID: FBXW7_HUMAN
• PDB ID: 2OVP; 2OVQ; 2OVR; 5IBK; 5V4B; 7T1Y; 7T1Z
• Pfam ID: PF12937 ; PF00400
• Sequence:
  MNQELLSVGSKRRRTGGSLRGNPSSSQVDEEQMNRVVEEEQQQQLRQQEEEHTARNGEVV
  GVEPRPGGQNDSQQGQLEENNNRFISVDEDSSGNQEEQEEDEEHAGEQDEEDEEEEEMDQ
  ESDDFDQSDDSSREDEHTHTNSVTNSSSIVDLPVHQLSSPFYTKTTKMKRKLDHGSEVRS
  FSLGKKPCKVSEYTSTTGLVPCSATPTTFGDLRAANGQGQQRRRITSVQPPTGLQEWLKM
  FQSWSGPEKLLALDELIDSCEPTQVKHMMQVIEPQFQRDFISLLPKELALYVLSFLEPKD
  LLQAAQTCRYWRILAEDNLLWREKCKEEGIDEPLHIKRRKVIKPGFIHSPWKSAYIRQHR
  IDTNWRRGELKSPKVLKGHDDHVITCLQFCGNRIVSGSDDNTLKVWSAVTGKCLRTLVGH
  TGGVWSSQMRDNIIISGSTDRTLKVWNAETGECIHTLYGHTSTVRCMHLHEKRVVSGSRD
  ATLRVWDIETGQCLHVLMGHVAAVRCVQYDGRRVVSGAYDFMVKVWDPETETCLHTLQGH
  TNRVYSLQFDGIHVVSGSLDTSIRVWDVETGNCIHTLTGHQSLTSGMELKDNILVSGNAD
  STVKIWDIKTGQCLQTLQGPNKHQSAVTCLQFNKNFVITSSDDGTVKLWDLKTGEFIRNL
  VTLESGGSGGVVWRIRASNTKLVCAVGSRNGTEETKLLVLDFDVDMK
• Function: Substrate recognition component of a SCF (SKP1-CUL1-F-box protein) E3 ubiquitin-protein ligase complex which mediates the ubiquitination and subsequent proteasomal degradation of target proteins. Recognizes and binds phosphorylated sites/phosphodegrons within target proteins and thereafter brings them to the SCF complex for ubiquitination. Identified substrates include cyclin-E (CCNE1 or CCNE2), DISC1, JUN, MYC, NOTCH1 released notch intracellular domain (NICD), NFE2L1, NOTCH2, MCL1, MLST8, RICTOR, and probably PSEN1. Acts as a negative regulator of JNK signaling by binding to phosphorylated JUN and promoting its ubiquitination and subsequent degradation. Involved in bone homeostasis and negative regulation of osteoclast differentiation. Regulates the amplitude of the cyclic expression of hepatic core clock genes and genes involved in lipid and glucose metabolism via ubiquitination and proteasomal degradation of their transcriptional repressor NR1D1; CDK1-dependent phosphorylation of NR1D1 is necessary for SCF(FBXW7)-mediated ubiquitination. Also able to promote 'Lys-63'-linked ubiquitination in response to DNA damage. The SCF(FBXW7) complex facilitates double-strand break repair following phosphorylation by ATM: phosphorylation promotes localization to sites of double-strand breaks and 'Lys-63'-linked ubiquitination of phosphorylated XRCC4, enhancing DNA non-homologous end joining.
• Tissue Specificity: .Widely expressed.; [Isoform 3]: Expressed in brain.
• KEGG Pathway: Ubiquitin mediated proteolysis (hsa04120)
• Reactome Pathway:
  Constitutive Signaling by NOTCH1 PEST Domain Mutants (R-HSA-2644606)
  Loss of Function of FBXW7 in Cancer and NOTCH1 Signaling (R-HSA-2644607)
  Constitutive Signaling by NOTCH1 HD+PEST Domain Mutants (R-HSA-2894862)
  Association of TriC/CCT with target proteins during biosynthesis (R-HSA-390471)
  Neddylation (R-HSA-8951664)
  Negative regulation of NOTCH4 signaling (R-HSA-9604323)
  Antigen processing (R-HSA-983168)
  NOTCH1 Intracellular Domain Regulates Transcription (R-HSA-2122947)

Molecular Interaction Atlas (MIA) of This DOT

1 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Developmental delay, hypotonia, and impaired language	DISI5M6G	Strong	Autosomal dominant	[1]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the methylation of F-box/WD repeat-containing protein 7 (FBXW7).	[2]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of F-box/WD repeat-containing protein 7 (FBXW7).	[15]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of F-box/WD repeat-containing protein 7 (FBXW7).	[3]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of F-box/WD repeat-containing protein 7 (FBXW7).	[4]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of F-box/WD repeat-containing protein 7 (FBXW7).	[5]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of F-box/WD repeat-containing protein 7 (FBXW7).	[6]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of F-box/WD repeat-containing protein 7 (FBXW7).	[7]
Quercetin	DM3NC4M	Approved	Quercetin increases the expression of F-box/WD repeat-containing protein 7 (FBXW7).	[8]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide increases the expression of F-box/WD repeat-containing protein 7 (FBXW7).	[9]
Demecolcine	DMCZQGK	Approved	Demecolcine increases the expression of F-box/WD repeat-containing protein 7 (FBXW7).	[10]
Bortezomib	DMNO38U	Approved	Bortezomib decreases the expression of F-box/WD repeat-containing protein 7 (FBXW7).	[11]
Cyclophosphamide	DM4O2Z7	Approved	Cyclophosphamide increases the expression of F-box/WD repeat-containing protein 7 (FBXW7).	[12]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of F-box/WD repeat-containing protein 7 (FBXW7).	[13]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of F-box/WD repeat-containing protein 7 (FBXW7).	[14]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A affects the expression of F-box/WD repeat-containing protein 7 (FBXW7).	[16]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of F-box/WD repeat-containing protein 7 (FBXW7).	[17]

References

• [1] 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.
• [2] 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.
• [3] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [4] 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.
• [5] Predictive toxicology using systemic biology and liver microfluidic "on chip" approaches: application to acetaminophen injury. Toxicol Appl Pharmacol. 2012 Mar 15;259(3):270-80.
• [6] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [7] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [8] Multifaceted preventive effects of single agent quercetin on a human prostate adenocarcinoma cell line (PC-3): implications for nutritional transcriptomics and multi-target therapy. Med Oncol. 2011 Dec;28(4):1395-404. doi: 10.1007/s12032-010-9603-3. Epub 2010 Jul 2.
• [9] Loss of Notch1-dependent p21(Waf1/Cip1) expression influences the Notch1 outcome in tumorigenesis. Cell Cycle. 2014;13(13):2046-55. doi: 10.4161/cc.29079. Epub 2014 May 6.
• [10] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [11] The proapoptotic effect of zoledronic acid is independent of either the bone microenvironment or the intrinsic resistance to bortezomib of myeloma cells and is enhanced by the combination with arsenic trioxide. Exp Hematol. 2011 Jan;39(1):55-65.
• [12] Comparison of Drug Metabolism and Its Related Hepatotoxic Effects in HepaRG, Cryopreserved Human Hepatocytes, and HepG2 Cell Cultures. Biol Pharm Bull. 2018 May 1;41(5):722-732. doi: 10.1248/bpb.b17-00913. Epub 2018 Feb 14.
• [13] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [14] Transcriptional signature of human macrophages exposed to the environmental contaminant benzo(a)pyrene. Toxicol Sci. 2010 Apr;114(2):247-59.
• [15] 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.
• [16] A trichostatin A expression signature identified by TempO-Seq targeted whole transcriptome profiling. PLoS One. 2017 May 25;12(5):e0178302. doi: 10.1371/journal.pone.0178302. eCollection 2017.
• [17] Gene expression changes in primary human nasal epithelial cells exposed to formaldehyde in vitro. Toxicol Lett. 2010 Oct 5;198(2):289-95.