Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTB90KV5)

• DOT Name: Small ribosomal subunit protein uS11 (RPS14)
• Synonyms: 40S ribosomal protein S14
• Gene Name: RPS14
• Related Disease:
  Carcinoma
  Acute myelogenous leukaemia
  Advanced cancer
  Anemia
  Bladder cancer
  Breast cancer
  Breast carcinoma
  Breast neoplasm
  Chromosomal disorder
  Diamond-Blackfan anemia
  Liposarcoma
  Lung squamous cell carcinoma
  Myelofibrosis
  Pancytopenia
  Partial trisomy of the long arm of chromosome 5
  Primary myelofibrosis
  Childhood myelodysplastic syndrome
  Treacher-Collins syndrome
  Neoplasm
  Undifferentiated carcinoma
  Lymphoid leukemia
  Myelodysplastic syndrome
• UniProt ID: RS14_HUMAN
• PDB ID: 4UG0 ; 4V6X ; 5A2Q ; 5AJ0 ; 5FLX ; 5LKS ; 5OA3 ; 5T2C ; 5VYC ; 6FEC ; 6G18 ; 6G4S ; 6G4W ; 6G51 ; 6G53 ; 6G5H ; 6G5I ; 6IP5 ; 6IP6 ; 6IP8 ; 6OLE ; 6OLF ; 6OLG ; 6OLI ; 6OLZ ; 6OM0 ; 6OM7 ; 6QZP ; 6XA1 ; 6Y0G ; 6Y2L ; 6Y57 ; 6YBD ; 6YBW ; 6Z6L ; 6Z6M ; 6Z6N ; 6ZLW ; 6ZM7 ; 6ZME ; 6ZMI ; 6ZMO ; 6ZMT ; 6ZMW ; 6ZN5 ; 6ZOJ ; 6ZOK ; 6ZON ; 6ZP4 ; 6ZUO ; 6ZV6 ; 6ZVH ; 6ZXD ; 6ZXE ; 6ZXF ; 6ZXG ; 6ZXH ; 7A09 ; 7K5I ; 7MQ8 ; 7MQ9 ; 7MQA ; 7QP6 ; 7QP7 ; 7R4X ; 7TQL ; 7WTS ; 7WTT ; 7WTU ; 7WTV ; 7WTW ; 7WTX ; 7WTZ ; 7WU0 ; 7XNX ; 7XNY ; 8G5Y ; 8G60 ; 8G61 ; 8G6J ; 8GLP ; 8JDJ ; 8JDK ; 8JDL ; 8JDM ; 8PPK ; 8PPL ; 8T4S
• Pfam ID: PF00411
• Sequence:
  MAPRKGKEKKEEQVISLGPQVAEGENVFGVCHIFASFNDTFVHVTDLSGKETICRVTGGM
  KVKADRDESSPYAAMLAAQDVAQRCKELGITALHIKLRATGGNRTKTPGPGAQSALRALA
  RSGMKIGRIEDVTPIPSDSTRRKGGRRGRRL
• Function: Component of the small ribosomal subunit. The ribosome is a large ribonucleoprotein complex responsible for the synthesis of proteins in the cell. Part of the small subunit (SSU) processome, first precursor of the small eukaryotic ribosomal subunit. During the assembly of the SSU processome in the nucleolus, many ribosome biogenesis factors, an RNA chaperone and ribosomal proteins associate with the nascent pre-rRNA and work in concert to generate RNA folding, modifications, rearrangements and cleavage as well as targeted degradation of pre-ribosomal RNA by the RNA exosome.
• KEGG Pathway:
  Ribosome (hsa03010)
  Coro.virus disease - COVID-19 (hsa05171)
• Reactome Pathway:
  Peptide chain elongation (R-HSA-156902)
  SRP-dependent cotranslational protein targeting to membrane (R-HSA-1799339)
  Viral mRNA Translation (R-HSA-192823)
  Selenocysteine synthesis (R-HSA-2408557)
  rRNA modification in the nucleus and cytosol (R-HSA-6790901)
  Major pathway of rRNA processing in the nucleolus and cytosol (R-HSA-6791226)
  Translation initiation complex formation (R-HSA-72649)
  Formation of a pool of free 40S subunits (R-HSA-72689)
  Formation of the ternary complex, and subsequently, the 43S complex (R-HSA-72695)
  Ribosomal scanning and start codon recognition (R-HSA-72702)
  GTP hydrolysis and joining of the 60S ribosomal subunit (R-HSA-72706)
  Eukaryotic Translation Termination (R-HSA-72764)
  Regulation of expression of SLITs and ROBOs (R-HSA-9010553)
  Response of EIF2AK4 (GCN2) to amino acid deficiency (R-HSA-9633012)
  SARS-CoV-1 modulates host translation machinery (R-HSA-9735869)
  SARS-CoV-2 modulates host translation machinery (R-HSA-9754678)
  Nonsense Mediated Decay (NMD) independent of the Exon Junction Complex (EJC) (R-HSA-975956)
  Nonsense Mediated Decay (NMD) enhanced by the Exon Junction Complex (EJC) (R-HSA-975957)
  L13a-mediated translational silencing of Ceruloplasmin expression (R-HSA-156827)

Molecular Interaction Atlas (MIA) of This DOT

22 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Carcinoma	DISH9F1N	Definitive	Biomarker	[1]
Acute myelogenous leukaemia	DISCSPTN	Strong	Biomarker	[2]
Advanced cancer	DISAT1Z9	Strong	Genetic Variation	[3]
Anemia	DISTVL0C	Strong	Biomarker	[4]
Bladder cancer	DISUHNM0	Strong	Biomarker	[5]
Breast cancer	DIS7DPX1	Strong	Altered Expression	[6]
Breast carcinoma	DIS2UE88	Strong	Altered Expression	[6]
Breast neoplasm	DISNGJLM	Strong	Altered Expression	[7]
Chromosomal disorder	DISM5BB5	Strong	Biomarker	[8]
Diamond-Blackfan anemia	DISI2SNW	Strong	Genetic Variation	[9]
Liposarcoma	DIS8IZVM	Strong	Altered Expression	[6]
Lung squamous cell carcinoma	DISXPIBD	Strong	Biomarker	[10]
Myelofibrosis	DISIMP21	Strong	Biomarker	[11]
Pancytopenia	DISVKEHV	Strong	Biomarker	[12]
Partial trisomy of the long arm of chromosome 5	DISFHG81	Strong	Biomarker	[13]
Primary myelofibrosis	DIS6L0CN	Strong	Biomarker	[11]
Childhood myelodysplastic syndrome	DISMN80I	moderate	Genetic Variation	[14]
Treacher-Collins syndrome	DIS2GXZ1	moderate	Genetic Variation	[15]
Neoplasm	DISZKGEW	Disputed	Biomarker	[16]
Undifferentiated carcinoma	DISIAZST	Disputed	Biomarker	[1]
Lymphoid leukemia	DIS65TYQ	Limited	Biomarker	[17]
Myelodysplastic syndrome	DISYHNUI	Limited	Biomarker	[18]

This DOT Affected the Drug Response of 1 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Cisplatin	DMRHGI9	Approved	Small ribosomal subunit protein uS11 (RPS14) affects the response to substance of Cisplatin.	[29]

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 Small ribosomal subunit protein uS11 (RPS14).	[19]
TAK-243	DM4GKV2	Phase 1	TAK-243 increases the sumoylation of Small ribosomal subunit protein uS11 (RPS14).	[25]

8 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 Small ribosomal subunit protein uS11 (RPS14).	[20]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Small ribosomal subunit protein uS11 (RPS14).	[21]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of Small ribosomal subunit protein uS11 (RPS14).	[22]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Small ribosomal subunit protein uS11 (RPS14).	[23]
Nabiximols	DMHKJ5I	Phase 3	Nabiximols increases the expression of Small ribosomal subunit protein uS11 (RPS14).	[24]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Small ribosomal subunit protein uS11 (RPS14).	[26]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 increases the expression of Small ribosomal subunit protein uS11 (RPS14).	[27]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Small ribosomal subunit protein uS11 (RPS14).	[28]

References

• [1] Global gene expression profiling of chemically induced rat mammary gland carcinomas and adenomas.Toxicol Pathol. 2005;33(7):768-75. doi: 10.1080/01926230500437027.
• [2] Ribosomal protein S14 silencing inhibits growth of acute myeloid leukemia transformed from myelodysplastic syndromes via activating p53.Hematology. 2014 Jun;19(4):225-31. doi: 10.1179/1607845413Y.0000000127. Epub 2013 Nov 25.
• [3] A cryptic deletion in 5q31.2 provides further evidence for a minimally deleted region in myelodysplastic syndromes.Cancer Genet. 2011 Apr;204(4):187-94. doi: 10.1016/j.cancergen.2011.02.001.
• [4] The molecular pathogenesis of the myelodysplastic syndromes.Eur J Haematol. 2015 Jul;95(1):3-15. doi: 10.1111/ejh.12515. Epub 2015 Feb 20.
• [5] Identification of new hub genes associated with bladder carcinoma via bioinformatics analysis.Tumori. 2015 Jan-Feb;101(1):117-22. doi: 10.5301/tj.5000196. Epub 2015 Feb 6.
• [6] Conjugated linoleic acid (CLA) inhibits expression of the Spot 14 (THRSP) and fatty acid synthase genes and impairs the growth of human breast cancer and liposarcoma cells.Nutr Cancer. 2009;61(1):114-22. doi: 10.1080/01635580802348666.
• [7] S14 protein in breast cancer cells: direct evidence of regulation by SREBP-1c, superinduction with progestin, and effects on cell growth.Exp Cell Res. 2006 Feb 1;312(3):278-88. doi: 10.1016/j.yexcr.2005.10.022. Epub 2005 Nov 21.
• [8] Changes in RPS14 expression levels during lenalidomide treatment in Low- and Intermediate-1-risk myelodysplastic syndromes with chromosome 5q deletion.Eur J Haematol. 2010 Sep;85(3):231-5. doi: 10.1111/j.1600-0609.2010.01473.x. Epub 2010 May 17.
• [9] Diminutive somatic deletions in the 5q region lead to a phenotype atypical of classical 5q- syndrome.Blood. 2013 Oct 3;122(14):2487-90. doi: 10.1182/blood-2013-06-509935. Epub 2013 Aug 13.
• [10] Identification of reference genes for qRT-PCR in human lung squamous-cell carcinoma by RNA-Seq.Acta Biochim Biophys Sin (Shanghai). 2014 Apr;46(4):330-7. doi: 10.1093/abbs/gmt153. Epub 2014 Jan 23.
• [11] The thrombopoietin/MPL axis is activated in the Gata1(low) mouse model of myelofibrosis and is associated with a defective RPS14 signature.Blood Cancer J. 2017 Jun 16;7(6):e572. doi: 10.1038/bcj.2017.51.
• [12] Acquired ribosomopathies in leukemia and solid tumors.Hematology Am Soc Hematol Educ Program. 2017 Dec 8;2017(1):716-719. doi: 10.1182/asheducation-2017.1.716.
• [13] Rps14, Csnk1a1 and miRNA145/miRNA146a deficiency cooperate in the clinical phenotype and activation of the innate immune system in the 5q- syndrome.Leukemia. 2019 Jul;33(7):1759-1772. doi: 10.1038/s41375-018-0350-3. Epub 2019 Jan 16.
• [14] Downregulation of GATA1 drives impaired hematopoiesis in primary myelofibrosis.J Clin Invest. 2017 Apr 3;127(4):1316-1320. doi: 10.1172/JCI82905. Epub 2017 Feb 27.
• [15] A YAC contig encompassing the Treacher Collins syndrome critical region at 5q31.3-32.Am J Hum Genet. 1994 Aug;55(2):372-8.
• [16] Gene expression profiling of CD34+ cells in patients with the 5q- syndrome.Br J Haematol. 2007 Nov;139(4):578-89. doi: 10.1111/j.1365-2141.2007.06833.x. Epub 2007 Oct 3.
• [17] Possible new genetic marker for human lymphoid leukemias as detected by ribosomal protein S14 cDNA.Leukemia. 1993 Feb;7(2):318-22.
• [18] MMP9 inhibition increases erythropoiesis in RPS14-deficient del(5q) MDS models through suppression of TGF- pathways.Blood Adv. 2019 Sep 24;3(18):2751-2763. doi: 10.1182/bloodadvances.2019000537.
• [19] 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.
• [20] Comparison of HepG2 and HepaRG by whole-genome gene expression analysis for the purpose of chemical hazard identification. Toxicol Sci. 2010 May;115(1):66-79.
• [21] Phenotypic characterization of retinoic acid differentiated SH-SY5Y cells by transcriptional profiling. PLoS One. 2013 May 28;8(5):e63862.
• [22] Genistein and bisphenol A exposure cause estrogen receptor 1 to bind thousands of sites in a cell type-specific manner. Genome Res. 2012 Nov;22(11):2153-62.
• [23] Quantitative proteomics reveals a broad-spectrum antiviral property of ivermectin, benefiting for COVID-19 treatment. J Cell Physiol. 2021 Apr;236(4):2959-2975. doi: 10.1002/jcp.30055. Epub 2020 Sep 22.
• [24] Clinical response to Nabiximols correlates with the downregulation of immune pathways in multiple sclerosis. Eur J Neurol. 2018 Jul;25(7):934-e70. doi: 10.1111/ene.13623. Epub 2018 Apr 16.
• [25] 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.
• [26] 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.
• [27] Comparative proteomics reveals concordant and discordant biochemical effects of caffeine versus epigallocatechin-3-gallate in human endothelial cells. Toxicol Appl Pharmacol. 2019 Sep 1;378:114621. doi: 10.1016/j.taap.2019.114621. Epub 2019 Jun 10.
• [28] Bisphenol A induces DSB-ATM-p53 signaling leading to cell cycle arrest, senescence, autophagy, stress response, and estrogen release in human fetal lung fibroblasts. Arch Toxicol. 2018 Apr;92(4):1453-1469.
• [29] Gene expression profiling of 30 cancer cell lines predicts resistance towards 11 anticancer drugs at clinically achieved concentrations. Int J Cancer. 2006 Apr 1;118(7):1699-712. doi: 10.1002/ijc.21570.