Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTG94HHL)

• DOT Name: Regulator of G-protein signaling 4 (RGS4)
• Synonyms: RGP4; RGS4
• Gene Name: RGS4
• UniProt ID: RGS4_HUMAN
• Pfam ID: PF00615
• Sequence:
  MCKGLAGLPASCLRSAKDMKHRLGFLLQKSDSCEHNSSHNKKDKVVICQRVSQEEVKKWA
  ESLENLISHECGLAAFKAFLKSEYSEENIDFWISCEEYKKIKSPSKLSPKAKKIYNEFIS
  VQATKEVNLDSCTREETSRNMLEPTITCFDEAQKKIFNLMEKDSYRRFLKSRFYLDLVNP
  SSCGAEKQKGAKSSADCASLVPQCA
• Function: Inhibits signal transduction by increasing the GTPase activity of G protein alpha subunits thereby driving them into their inactive GDP-bound form. Activity on G(z)-alpha is inhibited by phosphorylation of the G-protein. Activity on G(z)-alpha and G(i)-alpha-1 is inhibited by palmitoylation of the G-protein.
• Tissue Specificity: Expressed in brain and heart. Expressed in brain at protein level. Expressed in prefontal and visual cortex. Isoform 4 and isoform 5 are expressed ubiquitously. Isoform 1, isoform 2 and isoform 3 are not expressed in the cerebellum.
• Reactome Pathway:
  G alpha (i) signalling events (R-HSA-418594)
  G alpha (z) signalling events (R-HSA-418597)
  G alpha (q) signalling events (R-HSA-416476)

Molecular Interaction Atlas (MIA) of This DOT

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Fluorouracil	DMUM7HZ	Approved	Regulator of G-protein signaling 4 (RGS4) affects the response to substance of Fluorouracil.	[22]

24 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 4 (RGS4).	[1]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Regulator of G-protein signaling 4 (RGS4).	[2]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Regulator of G-protein signaling 4 (RGS4).	[3]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Regulator of G-protein signaling 4 (RGS4).	[4]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Regulator of G-protein signaling 4 (RGS4).	[5]
Temozolomide	DMKECZD	Approved	Temozolomide increases the expression of Regulator of G-protein signaling 4 (RGS4).	[6]
Methotrexate	DM2TEOL	Approved	Methotrexate decreases the expression of Regulator of G-protein signaling 4 (RGS4).	[7]
Marinol	DM70IK5	Approved	Marinol decreases the expression of Regulator of G-protein signaling 4 (RGS4).	[8]
Phenobarbital	DMXZOCG	Approved	Phenobarbital affects the expression of Regulator of G-protein signaling 4 (RGS4).	[9]
Progesterone	DMUY35B	Approved	Progesterone decreases the expression of Regulator of G-protein signaling 4 (RGS4).	[10]
Troglitazone	DM3VFPD	Approved	Troglitazone decreases the expression of Regulator of G-protein signaling 4 (RGS4).	[11]
Azathioprine	DMMZSXQ	Approved	Azathioprine decreases the expression of Regulator of G-protein signaling 4 (RGS4).	[12]
Cytarabine	DMZD5QR	Approved	Cytarabine decreases the expression of Regulator of G-protein signaling 4 (RGS4).	[13]
Diclofenac	DMPIHLS	Approved	Diclofenac decreases the expression of Regulator of G-protein signaling 4 (RGS4).	[12]
Piroxicam	DMTK234	Approved	Piroxicam decreases the expression of Regulator of G-protein signaling 4 (RGS4).	[12]
Dasatinib	DMJV2EK	Approved	Dasatinib decreases the expression of Regulator of G-protein signaling 4 (RGS4).	[14]
Prednisolone	DMQ8FR2	Approved	Prednisolone decreases the expression of Regulator of G-protein signaling 4 (RGS4).	[12]
Methylprednisolone	DM4BDON	Approved	Methylprednisolone decreases the expression of Regulator of G-protein signaling 4 (RGS4).	[12]
Curcumin	DMQPH29	Phase 3	Curcumin decreases the expression of Regulator of G-protein signaling 4 (RGS4).	[15]
GSK2110183	DMZHB37	Phase 2	GSK2110183 decreases the expression of Regulator of G-protein signaling 4 (RGS4).	[16]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Regulator of G-protein signaling 4 (RGS4).	[18]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Regulator of G-protein signaling 4 (RGS4).	[19]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of Regulator of G-protein signaling 4 (RGS4).	[20]
Lithium chloride	DMHYLQ2	Investigative	Lithium chloride increases the expression of Regulator of G-protein signaling 4 (RGS4).	[21]

1 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 Regulator of G-protein signaling 4 (RGS4).	[17]

References

• [1] 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.
• [2] Development of a neural teratogenicity test based on human embryonic stem cells: response to retinoic acid exposure. Toxicol Sci. 2011 Dec;124(2):370-7.
• [3] Blood transcript immune signatures distinguish a subset of people with elevated serum ALT from others given acetaminophen. Clin Pharmacol Ther. 2016 Apr;99(4):432-41.
• [4] 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.
• [5] 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.
• [6] Temozolomide induces activation of Wnt/-catenin signaling in glioma cells via PI3K/Akt pathway: implications in glioma therapy. Cell Biol Toxicol. 2020 Jun;36(3):273-278. doi: 10.1007/s10565-019-09502-7. Epub 2019 Nov 22.
• [7] The contribution of methotrexate exposure and host factors on transcriptional variance in human liver. Toxicol Sci. 2007 Jun;97(2):582-94.
• [8] 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.
• [9] Reproducible chemical-induced changes in gene expression profiles in human hepatoma HepaRG cells under various experimental conditions. Toxicol In Vitro. 2009 Apr;23(3):466-75. doi: 10.1016/j.tiv.2008.12.018. Epub 2008 Dec 30.
• [10] Unique transcriptome, pathways, and networks in the human endometrial fibroblast response to progesterone in endometriosis. Biol Reprod. 2011 Apr;84(4):801-15.
• [11] Effects of ciglitazone and troglitazone on the proliferation of human stomach cancer cells. World J Gastroenterol. 2009 Jan 21;15(3):310-20.
• [12] Antirheumatic drug response signatures in human chondrocytes: potential molecular targets to stimulate cartilage regeneration. Arthritis Res Ther. 2009;11(1):R15.
• [13] Cytosine arabinoside induces ectoderm and inhibits mesoderm expression in human embryonic stem cells during multilineage differentiation. Br J Pharmacol. 2011 Apr;162(8):1743-56.
• [14] Dasatinib reverses cancer-associated fibroblasts (CAFs) from primary lung carcinomas to a phenotype comparable to that of normal fibroblasts. Mol Cancer. 2010 Jun 27;9:168.
• [15] Curcumin suppresses growth of mesothelioma cells in vitro and in vivo, in part, by stimulating apoptosis. Mol Cell Biochem. 2011 Nov;357(1-2):83-94. doi: 10.1007/s11010-011-0878-2. Epub 2011 May 19.
• [16] Novel ATP-competitive Akt inhibitor afuresertib suppresses the proliferation of malignant pleural mesothelioma cells. Cancer Med. 2017 Nov;6(11):2646-2659. doi: 10.1002/cam4.1179. Epub 2017 Sep 27.
• [17] 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.
• [18] Inhibition of BRD4 attenuates tumor cell self-renewal and suppresses stem cell signaling in MYC driven medulloblastoma. Oncotarget. 2014 May 15;5(9):2355-71.
• [19] 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.
• [20] Regulation of chromatin assembly and cell transformation by formaldehyde exposure in human cells. Environ Health Perspect. 2017 Sep 21;125(9):097019.
• [21] Early gene response in lithium chloride induced apoptosis. Apoptosis. 2005 Jan;10(1):75-90. doi: 10.1007/s10495-005-6063-x.
• [22] 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.