Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTOXNDI9)

• DOT Name: Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-4 (GNG4)
• Synonyms: Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-4
• Gene Name: GNG4
• Related Disease:
  Advanced cancer
  Clear cell renal carcinoma
  Malignant thymoma
  Neoplasm
  Renal cell carcinoma
• UniProt ID: GBG4_HUMAN
• Pfam ID: PF00631
• Sequence:
  MKEGMSNNSTTSISQARKAVEQLKMEACMDRVKVSQAAADLLAYCEAHVREDPLIIPVPA
  SENPFREKKFFCTIL
• Function: Guanine nucleotide-binding proteins (G proteins) are involved as a modulator or transducer in various transmembrane signaling systems. The beta and gamma chains are required for the GTPase activity, for replacement of GDP by GTP, and for G protein-effector interaction.
• Tissue Specificity: Brain, kidney, pancreas, skeletal muscle and faintly in cardiac muscle.
• KEGG Pathway:
  Ras sig.ling pathway (hsa04014)
  Chemokine sig.ling pathway (hsa04062)
  PI3K-Akt sig.ling pathway (hsa04151)
  Apelin sig.ling pathway (hsa04371)
  Circadian entrainment (hsa04713)
  Retrograde endocan.binoid sig.ling (hsa04723)
  Glutamatergic sy.pse (hsa04724)
  Cholinergic sy.pse (hsa04725)
  Serotonergic sy.pse (hsa04726)
  GABAergic sy.pse (hsa04727)
  Dopaminergic sy.pse (hsa04728)
  Relaxin sig.ling pathway (hsa04926)
  Morphine addiction (hsa05032)
  Alcoholism (hsa05034)
  Human cytomegalovirus infection (hsa05163)
  Kaposi sarcoma-associated herpesvirus infection (hsa05167)
  Human immunodeficiency virus 1 infection (hsa05170)
  Pathways in cancer (hsa05200)
• Reactome Pathway:
  Glucagon signaling in metabolic regulation (R-HSA-163359)
  G-protein activation (R-HSA-202040)
  Glucagon-like Peptide-1 (GLP1) regulates insulin secretion (R-HSA-381676)
  ADP signalling through P2Y purinoceptor 12 (R-HSA-392170)
  G beta (R-HSA-392451)
  Prostacyclin signalling through prostacyclin receptor (R-HSA-392851)
  Adrenaline,noradrenaline inhibits insulin secretion (R-HSA-400042)
  Ca2+ pathway (R-HSA-4086398)
  G alpha (q) signalling events (R-HSA-416476)
  G alpha (12/13) signalling events (R-HSA-416482)
  G beta (R-HSA-418217)
  G alpha (s) signalling events (R-HSA-418555)
  ADP signalling through P2Y purinoceptor 1 (R-HSA-418592)
  G alpha (i) signalling events (R-HSA-418594)
  G alpha (z) signalling events (R-HSA-418597)
  Glucagon-type ligand receptors (R-HSA-420092)
  Thromboxane signalling through TP receptor (R-HSA-428930)
  Vasopressin regulates renal water homeostasis via Aquaporins (R-HSA-432040)
  Thrombin signalling through proteinase activated receptors (PARs) (R-HSA-456926)
  Presynaptic function of Kainate receptors (R-HSA-500657)
  Cooperation of PDCL (PhLP1) and TRiC/CCT in G-protein beta folding (R-HSA-6814122)
  G beta (R-HSA-8964315)
  G beta (R-HSA-8964616)
  Extra-nuclear estrogen signaling (R-HSA-9009391)
  GPER1 signaling (R-HSA-9634597)
  ADORA2B mediated anti-inflammatory cytokines production (R-HSA-9660821)
  Inhibition of voltage gated Ca2+ channels via Gbeta/gamma subunits (R-HSA-997272)
  Activation of G protein gated Potassium channels (R-HSA-1296041)

Molecular Interaction Atlas (MIA) of This DOT

5 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Advanced cancer	DISAT1Z9	Strong	Genetic Variation	[1]
Clear cell renal carcinoma	DISBXRFJ	Strong	Altered Expression	[2]
Malignant thymoma	DIS59MOU	Strong	Posttranslational Modification	[1]
Neoplasm	DISZKGEW	Strong	Altered Expression	[2]
Renal cell carcinoma	DISQZ2X8	Strong	Altered Expression	[2]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the expression of Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-4 (GNG4).	[3]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-4 (GNG4).	[4]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-4 (GNG4).	[5]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-4 (GNG4).	[6]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-4 (GNG4).	[7]
Testosterone	DM7HUNW	Approved	Testosterone decreases the expression of Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-4 (GNG4).	[8]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-4 (GNG4).	[9]
Isotretinoin	DM4QTBN	Approved	Isotretinoin decreases the expression of Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-4 (GNG4).	[10]
Ethanol	DMDRQZU	Approved	Ethanol decreases the expression of Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-4 (GNG4).	[11]
Diclofenac	DMPIHLS	Approved	Diclofenac affects the expression of Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-4 (GNG4).	[9]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-4 (GNG4).	[12]
Tamibarotene	DM3G74J	Phase 3	Tamibarotene decreases the expression of Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-4 (GNG4).	[5]
Tocopherol	DMBIJZ6	Phase 2	Tocopherol decreases the expression of Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-4 (GNG4).	[13]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde increases the expression of Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-4 (GNG4).	[16]

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 increases the methylation of Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-4 (GNG4).	[14]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-4 (GNG4).	[15]

References

• [1] DNA methylation of GHSR, GNG4, HOXD9 and SALL3 is a common epigenetic alteration in thymic carcinoma.Int J Oncol. 2020 Jan;56(1):315-326. doi: 10.3892/ijo.2019.4915. Epub 2019 Nov 18.
• [2] Identification of novel VHL target genes and relationship to hypoxic response pathways.Oncogene. 2005 Jun 30;24(28):4549-58. doi: 10.1038/sj.onc.1208649.
• [3] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [4] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [5] Differential modulation of PI3-kinase/Akt pathway during all-trans retinoic acid- and Am80-induced HL-60 cell differentiation revealed by DNA microarray analysis. Biochem Pharmacol. 2004 Dec 1;68(11):2177-86.
• [6] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [7] Comparison of phenotypic and transcriptomic effects of false-positive genotoxins, true genotoxins and non-genotoxins using HepG2 cells. Mutagenesis. 2011 Sep;26(5):593-604.
• [8] The exosome-like vesicles derived from androgen exposed-prostate stromal cells promote epithelial cells proliferation and epithelial-mesenchymal transition. Toxicol Appl Pharmacol. 2021 Jan 15;411:115384. doi: 10.1016/j.taap.2020.115384. Epub 2020 Dec 25.
• [9] Drug-induced endoplasmic reticulum and oxidative stress responses independently sensitize toward TNF-mediated hepatotoxicity. Toxicol Sci. 2014 Jul;140(1):144-59. doi: 10.1093/toxsci/kfu072. Epub 2014 Apr 20.
• [10] Temporal changes in gene expression in the skin of patients treated with isotretinoin provide insight into its mechanism of action. Dermatoendocrinol. 2009 May;1(3):177-87.
• [11] Chronic ethanol exposure increases goosecoid (GSC) expression in human embryonic carcinoma cell differentiation. J Appl Toxicol. 2014 Jan;34(1):66-75.
• [12] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [13] Selenium and vitamin E: cell type- and intervention-specific tissue effects in prostate cancer. J Natl Cancer Inst. 2009 Mar 4;101(5):306-20.
• [14] 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.
• [15] DNA methylome-wide alterations associated with estrogen receptor-dependent effects of bisphenols in breast cancer. Clin Epigenetics. 2019 Oct 10;11(1):138. doi: 10.1186/s13148-019-0725-y.
• [16] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.