Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTA0F7TM)

• DOT Name: F-box-like/WD repeat-containing protein TBL1Y (TBL1Y)
• Synonyms: Transducin beta-like protein 1Y; Transducin-beta-like protein 1, Y-linked
• Gene Name: TBL1Y
• Related Disease:
  Aorta coarctation
  Bone osteosarcoma
  Breast adenocarcinoma
  Breast cancer
  Breast carcinoma
  Fatty liver disease
  Non-alcoholic fatty liver disease
  Obesity
  Osteosarcoma
  Sensorineural hearing loss disorder
  Coronary atherosclerosis
  Coronary heart disease
  X-linked recessive ocular albinism
  Deafness, Y-linked 2
• UniProt ID: TBL1Y_HUMAN
• Pfam ID: PF08513 ; PF00400
• Sequence:
  MSITSDEVNFLVYRYLQESGFSHSAFTFGIESHISQSNINGTLVPPSALISILQKGLQYV
  EAEISINKDGTVFDSRPIESLSLIVAVIPDVVQMRQQAFGEKLTQQQASAAATEASAMAK
  AATMTPAAISQQNPPKNREATVNGEENGAHEINNHSKPMEIDGDVEIPPNKATVLRGHES
  EVFICAWNPVSDLLASGSGDSTARIWNLNENSNGGSTQLVLRHCIREGGHDVPSNKDVTS
  LDWNSDGTLLAMGSYDGFARIWTENGNLASTLGQHKGPIFALKWNKKGNYVLSAGVDKTT
  IIWDAHTGEAKQQFPFHSAPALDVDWQNNMTFASCSTDMCIHVCRLGCDHPVKTFQGHTN
  EVNAIKWDPSGMLLASCSDDMTLKIWSMKQDACVHDLQAHSKEIYTIKWSPTGPATSNPN
  SSIMLASASFDSTVRLWDVEQGVCTHTLMKHQEPVYSVAFSPDGKYLASGSFDKYVHIWN
  TQSGSLVHSYQGTGGIFEVCWNARGDKVGASASDGSVCVLDL
• Function: F-box-like protein involved in the recruitment of the ubiquitin/19S proteasome complex to nuclear receptor-regulated transcription units. Plays an essential role in transcription activation mediated by nuclear receptors. Probably acts as integral component of corepressor complexes that mediates the recruitment of the 19S proteasome complex, leading to the subsequent proteasomal degradation of transcription repressor complexes, thereby allowing cofactor exchange.
• Tissue Specificity: Fetal brain and prostate. Expressed in the cochlear spiral ganglion neurons, and in outer and inner hair cells .
• KEGG Pathway: Wnt sig.ling pathway (hsa04310)

Molecular Interaction Atlas (MIA) of This DOT

14 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Aorta coarctation	DISAFXDJ	Strong	Biomarker	[1]
Bone osteosarcoma	DIST1004	Strong	Biomarker	[2]
Breast adenocarcinoma	DISMPHJ0	Strong	Altered Expression	[3]
Breast cancer	DIS7DPX1	Strong	Biomarker	[4]
Breast carcinoma	DIS2UE88	Strong	Biomarker	[4]
Fatty liver disease	DIS485QZ	Strong	Altered Expression	[5]
Non-alcoholic fatty liver disease	DISDG1NL	Strong	Biomarker	[6]
Obesity	DIS47Y1K	Strong	Altered Expression	[5]
Osteosarcoma	DISLQ7E2	Strong	Biomarker	[2]
Sensorineural hearing loss disorder	DISJV45Z	Strong	Genetic Variation	[7]
Coronary atherosclerosis	DISKNDYU	moderate	Genetic Variation	[8]
Coronary heart disease	DIS5OIP1	moderate	Genetic Variation	[8]
X-linked recessive ocular albinism	DISI9S32	moderate	Biomarker	[9]
Deafness, Y-linked 2	DISNB2UF	Limited	Y-linked inheritance	[10]

1 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-like/WD repeat-containing protein TBL1Y (TBL1Y).	[11]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Methotrexate	DM2TEOL	Approved	Methotrexate decreases the expression of F-box-like/WD repeat-containing protein TBL1Y (TBL1Y).	[12]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of F-box-like/WD repeat-containing protein TBL1Y (TBL1Y).	[13]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde increases the expression of F-box-like/WD repeat-containing protein TBL1Y (TBL1Y).	[14]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of F-box-like/WD repeat-containing protein TBL1Y (TBL1Y).	[15]

References

• [1] Functional null mutations in the gonosomal homologue gene TBL1Y are associated with non-syndromic coarctation of the aorta.Curr Mol Med. 2012 Feb;12(2):199-205. doi: 10.2174/156652412798889027.
• [2] Tegavivint and the beta-Catenin/ALDH Axis in Chemotherapy-Resistant and Metastatic Osteosarcoma. J Natl Cancer Inst. 2019 Nov 1;111(11):1216-1227.
• [3] Transducin -like protein 1 recruits nuclear factor B to the target gene promoter for transcriptional activation.Mol Cell Biol. 2011 Mar;31(5):924-34. doi: 10.1128/MCB.00576-10. Epub 2010 Dec 28.
• [4] TBL1 is required for the mesenchymal phenotype of transformed breast cancer cells.Cell Death Dis. 2019 Jan 31;10(2):95. doi: 10.1038/s41419-019-1310-1.
• [5] Hepatic deficiency in transcriptional cofactor TBL1 promotes liver steatosis and hypertriglyceridemia.Cell Metab. 2011 Apr 6;13(4):389-400. doi: 10.1016/j.cmet.2011.02.011.
• [6] Up-regulation of microRNA-367 promotes liver steatosis through repressing TBL1 in obese mice.Eur Rev Med Pharmacol Sci. 2017 Apr;21(7):1598-1603.
• [7] A core SMRT corepressor complex containing HDAC3 and TBL1, a WD40-repeat protein linked to deafness.Genes Dev. 2000 May 1;14(9):1048-57.
• [8] Genetic variants of Y chromosome are associated with a protective lipid profile in black men.Arterioscler Thromb Vasc Biol. 2008 Aug;28(8):1569-74. doi: 10.1161/ATVBAHA.108.168641. Epub 2008 May 29.
• [9] X-linked late-onset sensorineural deafness caused by a deletion involving OA1 and a novel gene containing WD-40 repeats.Am J Hum Genet. 1999 Jun;64(6):1604-16. doi: 10.1086/302408.
• [10] TBL1Y: a new gene involved in syndromic hearing loss. Eur J Hum Genet. 2019 Mar;27(3):466-474. doi: 10.1038/s41431-018-0282-4. Epub 2018 Oct 19.
• [11] 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.
• [12] Global molecular effects of tocilizumab therapy in rheumatoid arthritis synovium. Arthritis Rheumatol. 2014 Jan;66(1):15-23.
• [13] Transcriptional signature of human macrophages exposed to the environmental contaminant benzo(a)pyrene. Toxicol Sci. 2010 Apr;114(2):247-59.
• [14] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [15] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.