Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTYG5OXI)

• DOT Name: Regulator of G-protein signaling 3 (RGS3)
• Synonyms: RGP3; RGS3
• Gene Name: RGS3
• Related Disease:
  Arteriosclerosis
  Atherosclerosis
  Bladder disease
  Breast cancer
  Hypertrophic cardiomyopathy
  Lung squamous cell carcinoma
  Neoplasm
  Non-small-cell lung cancer
  Triple negative breast cancer
  Gastric cancer
  Gonorrhea
  Stomach cancer
  Astrocytoma
  Glioma
• UniProt ID: RGS3_HUMAN
• PDB ID: 2F5Y; 2OJ4; 3FBK
• Pfam ID: PF00168 ; PF00595 ; PF00615
• Sequence:
  MPVIPALWEVEMGRSQGQEIETILANRSHSDSTPLPNFLSGSHRPECCTCRLLTASGAQD
  SLPFGRRLYSGPWRSCEEVCHVSVLSVLSTSCGLSLSLPIFPGWMEWLSPDIALPRRDEW
  TQTSPARKRITHAKVQGAGQLRLSIDAQDRVLLLHIIEGKGLISKQPGTCDPYVKISLIP
  EDSRLRHQKTQTVPDCRDPAFHEHFFFPVQEEDDQKRLLVTVWNRASQSRQSGLIGCMSF
  GVKSLLTPDKEISGWYYLLGEHLGRTKHLKVARRRLRPLRDPLLRMPGGGDTENGKKLKI
  TIPRGKDGFGFTICCDSPVRVQAVDSGGPAERAGLQQLDTVLQLNERPVEHWKCVELAHE
  IRSCPSEIILLVWRMVPQVKPGPDGGVLRRASCKSTHDLQSPPNKREKNCTHGVQARPEQ
  RHSCHLVCDSSDGLLLGGWERYTEVAKRGGQHTLPALSRATAPTDPNYIILAPLNPGSQL
  LRPVYQEDTIPEESGSPSKGKSYTGLGKKSRLMKTVQTMKGHGNYQNCPVVRPHATHSSY
  GTYVTLAPKVLVFPVFVQPLDLCNPARTLLLSEELLLYEGRNKAAEVTLFAYSDLLLFTK
  EDEPGRCDVLRNPLYLQSVKLQEGSSEDLKFCVLYLAEKAECLFTLEAHSQEQKKRVCWC
  LSENIAKQQQLAASPPDSKMFETEADEKREMALEEGKGPGAEDSPPSKEPSPGQELPPGQ
  DLPPNKDSPSGQEPAPSQEPLSSKDSATSEGSPPGPDAPPSKDVPPCQEPPPAQDLSPCQ
  DLPAGQEPLPHQDPLLTKDLPAIQESPTRDLPPCQDLPPSQVSLPAKALTEDTMSSGDLL
  AATGDPPAAPRPAFVIPEVRLDSTYSQKAGAEQGCSGDEEDAEEAEEVEEGEEGEEDEDE
  DTSDDNYGERSEAKRSSMIETGQGAEGGLSLRVQNSLRRRTHSEGSLLQEPRGPCFASDT
  TLHCSDGEGAASTWGMPSPSTLKKELGRNGGSMHHLSLFFTGHRKMSGADTVGDDDEASR
  KRKSKNLAKDMKNKLGIFRRRNESPGAPPAGKADKMMKSFKPTSEEALKWGESLEKLLVH
  KYGLAVFQAFLRTEFSEENLEFWLACEDFKKVKSQSKMASKAKKIFAEYIAIQACKEVNL
  DSYTREHTKDNLQSVTRGCFDLAQKRIFGLMEKDSYPRFLRSDLYLDLINQKKMSPPL
• Function: Down-regulates signaling from heterotrimeric G-proteins by increasing the GTPase activity of the alpha subunits, thereby driving them into their inactive GDP-bound form. Down-regulates G-protein-mediated release of inositol phosphates and activation of MAP kinases.
• KEGG Pathway: Axon guidance (hsa04360)
• 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

14 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Arteriosclerosis	DISK5QGC	Strong	Biomarker	[1]
Atherosclerosis	DISMN9J3	Strong	Biomarker	[1]
Bladder disease	DISTVIQI	Strong	Therapeutic	[2]
Breast cancer	DIS7DPX1	Strong	Altered Expression	[3]
Hypertrophic cardiomyopathy	DISQG2AI	Strong	Genetic Variation	[4]
Lung squamous cell carcinoma	DISXPIBD	Strong	Altered Expression	[5]
Neoplasm	DISZKGEW	Strong	Altered Expression	[6]
Non-small-cell lung cancer	DIS5Y6R9	Strong	Altered Expression	[5]
Triple negative breast cancer	DISAMG6N	Strong	Biomarker	[7]
Gastric cancer	DISXGOUK	moderate	Biomarker	[6]
Gonorrhea	DISQ5AO6	moderate	Altered Expression	[6]
Stomach cancer	DISKIJSX	moderate	Biomarker	[6]
Astrocytoma	DISL3V18	Limited	Altered Expression	[8]
Glioma	DIS5RPEH	Limited	Biomarker	[9]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the methylation of Regulator of G-protein signaling 3 (RGS3).	[10]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Regulator of G-protein signaling 3 (RGS3).	[11]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Regulator of G-protein signaling 3 (RGS3).	[12]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Regulator of G-protein signaling 3 (RGS3).	[13]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of Regulator of G-protein signaling 3 (RGS3).	[14]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of Regulator of G-protein signaling 3 (RGS3).	[15]
Calcitriol	DM8ZVJ7	Approved	Calcitriol decreases the expression of Regulator of G-protein signaling 3 (RGS3).	[16]
Testosterone	DM7HUNW	Approved	Testosterone decreases the expression of Regulator of G-protein signaling 3 (RGS3).	[16]
Menadione	DMSJDTY	Approved	Menadione affects the expression of Regulator of G-protein signaling 3 (RGS3).	[15]
Folic acid	DMEMBJC	Approved	Folic acid decreases the expression of Regulator of G-protein signaling 3 (RGS3).	[17]
Demecolcine	DMCZQGK	Approved	Demecolcine increases the expression of Regulator of G-protein signaling 3 (RGS3).	[18]
Afimoxifene	DMFORDT	Phase 2	Afimoxifene increases the expression of Regulator of G-protein signaling 3 (RGS3).	[19]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene affects the expression of Regulator of G-protein signaling 3 (RGS3).	[20]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Regulator of G-protein signaling 3 (RGS3).	[21]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Regulator of G-protein signaling 3 (RGS3).	[22]

References

• [1] RGS3 inhibits TGF-1/Smad signalling in adventitial fibroblasts.Cell Biochem Funct. 2017 Aug;35(6):334-338. doi: 10.1002/cbf.3280.
• [2] Identification of potential therapeutic targets in hypertension-associated bladder dysfunction.BJU Int. 2010 Mar;105(6):877-83. doi: 10.1111/j.1464-410X.2009.08809.x. Epub 2009 Aug 18.
• [3] Possible involvement of CCT5, RGS3, and YKT6 genes up-regulated in p53-mutated tumors in resistance to docetaxel in human breast cancers.Breast Cancer Res Treat. 2007 Mar;101(3):305-15. doi: 10.1007/s10549-006-9293-x. Epub 2006 Jul 5.
• [4] Formin homology 2 domain containing 3 variants associated with hypertrophic cardiomyopathy.Circ Cardiovasc Genet. 2013 Feb;6(1):10-8. doi: 10.1161/CIRCGENETICS.112.965277. Epub 2012 Dec 19.
• [5] MiR-92a Family: A Novel Diagnostic Biomarker and Potential Therapeutic Target in Human Cancers.Front Mol Biosci. 2019 Oct 1;6:98. doi: 10.3389/fmolb.2019.00098. eCollection 2019.
• [6] Regulator of G-protein signaling 3 targeted by miR-126 correlates with poor prognosis in gastric cancer patients.Anticancer Drugs. 2017 Feb;28(2):161-169. doi: 10.1097/CAD.0000000000000446.
• [7] MicroRNA?26?p inhibits the proliferation, migration, invasion, and angiogenesis of triplenegative breast cancer cells by targeting RGS3.Oncol Rep. 2019 Oct;42(4):1569-1579. doi: 10.3892/or.2019.7251. Epub 2019 Jul 26.
• [8] Adenosine Receptors Differentially Regulate the Expression of Regulators of G-Protein Signalling (RGS) 2, 3 and 4 in Astrocyte-Like Cells.PLoS One. 2015 Aug 11;10(8):e0134934. doi: 10.1371/journal.pone.0134934. eCollection 2015.
• [9] Regulators of G-protein signaling 3 and 4 (RGS3, RGS4) are associated with glioma cell motility.J Neuropathol Exp Neurol. 2004 Mar;63(3):210-22. doi: 10.1093/jnen/63.3.210.
• [10] 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.
• [11] Integrative "-Omics" analysis in primary human hepatocytes unravels persistent mechanisms of cyclosporine A-induced cholestasis. Chem Res Toxicol. 2016 Dec 19;29(12):2164-2174.
• [12] Gene expression analysis of precision-cut human liver slices indicates stable expression of ADME-Tox related genes. Toxicol Appl Pharmacol. 2011 May 15;253(1):57-69.
• [13] The thioxotriazole copper(II) complex A0 induces endoplasmic reticulum stress and paraptotic death in human cancer cells. J Biol Chem. 2009 Sep 4;284(36):24306-19.
• [14] 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.
• [15] Time series analysis of oxidative stress response patterns in HepG2: a toxicogenomics approach. Toxicology. 2013 Apr 5;306:24-34.
• [16] Effects of 1alpha,25 dihydroxyvitamin D3 and testosterone on miRNA and mRNA expression in LNCaP cells. Mol Cancer. 2011 May 18;10:58.
• [17] Folic acid supplementation dysregulates gene expression in lymphoblastoid cells--implications in nutrition. Biochem Biophys Res Commun. 2011 Sep 9;412(4):688-92. doi: 10.1016/j.bbrc.2011.08.027. Epub 2011 Aug 16.
• [18] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [19] Gene expression preferentially regulated by tamoxifen in breast cancer cells and correlations with clinical outcome. Cancer Res. 2006 Jul 15;66(14):7334-40.
• [20] Influence of cell cycle on responses of MCF-7 cells to benzo[a]pyrene. BMC Genomics. 2011 Jun 29;12:333.
• [21] Bisphenolic compounds alter gene expression in MCF-7 cells through interaction with estrogen receptor . Toxicol Appl Pharmacol. 2020 Jul 15;399:115030. doi: 10.1016/j.taap.2020.115030. Epub 2020 May 6.
• [22] 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.