Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTUY0Q2I)

• DOT Name: Regulator of G-protein signaling 5 (RGS5)
• Synonyms: RGS5
• Gene Name: RGS5
• Related Disease:
  Advanced cancer
  Arteriosclerosis
  Carcinoma of liver and intrahepatic biliary tract
  Cardiovascular disease
  Clear cell renal carcinoma
  Coronary heart disease
  Depression
  Essential hypertension
  Hepatocellular carcinoma
  High blood pressure
  Hyperparathyroidism
  Liver cancer
  Metastatic malignant neoplasm
  Myocardial infarction
  Neuroblastoma
  Ovarian cancer
  Ovarian neoplasm
  Primary hyperparathyroidism
  Renal cell carcinoma
  Schizophrenia
  Stroke
  Lung cancer
  Lung carcinoma
  Rhabdomyosarcoma
  Atherosclerosis
  Benign neoplasm
  Melanoma
  Essential hypertension, genetic
• UniProt ID: RGS5_HUMAN
• PDB ID: 2CRP
• Pfam ID: PF00615
• Sequence:
  MCKGLAALPHSCLERAKEIKIKLGILLQKPDSVGDLVIPYNEKPEKPAKTQKTSLDEALQ
  WRDSLDKLLQNNYGLASFKSFLKSEFSEENLEFWIACEDYKKIKSPAKMAEKAKQIYEEF
  IQTEAPKEVNIDHFTKDITMKNLVEPSLSSFDMAQKRIHALMEKDSLPRFVRSEFYQELI
  K
• Function: Inhibits signal transduction by increasing the GTPase activity of G protein alpha subunits thereby driving them into their inactive GDP-bound form. Binds to G(i)-alpha and G(o)-alpha, but not to G(s)-alpha.
• Reactome Pathway:
  G alpha (i) signalling events (R-HSA-418594)
  G alpha (q) signalling events (R-HSA-416476)

Molecular Interaction Atlas (MIA) of This DOT

28 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Advanced cancer	DISAT1Z9	Strong	Altered Expression	[1]
Arteriosclerosis	DISK5QGC	Strong	Genetic Variation	[2]
Carcinoma of liver and intrahepatic biliary tract	DIS8WA0W	Strong	Altered Expression	[3]
Cardiovascular disease	DIS2IQDX	Strong	Genetic Variation	[4]
Clear cell renal carcinoma	DISBXRFJ	Strong	Biomarker	[5]
Coronary heart disease	DIS5OIP1	Strong	Genetic Variation	[2]
Depression	DIS3XJ69	Strong	Biomarker	[6]
Essential hypertension	DIS7WI98	Strong	Genetic Variation	[4]
Hepatocellular carcinoma	DIS0J828	Strong	Altered Expression	[7]
High blood pressure	DISY2OHH	Strong	Altered Expression	[8]
Hyperparathyroidism	DIS4FVAT	Strong	Altered Expression	[9]
Liver cancer	DISDE4BI	Strong	Altered Expression	[3]
Metastatic malignant neoplasm	DIS86UK6	Strong	Altered Expression	[3]
Myocardial infarction	DIS655KI	Strong	Biomarker	[10]
Neuroblastoma	DISVZBI4	Strong	Biomarker	[11]
Ovarian cancer	DISZJHAP	Strong	Altered Expression	[1]
Ovarian neoplasm	DISEAFTY	Strong	Biomarker	[1]
Primary hyperparathyroidism	DISB4U1Q	Strong	Biomarker	[9]
Renal cell carcinoma	DISQZ2X8	Strong	Biomarker	[5]
Schizophrenia	DISSRV2N	Strong	Genetic Variation	[12]
Stroke	DISX6UHX	Strong	Biomarker	[13]
Lung cancer	DISCM4YA	moderate	Altered Expression	[14]
Lung carcinoma	DISTR26C	moderate	Altered Expression	[14]
Rhabdomyosarcoma	DISNR7MS	moderate	Biomarker	[15]
Atherosclerosis	DISMN9J3	Limited	Genetic Variation	[2]
Benign neoplasm	DISDUXAD	Limited	Biomarker	[16]
Melanoma	DIS1RRCY	Limited	Biomarker	[17]
Essential hypertension, genetic	DISIVD4P	No Known	Unknown	[18]

19 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 Regulator of G-protein signaling 5 (RGS5).	[19]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Regulator of G-protein signaling 5 (RGS5).	[20]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Regulator of G-protein signaling 5 (RGS5).	[21]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of Regulator of G-protein signaling 5 (RGS5).	[22]
Quercetin	DM3NC4M	Approved	Quercetin increases the expression of Regulator of G-protein signaling 5 (RGS5).	[24]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of Regulator of G-protein signaling 5 (RGS5).	[25]
Vorinostat	DMWMPD4	Approved	Vorinostat increases the expression of Regulator of G-protein signaling 5 (RGS5).	[19]
Panobinostat	DM58WKG	Approved	Panobinostat increases the expression of Regulator of G-protein signaling 5 (RGS5).	[19]
Permethrin	DMZ0Q1G	Approved	Permethrin decreases the expression of Regulator of G-protein signaling 5 (RGS5).	[26]
Clorgyline	DMCEUJD	Approved	Clorgyline increases the expression of Regulator of G-protein signaling 5 (RGS5).	[27]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of Regulator of G-protein signaling 5 (RGS5).	[19]
Resveratrol	DM3RWXL	Phase 3	Resveratrol decreases the expression of Regulator of G-protein signaling 5 (RGS5).	[28]
Fenretinide	DMRD5SP	Phase 3	Fenretinide increases the expression of Regulator of G-protein signaling 5 (RGS5).	[29]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Regulator of G-protein signaling 5 (RGS5).	[31]
THAPSIGARGIN	DMDMQIE	Preclinical	THAPSIGARGIN decreases the expression of Regulator of G-protein signaling 5 (RGS5).	[32]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Regulator of G-protein signaling 5 (RGS5).	[34]
Manganese	DMKT129	Investigative	Manganese decreases the expression of Regulator of G-protein signaling 5 (RGS5).	[35]
Okadaic acid	DM47CO1	Investigative	Okadaic acid affects the expression of Regulator of G-protein signaling 5 (RGS5).	[11]
ELLAGIC ACID	DMX8BS5	Investigative	ELLAGIC ACID decreases the expression of Regulator of G-protein signaling 5 (RGS5).	[37]

3 Drug(s) Affected the Post-Translational Modifications of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of Regulator of G-protein signaling 5 (RGS5).	[23]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Regulator of G-protein signaling 5 (RGS5).	[30]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A affects the methylation of Regulator of G-protein signaling 5 (RGS5).	[33]

References

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• [2] Down-regulated RGS5 by genetic variants impairs endothelial cell function and contributes to coronary artery disease.Cardiovasc Res. 2021 Jan 1;117(1):240-255. doi: 10.1093/cvr/cvz268.
• [3] Over-expression of regulator of G protein signaling 5 promotes tumor metastasis by inducing epithelial-mesenchymal transition in hepatocellular carcinoma cells.J Surg Oncol. 2013 Sep;108(3):192-6. doi: 10.1002/jso.23367. Epub 2013 Jul 19.
• [4] Association of regulator of G protein signaling (RGS5) gene variants and essential hypertension in Mongolian and Han populations.Genet Mol Res. 2015 Dec 21;14(4):17641-50. doi: 10.4238/2015.December.21.37.
• [5] Expression of regulator of G protein signalling protein 5 (RGS5) in the tumour vasculature of human renal cell carcinoma.J Pathol. 2004 May;203(1):551-8. doi: 10.1002/path.1543.
• [6] Regulator of G-protein signaling 5 protein protects against anxiety- and depression-like behavior.Behav Pharmacol. 2019 Dec;30(8):712-721. doi: 10.1097/FBP.0000000000000506.
• [7] Programmed death-ligand 1 expression is an unfavorable prognostic factor of hepatocellular carcinoma after archiving sustained virologic response for hepatitis C virus infection.Oncol Lett. 2019 Aug;18(2):1458-1466. doi: 10.3892/ol.2019.10448. Epub 2019 Jun 7.
• [8] Hypertension-evoked RhoA activity in vascular smooth muscle cells requires RGS5.FASEB J. 2018 Apr;32(4):2021-2035. doi: 10.1096/fj.201700384RR. Epub 2018 Jan 5.
• [9] Parathyroid-Targeted Overexpression of Regulator of G-Protein Signaling 5 (RGS5) Causes Hyperparathyroidism in Transgenic Mice.J Bone Miner Res. 2019 May;34(5):955-963. doi: 10.1002/jbmr.3674. Epub 2019 Feb 28.
• [10] Regulator of G-protein signalling 5 deficiency impairs ventricular remodelling after myocardial infarction by promoting NF-B and MAPK signalling in mice.Biochem Biophys Res Commun. 2018 May 5;499(2):143-149. doi: 10.1016/j.bbrc.2018.03.082. Epub 2018 Mar 24.
• [11] Alterations in metabolism-related genes induced in SHSY5Y cells by okadaic acid exposure. J Toxicol Environ Health A. 2012;75(13-15):844-56. doi: 10.1080/15287394.2012.690703.
• [12] Association of RGS2 and RGS5 variants with schizophrenia symptom severity.Schizophr Res. 2008 Apr;101(1-3):67-75. doi: 10.1016/j.schres.2008.01.006. Epub 2008 Feb 11.
• [13] Regulator of G-protein signaling 5 regulates the shift from perivascular to parenchymal pericytes in the chronic phase after stroke.FASEB J. 2019 Aug;33(8):8990-8998. doi: 10.1096/fj.201900153R. Epub 2019 May 2.
• [14] Overexpression of the regulator of G-protein signaling5 reduces the survival rate and enhances the radiation response of human lung cancer cells.Oncol Rep. 2015 Jun;33(6):2899-907. doi: 10.3892/or.2015.3917. Epub 2015 Apr 20.
• [15] Muscle Stem Cells Give Rise to Rhabdomyosarcomas in a Severe Mouse Model of Duchenne Muscular Dystrophy.Cell Rep. 2019 Jan 15;26(3):689-701.e6. doi: 10.1016/j.celrep.2018.12.089.
• [16] Pericytes in Sarcomas and Other Mesenchymal Tumors.Adv Exp Med Biol. 2019;1147:109-124. doi: 10.1007/978-3-030-16908-4_4.
• [17] Regulator of G-protein signaling 5 (RGS5) protein: a novel marker of cancer vasculature elicited and sustained by the tumor's proangiogenic microenvironment.Cell Mol Life Sci. 2012 Apr;69(7):1167-78. doi: 10.1007/s00018-011-0862-8. Epub 2011 Dec 1.
• [18] Multiple genes for essential-hypertension susceptibility on chromosome 1q. Am J Hum Genet. 2007 Feb;80(2):253-64. doi: 10.1086/510918. Epub 2006 Dec 20.
• [19] A transcriptome-based classifier to identify developmental toxicants by stem cell testing: design, validation and optimization for histone deacetylase inhibitors. Arch Toxicol. 2015 Sep;89(9):1599-618.
• [20] 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.
• [21] 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.
• [22] Effects of progesterone treatment on expression of genes involved in uterine quiescence. Reprod Sci. 2011 Aug;18(8):781-97.
• [23] Prenatal arsenic exposure and the epigenome: identifying sites of 5-methylcytosine alterations that predict functional changes in gene expression in newborn cord blood and subsequent birth outcomes. Toxicol Sci. 2015 Jan;143(1):97-106. doi: 10.1093/toxsci/kfu210. Epub 2014 Oct 10.
• [24] 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.
• [25] Minimal peroxide exposure of neuronal cells induces multifaceted adaptive responses. PLoS One. 2010 Dec 17;5(12):e14352. doi: 10.1371/journal.pone.0014352.
• [26] Exposure to Insecticides Modifies Gene Expression and DNA Methylation in Hematopoietic Tissues In Vitro. Int J Mol Sci. 2023 Mar 26;24(7):6259. doi: 10.3390/ijms24076259.
• [27] Anti-oncogenic and pro-differentiation effects of clorgyline, a monoamine oxidase A inhibitor, on high grade prostate cancer cells. BMC Med Genomics. 2009 Aug 20;2:55. doi: 10.1186/1755-8794-2-55.
• [28] Differential expression of genes induced by resveratrol in LNCaP cells: P53-mediated molecular targets. Int J Cancer. 2003 Mar 20;104(2):204-12.
• [29] Regulation of lipocalin-2 gene by the cancer chemopreventive retinoid 4-HPR. Int J Cancer. 2006 Oct 1;119(7):1599-606.
• [30] 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.
• [31] 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.
• [32] Endoplasmic reticulum stress impairs insulin signaling through mitochondrial damage in SH-SY5Y cells. Neurosignals. 2012;20(4):265-80.
• [33] 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.
• [34] From transient transcriptome responses to disturbed neurodevelopment: role of histone acetylation and methylation as epigenetic switch between reversible and irreversible drug effects. Arch Toxicol. 2014 Jul;88(7):1451-68.
• [35] Gene expression profiling of human primary astrocytes exposed to manganese chloride indicates selective effects on several functions of the cells. Neurotoxicology. 2007 May;28(3):478-89.
• [36] Alterations in metabolism-related genes induced in SHSY5Y cells by okadaic acid exposure. J Toxicol Environ Health A. 2012;75(13-15):844-56. doi: 10.1080/15287394.2012.690703.
• [37] Interactive gene expression pattern in prostate cancer cells exposed to phenolic antioxidants. Life Sci. 2002 Mar 1;70(15):1821-39.