Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTAGWV4B)

• DOT Name: F-box only protein 10 (FBXO10)
• Gene Name: FBXO10
• Related Disease:
  Breast carcinoma
  Mantle cell lymphoma
  Breast cancer
• UniProt ID: FBX10_HUMAN
• Pfam ID: PF13229 ; PF12937 ; PF05048
• Sequence:
  MEAGGLPLELWRMILAYLHLPDLGRCSLVCRAWYELILSLDSTRWRQLCLGCTECRHPNW
  PNQPDVEPESWREAFKQHYLASKTWTKNALDLESSICFSLFRRRRERRTLSVGPGREFDS
  LGSALAMASLYDRIVLFPGVYEEQGEIILKVPVEIVGQGKLGEVALLASIDQHCSTTRLC
  NLVFTPAWFSPIMYKTTSGHVQFDNCNFENGHIQVHGPGTCQVKFCTFKNTHIFLHNVPL
  CVLENCEFVGSENNSVTVEGHPSADKNWAYKYLLGLIKSSPTFLPTEDSDFLMSLDLESR
  DQAWSPKTCDIVIEGSQSPTSPASSSPKPGSKAGSQEAEVGSDGERVAQTPDSSDGGLSP
  SGEDEDEDQLMYRLSYQVQGPRPVLGGSFLGPPLPGASIQLPSCLVLNSLQQELQKDKEA
  MALANSVQGCLIRKCLFRDGKGGVFVCSHGRAKMEGNIFRNLTYAVRCIHNSKIIMLRND
  IYRCRASGIFLRLEGGGLIAGNNIYHNAEAGVDIRKKSNPLILCNQIHHGLRSGIVVLGN
  GKGIIRNNQIFSNKEAGIYILYHGNPVVSGNHIFKGRAAGIAVNENGKGLITENVIRENQ
  WGGVDIRRGGIPVLRSNLICFGYSDGVVVGDEGKGLIEGNTIYANKGCGVWMMSSSLPHV
  TSNHVSYNGLYGVAVFSQKDGSSELPRGHRAQENFSEDGDAILWETELEKEDDPLRRPIT
  IALVESNSINHNGASGLYVQSSEALHVITNVIHANGDRGITVAQSSQPTRVANNSISCNR
  QSGVKVEAQCKVELRGNGIYDNRGHGIITKGDSTIVIENDIIGNRGSGLQLLPRSDTKVI
  KNRIHSFRAYGIAVRGRAKALVQENIIFQGKTSKTIFQQISNNRECIMQNNKFLVFKKKS
  DTWRLVNPPARPHLENSLRRPSAAHNGQKVTAMATRITARVEGGYHSNRSVFCTIL
• Function: Substrate-recognition component of the SCF (SKP1-CUL1-F-box protein)-type E3 ubiquitin ligase complex. Mediates the ubiquitination and degradation of BCL2, an antiapoptotic protein, thereby playing a role in apoptosis by controlling the stability of BCL2. Targets also the receptor for advanced glycation end products RAGE for ubiquitination and subsequent lysosomal degradation. Directly controls HGAL/GCSAM ubiquitination and degradation and thereby decreases BCR signaling.
• Reactome Pathway:
  Antigen processing (R-HSA-983168)
  Neddylation (R-HSA-8951664)

Molecular Interaction Atlas (MIA) of This DOT

3 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Breast carcinoma	DIS2UE88	Strong	Genetic Variation	[1]
Mantle cell lymphoma	DISFREOV	Strong	Biomarker	[2]
Breast cancer	DIS7DPX1	moderate	Genetic Variation	[1]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of F-box only protein 10 (FBXO10).	[3]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of F-box only protein 10 (FBXO10).	[4]
Quercetin	DM3NC4M	Approved	Quercetin increases the expression of F-box only protein 10 (FBXO10).	[5]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of F-box only protein 10 (FBXO10).	[8]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the methylation of F-box only protein 10 (FBXO10).	[6]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of F-box only protein 10 (FBXO10).	[7]

References

• [1] Differential 12-O-Tetradecanoylphorbol-13-acetate-induced activation of rat mammary carcinoma susceptibility Fbxo10 variant promoters via a PKC-AP1 pathway.Mol Carcinog. 2015 Feb;54(2):134-47. doi: 10.1002/mc.22081. Epub 2013 Sep 5.
• [2] FBXO10 deficiency and BTK activation upregulate BCL2 expression in mantle cell lymphoma.Oncogene. 2016 Dec 1;35(48):6223-6234. doi: 10.1038/onc.2016.155. Epub 2016 May 9.
• [3] 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.
• [4] Transforming growth factor beta1 targets estrogen receptor signaling in bronchial epithelial cells. Respir Res. 2018 Aug 30;19(1):160. doi: 10.1186/s12931-018-0861-5.
• [5] 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.
• [6] 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.
• [7] 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.
• [8] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.