Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTPC9LQI)

• DOT Name: Protein lin-54 homolog (LIN54)
• Synonyms: CXC domain-containing protein 1
• Gene Name: LIN54
• Related Disease:
  Cardiovascular disease
  Esophageal adenocarcinoma
• UniProt ID: LIN54_HUMAN
• PDB ID: 5FD3
• Pfam ID: PF03638
• Sequence:
  MEVVPAEVNSLLPEEIMDTGITLVDDDSIEAVIVSSPIPMETELEEIVNINSTGDSTATP
  ISTEPITVYSNHTNQVAVNTTITKADSNTTVKPAFPSGLQKLGAQTPVTISANQIILNKV
  SQTSDLKLGNQTLKPDGQKLILTTLGKSGSPIVLALPHSQLPQAQKVTTQAQSGDAKLPP
  QQIKVVTIGGRPEVKPVIGVSALTPGSQLINTTTQPSVLQTQQLKTVQIAKKPRTPTSGP
  VITKLIFAKPINSKAVTGQTTQVSPPVIAGRVLSQSTPGTPSKTITISESGVIGSTLNST
  TQTPNKIAISPLKSPNKAVKSTVQTITVGGVSTSQFKTIIPLATAPNVQQIQVPGSKFHY
  VRLVTATSASSSTQPVSQNPSTNTQPLQQAKPVVVNTTPVRMSVPIVSAQAVKQVVPKPI
  NPTSQIVTTSQPQQRLIMPATPLPQIQPNLTNLPPGTVLAPAPGTGNVGYAVLPAQYVTQ
  LQQSSYVSIASNSTFTGTSGIQTQARLPFNGIIPSESASRPRKPCNCTKSLCLKLYCDCF
  ANGEFCNNCNCTNCYNNLEHENERQKAIKACLDRNPEAFKPKIGKGKEGESDRRHSKGCN
  CKRSGCLKNYCECYEAKIMCSSICKCIGCKNFEESPERKTLMHLADAAEVRVQQQTAAKT
  KLSSQISDLLTRPTPALNSGGGKLPFTFVTKEVAEATCNCLLAQAEQADKKGKSKAAAER
  MILEEFGRCLMSVINSAGKAKSDPCAMNC
• Function: Component of the DREAM complex, a multiprotein complex that can both act as a transcription activator or repressor depending on the context. In G0 phase, the complex binds to more than 800 promoters and is required for repression of E2F target genes. In S phase, the complex selectively binds to the promoters of G2/M genes whose products are required for mitosis and participates in their cell cycle dependent activation. In the complex, acts as a DNA-binding protein that binds the promoter of CDK1 in a sequence-specific manner. Specifically recognizes the consensus motif 5'-TTYRAA-3' in target DNA.
• KEGG Pathway: Cellular senescence (hsa04218)
• Reactome Pathway:
  Transcription of E2F targets under negative control by p107 (RBL1) and p130 (RBL2) in complex with HDAC1 (R-HSA-1362300)
  G0 and Early G1 (R-HSA-1538133)
  Polo-like kinase mediated events (R-HSA-156711)
  Cyclin E associated events during G1/S transition (R-HSA-69202)
  G1/S-Specific Transcription (R-HSA-69205)
  Cyclin A (R-HSA-69656)
  Transcription of E2F targets under negative control by DREAM complex (R-HSA-1362277)

Molecular Interaction Atlas (MIA) of This DOT

2 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Cardiovascular disease	DIS2IQDX	Strong	Genetic Variation	[1]
Esophageal adenocarcinoma	DISODWFP	Strong	Biomarker	[2]

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 Protein lin-54 homolog (LIN54).	[3]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Protein lin-54 homolog (LIN54).	[4]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of Protein lin-54 homolog (LIN54).	[5]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Protein lin-54 homolog (LIN54).	[6]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide increases the expression of Protein lin-54 homolog (LIN54).	[8]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Protein lin-54 homolog (LIN54).	[10]
Resorcinol	DMM37C0	Investigative	Resorcinol increases the expression of Protein lin-54 homolog (LIN54).	[12]

3 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 Protein lin-54 homolog (LIN54).	[7]
TAK-243	DM4GKV2	Phase 1	TAK-243 increases the sumoylation of Protein lin-54 homolog (LIN54).	[9]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 decreases the phosphorylation of Protein lin-54 homolog (LIN54).	[11]

References

• [1] Leveraging Polygenic Functional Enrichment to Improve GWAS Power.Am J Hum Genet. 2019 Jan 3;104(1):65-75. doi: 10.1016/j.ajhg.2018.11.008. Epub 2018 Dec 27.
• [2] Deregulation of the FOXM1 target gene network and its coregulatory partners in oesophageal adenocarcinoma.Mol Cancer. 2015 Mar 26;14:69. doi: 10.1186/s12943-015-0339-8.
• [3] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [4] 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.
• [5] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [6] Low doses of cisplatin induce gene alterations, cell cycle arrest, and apoptosis in human promyelocytic leukemia cells. Biomark Insights. 2016 Aug 24;11:113-21.
• [7] 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.
• [8] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [9] Inhibiting ubiquitination causes an accumulation of SUMOylated newly synthesized nuclear proteins at PML bodies. J Biol Chem. 2019 Oct 18;294(42):15218-15234. doi: 10.1074/jbc.RA119.009147. Epub 2019 Jul 8.
• [10] 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.
• [11] Quantitative phosphoproteomics reveal cellular responses from caffeine, coumarin and quercetin in treated HepG2 cells. Toxicol Appl Pharmacol. 2022 Aug 15;449:116110. doi: 10.1016/j.taap.2022.116110. Epub 2022 Jun 7.
• [12] A transcriptomics-based in vitro assay for predicting chemical genotoxicity in vivo. Carcinogenesis. 2012 Jul;33(7):1421-9.