Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTIH80EK)

• DOT Name: Small ribosomal subunit protein eS4, X isoform (RPS4X)
• Synonyms: 40S ribosomal protein S4; SCR10; Single copy abundant mRNA protein
• Gene Name: RPS4X
• Related Disease:
  Breast cancer
  Breast carcinoma
  Breast neoplasm
  Cerebellar ataxia
  Cryptococcosis
  Hepatitis C virus infection
  Histoplasmosis
  Intrahepatic cholangiocarcinoma
  Psoriatic arthritis
  Advanced cancer
  Colorectal carcinoma
  Neoplasm
  Tuberculosis
  Multiple sclerosis
  Rheumatoid arthritis
  Turner syndrome
• UniProt ID: RS4X_HUMAN
• PDB ID: 4UG0 ; 4V6X ; 5A2Q ; 5LKS ; 5OA3 ; 5T2C ; 5VYC ; 6FEC ; 6G18 ; 6G4S ; 6G4W ; 6G51 ; 6G53 ; 6G5H ; 6G5I ; 6IP5 ; 6IP6 ; 6IP8 ; 6OLE ; 6OLF ; 6OLI ; 6OM0 ; 6OM7 ; 6QZP ; 6XA1 ; 6Y0G ; 6Y2L ; 6Y57 ; 6YBW ; 6Z6L ; 6Z6M ; 6Z6N ; 6ZLW ; 6ZM7 ; 6ZME ; 6ZMI ; 6ZMO ; 6ZMT ; 6ZMW ; 6ZN5 ; 6ZOJ ; 6ZOK ; 6ZON ; 6ZP4 ; 6ZUO ; 6ZV6 ; 6ZVH ; 6ZVJ ; 6ZXD ; 6ZXE ; 6ZXF ; 6ZXG ; 6ZXH ; 7A09 ; 7K5I ; 7MQ8 ; 7MQA ; 7QP6 ; 7QP7 ; 7QVP ; 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: PF16121 ; PF00467 ; PF00900 ; PF08071
• Sequence:
  MARGPKKHLKRVAAPKHWMLDKLTGVFAPRPSTGPHKLRECLPLIIFLRNRLKYALTGDE
  VKKICMQRFIKIDGKVRTDITYPAGFMDVISIDKTGENFRLIYDTKGRFAVHRITPEEAK
  YKLCKVRKIFVGTKGIPHLVTHDARTIRYPDPLIKVNDTIQIDLETGKITDFIKFDTGNL
  CMVTGGANLGRIGVITNRERHPGSFDVVHVKDANGNSFATRLSNIFVIGKGNKPWISLPR
  GKGIRLTIAEERDKRLAAKQSSG
• 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)
  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

16 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Breast cancer	DIS7DPX1	Strong	Altered Expression	[1]
Breast carcinoma	DIS2UE88	Strong	Altered Expression	[1]
Breast neoplasm	DISNGJLM	Strong	Biomarker	[2]
Cerebellar ataxia	DIS9IRAV	Strong	Genetic Variation	[3]
Cryptococcosis	DISDYDTK	Strong	Biomarker	[4]
Hepatitis C virus infection	DISQ0M8R	Strong	Altered Expression	[5]
Histoplasmosis	DISGTF4W	Strong	Biomarker	[4]
Intrahepatic cholangiocarcinoma	DIS6GOC8	Strong	Altered Expression	[6]
Psoriatic arthritis	DISLWTG2	Strong	Biomarker	[7]
Advanced cancer	DISAT1Z9	Disputed	Altered Expression	[8]
Colorectal carcinoma	DIS5PYL0	Disputed	Altered Expression	[8]
Neoplasm	DISZKGEW	Disputed	Altered Expression	[8]
Tuberculosis	DIS2YIMD	Disputed	Biomarker	[9]
Multiple sclerosis	DISB2WZI	Limited	Biomarker	[10]
Rheumatoid arthritis	DISTSB4J	Limited	Biomarker	[11]
Turner syndrome	DIS2035C	Limited	Biomarker	[12]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Small ribosomal subunit protein eS4, X isoform (RPS4X).	[13]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Small ribosomal subunit protein eS4, X isoform (RPS4X).	[14]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Small ribosomal subunit protein eS4, X isoform (RPS4X).	[15]
Marinol	DM70IK5	Approved	Marinol increases the expression of Small ribosomal subunit protein eS4, X isoform (RPS4X).	[16]
Epigallocatechin gallate	DMCGWBJ	Phase 3	Epigallocatechin gallate decreases the expression of Small ribosomal subunit protein eS4, X isoform (RPS4X).	[17]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Small ribosomal subunit protein eS4, X isoform (RPS4X).	[20]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Small ribosomal subunit protein eS4, X isoform (RPS4X).	[21]
chloropicrin	DMSGBQA	Investigative	chloropicrin affects the expression of Small ribosomal subunit protein eS4, X isoform (RPS4X).	[22]

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 affects the methylation of Small ribosomal subunit protein eS4, X isoform (RPS4X).	[18]
TAK-243	DM4GKV2	Phase 1	TAK-243 increases the sumoylation of Small ribosomal subunit protein eS4, X isoform (RPS4X).	[19]

References

• [1] Development of diagnostic SCAR markers for genomic DNA amplifications in breast carcinoma by DNA cloning of high-GC RAMP-PCR fragments.Oncotarget. 2017 Jul 4;8(27):43866-43877. doi: 10.18632/oncotarget.16704.
• [2] An integrative approach to identify YB-1-interacting proteins required for cisplatin resistance in MCF7 and MDA-MB-231 breast cancer cells. Cancer Sci. 2011 Jul;102(7):1410-7. doi: 10.1111/j.1349-7006.2011.01948.x. Epub 2011 May 5.
• [3] Heterozygous Missense Pathogenic Variants Within the Second Spectrin Repeat of SPTBN2 Lead to Infantile-Onset Cerebellar Ataxia.J Child Neurol. 2020 Feb;35(2):106-110. doi: 10.1177/0883073819878917. Epub 2019 Oct 16.
• [4] Development of specific sequence-characterized amplified region markers for detecting Histoplasma capsulatum in clinical and environmental samples.J Clin Microbiol. 2012 Mar;50(3):673-9. doi: 10.1128/JCM.05271-11. Epub 2011 Dec 21.
• [5] In vitro selection of the 3'-untranslated regions of the human liver mRNA that bind to the HCV nonstructural protein 5B.Virology. 2014 Feb;450-451:13-23. doi: 10.1016/j.virol.2013.11.036. Epub 2013 Dec 18.
• [6] Overexpression of the X-linked ribosomal protein S4 predicts poor prognosis in patients with intrahepatic cholangiocarcinoma.Oncol Lett. 2017 Jul;14(1):41-46. doi: 10.3892/ol.2017.6137. Epub 2017 May 8.
• [7] Activatable Small-Molecule Photoacoustic Probes that Cross the Blood-Brain Barrier for Visualization of Copper(II) in Mice with Alzheimer's Disease.Angew Chem Int Ed Engl. 2019 Sep 2;58(36):12415-12419. doi: 10.1002/anie.201904047. Epub 2019 Aug 1.
• [8] Clinical validation of colorectal cancer biomarkers identified from bioinformatics analysis of public expression data.Clin Cancer Res. 2011 Feb 15;17(4):700-9. doi: 10.1158/1078-0432.CCR-10-1300. Epub 2011 Feb 8.
• [9] The conservation and application of three hypothetical protein coding gene for direct detection of Mycobacterium tuberculosis in sputum specimens.PLoS One. 2013 Sep 13;8(9):e73955. doi: 10.1371/journal.pone.0073955. eCollection 2013.
• [10] Quantitative and qualitative changes in gene expression patterns characterize the activity of plaques in multiple sclerosis.Brain Res Mol Brain Res. 2003 Nov 26;119(2):170-83. doi: 10.1016/j.molbrainres.2003.09.008.
• [11] Anti-citrullinated glucose-6-phosphate isomerase peptide antibodies in patients with rheumatoid arthritis are associated with HLA-DRB1 shared epitope alleles and disease activity.Clin Exp Immunol. 2013 Apr;172(1):44-53. doi: 10.1111/cei.12033.
• [12] Ullrich-Turner syndrome is not caused by haploinsufficiency of RPS4X.Hum Genet. 1996 Jan;97(1):39-44. doi: 10.1007/BF00218830.
• [13] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [14] Identification of estrogen-induced genes downregulated by AhR agonists in MCF-7 breast cancer cells using suppression subtractive hybridization. Gene. 2001 Jan 10;262(1-2):207-14. doi: 10.1016/s0378-1119(00)00530-8.
• [15] 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.
• [16] Genomic and proteomic analysis of the effects of cannabinoids on normal human astrocytes. Brain Res. 2008 Jan 29;1191:1-11.
• [17] 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.
• [18] 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.
• [19] 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.
• [20] 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.
• [21] Low-dose Bisphenol A exposure alters the functionality and cellular environment in a human cardiomyocyte model. Environ Pollut. 2023 Oct 15;335:122359. doi: 10.1016/j.envpol.2023.122359. Epub 2023 Aug 9.
• [22] Transcriptomic analysis of human primary bronchial epithelial cells after chloropicrin treatment. Chem Res Toxicol. 2015 Oct 19;28(10):1926-35.