Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT6ZHAWC)

• DOT Name: GTP-binding protein 4 (GTPBP4)
• Synonyms: Chronic renal failure gene protein; GTP-binding protein NGB; Nucleolar GTP-binding protein 1
• Gene Name: GTPBP4
• Related Disease:
  Chronic renal failure
  End-stage renal disease
  Cleft lip/palate
  Cleft palate
  Colorectal carcinoma
  Isolated cleft palate
  Metastatic malignant neoplasm
  Neoplasm
  Advanced cancer
  Hepatocellular carcinoma
  Gastric cancer
  Lentivirus infection
  Stomach cancer
• UniProt ID: GTPB4_HUMAN
• PDB ID: 6LSS ; 6LU8 ; 8FKP ; 8FKQ ; 8FKR ; 8FKS ; 8FKT ; 8FKU ; 8FKV ; 8FKW ; 8FKX ; 8FKY ; 8FKZ ; 8FL0 ; 8FL2 ; 8FL3 ; 8FL4 ; 8FL6 ; 8FL7 ; 8FL9 ; 8FLA ; 8FLB ; 8FLC ; 8FLD ; 8FLE ; 8FLF ; 8IDT ; 8IDY ; 8IE3 ; 8INE ; 8INF ; 8INK ; 8IPD ; 8IPX ; 8IPY ; 8IR1 ; 8IR3
• Pfam ID: PF06858 ; PF17835 ; PF08155
• Sequence:
  MAHYNFKKITVVPSAKDFIDLTLSKTQRKTPTVIHKHYQIHRIRHFYMRKVKFTQQNYHD
  RLSQILTDFPKLDDIHPFYADLMNILYDKDHYKLALGQINIAKNLVDNVAKDYVRLMKYG
  DSLYRCKQLKRAALGRMCTVIKRQKQSLEYLEQVRQHLSRLPTIDPNTRTLLLCGYPNVG
  KSSFINKVTRADVDVQPYAFTTKSLFVGHMDYKYLRWQVVDTPGILDHPLEDRNTIEMQA
  ITALAHLRAAVLYVMDLSEQCGHGLREQLELFQNIRPLFINKPLIVVANKCDVKRIAELS
  EDDQKIFTDLQSEGFPVIETSTLTEEGVIKVKTEACDRLLAHRVETKMKGNKVNEVLNRL
  HLAIPTRRDDKERPPFIPEGVVARRKRMETEESRKKRERDLELEMGDDYILDLQKYWDLM
  NLSEKHDKIPEIWEGHNIADYIDPAIMKKLEELEKEEELRTAAGEYDSVSESEDEEMLEI
  RQLAKQIREKKKLKILESKEKNTQGPRMPRTAKKVQRTVLEKEMRSLGVDMDDKDDAHYA
  VQARRSRSITRKRKREDSAPPSSVARSGSCSRTPRDVSGLRDVKMVKKAKTMMKNAQKKM
  NRLGKKGEADRHVFDMKPKHLLSGKRKAGKKDRR
• Function: Involved in the biogenesis of the 60S ribosomal subunit. Acts as a TP53 repressor, preventing TP53 stabilization and cell cycle arrest.
• KEGG Pathway: Ribosome biogenesis in eukaryotes (hsa03008)

Molecular Interaction Atlas (MIA) of This DOT

13 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Chronic renal failure	DISGG7K6	Definitive	Genetic Variation	[1]
End-stage renal disease	DISXA7GG	Definitive	Biomarker	[2]
Cleft lip/palate	DIS14IG3	Strong	Biomarker	[3]
Cleft palate	DIS6G5TF	Strong	Genetic Variation	[3]
Colorectal carcinoma	DIS5PYL0	Strong	Biomarker	[4]
Isolated cleft palate	DISV80CD	Strong	Genetic Variation	[3]
Metastatic malignant neoplasm	DIS86UK6	Strong	Biomarker	[4]
Neoplasm	DISZKGEW	Strong	Biomarker	[4]
Advanced cancer	DISAT1Z9	moderate	Biomarker	[5]
Hepatocellular carcinoma	DIS0J828	moderate	Biomarker	[5]
Gastric cancer	DISXGOUK	Limited	Altered Expression	[6]
Lentivirus infection	DISX17PY	Limited	Biomarker	[6]
Stomach cancer	DISKIJSX	Limited	Altered Expression	[6]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Fluorouracil	DMUM7HZ	Approved	GTP-binding protein 4 (GTPBP4) affects the response to substance of Fluorouracil.	[24]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the expression of GTP-binding protein 4 (GTPBP4).	[7]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of GTP-binding protein 4 (GTPBP4).	[8]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of GTP-binding protein 4 (GTPBP4).	[9]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of GTP-binding protein 4 (GTPBP4).	[10]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of GTP-binding protein 4 (GTPBP4).	[11]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of GTP-binding protein 4 (GTPBP4).	[12]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of GTP-binding protein 4 (GTPBP4).	[13]
Vorinostat	DMWMPD4	Approved	Vorinostat decreases the expression of GTP-binding protein 4 (GTPBP4).	[14]
Marinol	DM70IK5	Approved	Marinol decreases the expression of GTP-binding protein 4 (GTPBP4).	[15]
Menadione	DMSJDTY	Approved	Menadione affects the expression of GTP-binding protein 4 (GTPBP4).	[13]
Diethylstilbestrol	DMN3UXQ	Approved	Diethylstilbestrol decreases the expression of GTP-binding protein 4 (GTPBP4).	[16]
Benzatropine	DMF7EXL	Approved	Benzatropine increases the expression of GTP-binding protein 4 (GTPBP4).	[17]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of GTP-binding protein 4 (GTPBP4).	[18]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of GTP-binding protein 4 (GTPBP4).	[22]

4 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 GTP-binding protein 4 (GTPBP4).	[19]
TAK-243	DM4GKV2	Phase 1	TAK-243 increases the sumoylation of GTP-binding protein 4 (GTPBP4).	[20]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 decreases the phosphorylation of GTP-binding protein 4 (GTPBP4).	[21]
Glyphosate	DM0AFY7	Investigative	Glyphosate affects the methylation of GTP-binding protein 4 (GTPBP4).	[23]

References

• [1] Genetic associations at 53 loci highlight cell types and biological pathways relevant for kidney function.Nat Commun. 2016 Jan 21;7:10023. doi: 10.1038/ncomms10023.
• [2] Identification of a novel nuclear guanosine triphosphate-binding protein differentially expressed in renal disease.J Am Soc Nephrol. 2001 May;12(5):883-890. doi: 10.1681/ASN.V125883.
• [3] A Population-Based Study of Effects of Genetic Loci on Orofacial Clefts.J Dent Res. 2017 Oct;96(11):1322-1329. doi: 10.1177/0022034517716914. Epub 2017 Jun 29.
• [4] Up-regulation of GTPBP4 in colorectal carcinoma is responsible for tumor metastasis.Biochem Biophys Res Commun. 2016 Nov 4;480(1):48-54. doi: 10.1016/j.bbrc.2016.10.010. Epub 2016 Oct 5.
• [5] Knockdown of GTPBP4 inhibits cell growth and survival in human hepatocellular carcinoma and its prognostic significance.Oncotarget. 2017 Oct 5;8(55):93984-93997. doi: 10.18632/oncotarget.21500. eCollection 2017 Nov 7.
• [6] GTPBP4 Promotes Gastric Cancer Progression via Regulating P53 Activity.Cell Physiol Biochem. 2018;45(2):667-676. doi: 10.1159/000487160. Epub 2018 Jan 31.
• [7] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [8] 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.
• [9] Transcriptional and Metabolic Dissection of ATRA-Induced Granulocytic Differentiation in NB4 Acute Promyelocytic Leukemia Cells. Cells. 2020 Nov 5;9(11):2423. doi: 10.3390/cells9112423.
• [10] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [11] 17-Estradiol Activates HSF1 via MAPK Signaling in ER-Positive Breast Cancer Cells. Cancers (Basel). 2019 Oct 11;11(10):1533. doi: 10.3390/cancers11101533.
• [12] 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.
• [13] Global gene expression analysis reveals differences in cellular responses to hydroxyl- and superoxide anion radical-induced oxidative stress in caco-2 cells. Toxicol Sci. 2010 Apr;114(2):193-203. doi: 10.1093/toxsci/kfp309. Epub 2009 Dec 31.
• [14] A genomic approach to predict synergistic combinations for breast cancer treatment. Pharmacogenomics J. 2013 Feb;13(1):94-104. doi: 10.1038/tpj.2011.48. Epub 2011 Nov 15.
• [15] THC exposure of human iPSC neurons impacts genes associated with neuropsychiatric disorders. Transl Psychiatry. 2018 Apr 25;8(1):89. doi: 10.1038/s41398-018-0137-3.
• [16] Identification of biomarkers and outcomes of endocrine disruption in human ovarian cortex using In Vitro Models. Toxicology. 2023 Feb;485:153425. doi: 10.1016/j.tox.2023.153425. Epub 2023 Jan 5.
• [17] Cannabidiol Displays Proteomic Similarities to Antipsychotics in Cuprizone-Exposed Human Oligodendrocytic Cell Line MO3.13. Front Mol Neurosci. 2021 May 28;14:673144. doi: 10.3389/fnmol.2021.673144. eCollection 2021.
• [18] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [19] 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.
• [20] 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.
• [21] 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.
• [22] 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.
• [23] Association of Glyphosate Exposure with Blood DNA Methylation in a Cross-Sectional Study of Postmenopausal Women. Environ Health Perspect. 2022 Apr;130(4):47001. doi: 10.1289/EHP10174. Epub 2022 Apr 4.
• [24] 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.