Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTN2QQPG)

DOT Name	Activity-regulated cytoskeleton-associated protein (ARC)
Synonyms	hArc; Activity-regulated gene 3.1 protein homolog; ARC/ARG3.1; Arg3.1
Gene Name	ARC
Related Disease	Cognitive impairment ( ) Acquired immune deficiency syndrome ( ) Acute myelogenous leukaemia ( ) Adenoma ( ) Alcohol dependence ( ) Alzheimer disease ( ) Amyloidosis ( ) Arthrogryposis, renal dysfunction, and cholestasis 1 ( ) Bone osteosarcoma ( ) Cardiac failure ( ) Cataract ( ) Chronic hepatitis B virus infection ( ) Clear cell renal carcinoma ( ) Colon cancer ( ) Colon carcinoma ( ) Congestive heart failure ( ) Coronary atherosclerosis ( ) Deafness ( ) Dengue ( ) Depression ( ) Familial Alzheimer disease ( ) Glioma ( ) Hepatitis ( ) Hepatitis A virus infection ( ) Hepatitis B virus infection ( ) Metabolic disorder ( ) Movement disorder ( ) Myocardial infarction ( ) Myocardial ischemia ( ) Neoplasm ( ) Neuroblastoma ( ) Parkinson disease ( ) Renal cell carcinoma ( ) Retinitis pigmentosa ( ) Advanced cancer ( ) Anxiety ( ) Anxiety disorder ( ) Cocaine addiction ( ) Colorectal carcinoma ( ) Dilated cardiomyopathy ( ) Inflammation ( ) Kaposi sarcoma ( ) Non-insulin dependent diabetes ( ) Primary cutaneous T-cell lymphoma ( ) Rheumatoid arthritis ( )
UniProt ID	ARC_HUMAN
3D Structure	Download 2D Sequence (FASTA) Download 3D Structure (PDB) Download
PDB ID	6TN7; 6TNQ; 6TQ0; 6YTU; 7R1Z; 7R23
Pfam ID	PF18162 ; PF21395 ; PF19284
Sequence	MELDHRTSGGLHAYPGPRGGQVAKPNVILQIGKCRAEMLEHVRRTHRHLLAEVSKQVERE LKGLHRSVGKLESNLDGYVPTSDSQRWKKSIKACLCRCQETIANLERWVKREMHVWREVF YRLERWADRLESTGGKYPVGSESARHTVSVGVGGPESYCHEADGYDYTVSPYAITPPPAA GELPGQEPAEAQQYQPWVPGEDGQPSPGVDTQIFEDPREFLSHLEEYLRQVGGSEEYWLS QIQNHMNGPAKKWWEFKQGSVKNWVEFKKEFLQYSEGTLSREAIQRELDLPQKQGEPLDQ FLWRKRDLYQTLYVDADEEEIIQYVVGTLQPKLKRFLRHPLPKTLEQLIQRGMEVQDDLE QAAEPAGPHLPVEDEAETLTPAPNSESVASDRTQPE
Function	Master regulator of synaptic plasticity that self-assembles into virion-like capsids that encapsulate RNAs and mediate intercellular RNA transfer in the nervous system. ARC protein is released from neurons in extracellular vesicles that mediate the transfer of ARC mRNA into new target cells, where ARC mRNA can undergo activity-dependent translation. ARC capsids are endocytosed and are able to transfer ARC mRNA into the cytoplasm of neurons. Acts as a key regulator of synaptic plasticity: required for protein synthesis-dependent forms of long-term potentiation (LTP) and depression (LTD) and for the formation of long-term memory. Regulates synaptic plasticity by promoting endocytosis of AMPA receptors (AMPARs) in response to synaptic activity: this endocytic pathway maintains levels of surface AMPARs in response to chronic changes in neuronal activity through synaptic scaling, thereby contributing to neuronal homeostasis. Acts as a postsynaptic mediator of activity-dependent synapse elimination in the developing cerebellum by mediating elimination of surplus climbing fiber synapses. Accumulates at weaker synapses, probably to prevent their undesired enhancement. This suggests that ARC-containing virion-like capsids may be required to eliminate synaptic material. Required to transduce experience into long-lasting changes in visual cortex plasticity and for long-term memory. Involved in postsynaptic trafficking and processing of amyloid-beta A4 (APP) via interaction with PSEN1. In addition to its role in synapses, also involved in the regulation of the immune system: specifically expressed in skin-migratory dendritic cells and regulates fast dendritic cell migration, thereby regulating T-cell activation.
KEGG Pathway	Amphetamine addiction (hsa05031 )
Reactome Pathway	NGF-stimulated transcription (R-HSA-9031628 )

Molecular Interaction Atlas (MIA) of This DOT

45 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance
Cognitive impairment	DISH2ERD	Definitive	Biomarker	[1]
Acquired immune deficiency syndrome	DISL5UOX	Strong	Genetic Variation	[2]
Acute myelogenous leukaemia	DISCSPTN	Strong	Biomarker	[3]
Adenoma	DIS78ZEV	Strong	Biomarker	[4]
Alcohol dependence	DIS4ZSCO	Strong	Biomarker	[5]
Alzheimer disease	DISF8S70	Strong	Biomarker	[6]
Amyloidosis	DISHTAI2	Strong	Genetic Variation	[6]
Arthrogryposis, renal dysfunction, and cholestasis 1	DISRS2RG	Strong	Biomarker	[7]
Bone osteosarcoma	DIST1004	Strong	Altered Expression	[8]
Cardiac failure	DISDC067	Strong	Biomarker	[9]
Cataract	DISUD7SL	Strong	Biomarker	[10]
Chronic hepatitis B virus infection	DISHL4NT	Strong	Biomarker	[11]
Clear cell renal carcinoma	DISBXRFJ	Strong	Biomarker	[12]
Colon cancer	DISVC52G	Strong	Biomarker	[13]
Colon carcinoma	DISJYKUO	Strong	Biomarker	[13]
Congestive heart failure	DIS32MEA	Strong	Biomarker	[9]
Coronary atherosclerosis	DISKNDYU	Strong	Altered Expression	[14]
Deafness	DISKCLH4	Strong	Biomarker	[15]
Dengue	DISKH221	Strong	Genetic Variation	[16]
Depression	DIS3XJ69	Strong	Genetic Variation	[17]
Familial Alzheimer disease	DISE75U4	Strong	Biomarker	[18]
Glioma	DIS5RPEH	Strong	Altered Expression	[19]
Hepatitis	DISXXX35	Strong	Altered Expression	[20]
Hepatitis A virus infection	DISUMFQV	Strong	Altered Expression	[20]
Hepatitis B virus infection	DISLQ2XY	Strong	Biomarker	[11]
Metabolic disorder	DIS71G5H	Strong	Biomarker	[21]
Movement disorder	DISOJJ2D	Strong	Biomarker	[22]
Myocardial infarction	DIS655KI	Strong	Biomarker	[9]
Myocardial ischemia	DISFTVXF	Strong	Altered Expression	[14]
Neoplasm	DISZKGEW	Strong	Biomarker	[13]
Neuroblastoma	DISVZBI4	Strong	Biomarker	[23]
Parkinson disease	DISQVHKL	Strong	Biomarker	[24]
Renal cell carcinoma	DISQZ2X8	Strong	Biomarker	[12]
Retinitis pigmentosa	DISCGPY8	Strong	Biomarker	[10]
Advanced cancer	DISAT1Z9	Limited	Biomarker	[25]
Anxiety	DISIJDBA	Limited	Biomarker	[26]
Anxiety disorder	DISBI2BT	Limited	Biomarker	[26]
Cocaine addiction	DISHTRXG	Limited	Biomarker	[27]
Colorectal carcinoma	DIS5PYL0	Limited	Biomarker	[28]
Dilated cardiomyopathy	DISX608J	Limited	Altered Expression	[29]
Inflammation	DISJUQ5T	Limited	Genetic Variation	[30]
Kaposi sarcoma	DISC1H1Z	Limited	Biomarker	[31]
Non-insulin dependent diabetes	DISK1O5Z	Limited	Biomarker	[32]
Primary cutaneous T-cell lymphoma	DIS35WVW	Limited	Altered Expression	[33]
Rheumatoid arthritis	DISTSB4J	Limited	Genetic Variation	[34]
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⏷ Show the Full List of 45 Disease(s)

Molecular Interaction Atlas (MIA)

MIA Detail

Jump to Detail Molecular Interaction Atlas of This DOT

3 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 Activity-regulated cytoskeleton-associated protein (ARC).	[35]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the methylation of Activity-regulated cytoskeleton-associated protein (ARC).	[45]
TAK-243	DM4GKV2	Phase 1	TAK-243 increases the sumoylation of Activity-regulated cytoskeleton-associated protein (ARC).	[47]
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12 Drug(s) Affected the Gene/Protein Processing of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Activity-regulated cytoskeleton-associated protein (ARC).	[36]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of Activity-regulated cytoskeleton-associated protein (ARC).	[37]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Activity-regulated cytoskeleton-associated protein (ARC).	[38]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Activity-regulated cytoskeleton-associated protein (ARC).	[39]
Temozolomide	DMKECZD	Approved	Temozolomide decreases the expression of Activity-regulated cytoskeleton-associated protein (ARC).	[40]
Nicotine	DMWX5CO	Approved	Nicotine increases the expression of Activity-regulated cytoskeleton-associated protein (ARC).	[41]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of Activity-regulated cytoskeleton-associated protein (ARC).	[42]
Amiodarone	DMUTEX3	Phase 2/3 Trial	Amiodarone increases the expression of Activity-regulated cytoskeleton-associated protein (ARC).	[43]
OTX-015	DMI8RG1	Phase 1/2	OTX-015 increases the expression of Activity-regulated cytoskeleton-associated protein (ARC).	[44]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 increases the expression of Activity-regulated cytoskeleton-associated protein (ARC).	[46]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde increases the expression of Activity-regulated cytoskeleton-associated protein (ARC).	[48]
Acetaldehyde	DMJFKG4	Investigative	Acetaldehyde increases the expression of Activity-regulated cytoskeleton-associated protein (ARC).	[49]
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⏷ Show the Full List of 12 Drug(s)

References

1	Neuronal Activity-Induced Sterol Regulatory Element Binding Protein-1 (SREBP1) is Disrupted in Dysbindin-Null Mice-Potential Link to Cognitive Impairment in Schizophrenia.Mol Neurobiol. 2017 Apr;54(3):1699-1709. doi: 10.1007/s12035-016-9773-x. Epub 2016 Feb 12.
2	Differential expression of tumor necrosis factor alpha and interleukin 1 beta compared with interleukin 6 in monocytes from human immunodeficiency virus-positive individuals measured by polymerase chain reaction.J Acquir Immune Defic Syndr (1988). 1994 Feb;7(2):109-15.
3	An ARC-Regulated IL1/Cox-2/PGE2/-Catenin/ARC Circuit Controls Leukemia-Microenvironment Interactions and Confers Drug Resistance in AML.Cancer Res. 2019 Mar 15;79(6):1165-1177. doi: 10.1158/0008-5472.CAN-18-0921. Epub 2019 Jan 23.
4	Impact of a new distal attachment on colonoscopy performance in an academic screening center.Gastrointest Endosc. 2018 Jan;87(1):280-287. doi: 10.1016/j.gie.2017.04.001. Epub 2017 Apr 13.
5	The role of amygdaloid brain-derived neurotrophic factor, activity-regulated cytoskeleton-associated protein and dendritic spines in anxiety and alcoholism.Addict Biol. 2011 Apr;16(2):238-50. doi: 10.1111/j.1369-1600.2010.00275.x. Epub 2010 Dec 23.
6	The Arc Gene Confers Genetic Susceptibility to Alzheimer's Disease in Han Chinese.Mol Neurobiol. 2018 Feb;55(2):1217-1226. doi: 10.1007/s12035-017-0397-6. Epub 2017 Jan 20.
7	ARC syndrome in preterm baby.J Perinatol. 2013 Oct;33(10):821-2. doi: 10.1038/jp.2013.62.
8	Electrical peripheral nerve stimulation relieves bone cancer pain by inducing Arc protein expression in the spinal cord dorsal horn.J Pain Res. 2018 Mar 21;11:599-609. doi: 10.2147/JPR.S149470. eCollection 2018.
9	Autophagic program is regulated by miR-325.Cell Death Differ. 2014 Jun;21(6):967-77. doi: 10.1038/cdd.2014.18. Epub 2014 Feb 14.
10	Multiple cytokine analyses of aqueous humor from the patients with retinitis pigmentosa.Cytokine. 2020 Mar;127:154943. doi: 10.1016/j.cyto.2019.154943. Epub 2019 Dec 3.
11	RNA Interference Therapy With ARC-520 Results in Prolonged Hepatitis B Surface Antigen Response in Patients With Chronic Hepatitis B Infection.Hepatology. 2020 Jul;72(1):19-31. doi: 10.1002/hep.31008. Epub 2020 Apr 23.
12	The role of apoptosis repressor with a CARD domain (ARC) in the therapeutic resistance of renal cell carcinoma (RCC): the crucial role of ARC in the inhibition of extrinsic and intrinsic apoptotic signalling.Cell Commun Signal. 2017 May 2;15(1):16. doi: 10.1186/s12964-017-0170-5.
13	Arctigenin blocks the unfolded protein response and shows therapeutic antitumor activity.J Cell Physiol. 2010 Jul;224(1):33-40. doi: 10.1002/jcp.22085.
14	The apoptosis inhibitor ARC undergoes ubiquitin-proteasomal-mediated degradation in response to death stimuli: identification of a degradation-resistant mutant.J Biol Chem. 2007 Feb 23;282(8):5522-8. doi: 10.1074/jbc.M609186200. Epub 2006 Dec 1.
15	Midazolam reverses salicylate-induced changes in brain-derived neurotrophic factor and arg3.1 expression: implications for tinnitus perception and auditory plasticity.Mol Pharmacol. 2008 Sep;74(3):595-604. doi: 10.1124/mol.108.046375. Epub 2008 Jun 4.
16	Duplex nucleic acid test for the detection of chikungunya and dengue RNA viruses in blood donations.Transfusion. 2019 Apr;59(4):1283-1290. doi: 10.1111/trf.15128. Epub 2019 Jan 4.
17	The Arc of cognition: Signaling cascades regulating Arc and implications for cognitive function and disease.Semin Cell Dev Biol. 2018 May;77:63-72. doi: 10.1016/j.semcdb.2017.09.023.
18	Activity-regulated cytoskeleton-associated protein in rodent brain is down-regulated by high fat diet in vivo and by 27-hydroxycholesterol in vitro.Brain Pathol. 2009 Jan;19(1):69-80. doi: 10.1111/j.1750-3639.2008.00174.x. Epub 2008 May 23.
19	Knockdown of apoptosis repressor with caspase recruitment domain (ARC) increases the sensitivity of human glioma cell line U251MG to VM-26.Int J Clin Exp Pathol. 2012;5(6):555-61. Epub 2012 Jul 29.
20	Is liver-targeted FOXp3 staining beneficial after living-donor liver transplantation?.Transpl Infect Dis. 2012 Apr;14(2):156-62. doi: 10.1111/j.1399-3062.2011.00690.x. Epub 2011 Oct 31.
21	Dietary sugars, not lipids, drive hypothalamic inflammation.Mol Metab. 2017 Jun 20;6(8):897-908. doi: 10.1016/j.molmet.2017.06.008. eCollection 2017 Aug.
22	Methamphetamine-induced stereotypy correlates negatively with patch-enhanced prodynorphin and arc mRNA expression in the rat caudate putamen: the role of mu opioid receptor activation.Pharmacol Biochem Behav. 2010 Jun;95(4):410-21. doi: 10.1016/j.pbb.2010.02.019. Epub 2010 Mar 15.
23	The Neuroprotective Effects of Brazilian Green Propolis on Neurodegenerative Damage in Human Neuronal SH-SY5Y Cells.Oxid Med Cell Longev. 2017;2017:7984327. doi: 10.1155/2017/7984327. Epub 2017 Feb 6.
24	The Impact of Short and Long-Term Exercise on the Expression of Arc and AMPARs During Evolution of the 6-Hydroxy-Dopamine Animal Model of Parkinson's Disease.J Mol Neurosci. 2017 Apr;61(4):542-552. doi: 10.1007/s12031-017-0896-y. Epub 2017 Feb 28.
25	Conceptual framework for living with and beyond cancer: A systematic review and narrative synthesis.Psychooncology. 2019 May;28(5):948-959. doi: 10.1002/pon.5046. Epub 2019 Mar 25.
26	Activity-regulated cytoskeleton-associated protein (Arc/Arg3.1) regulates anxiety- and novelty-related behaviors.Genes Brain Behav. 2019 Sep;18(7):e12561. doi: 10.1111/gbb.12561. Epub 2019 Apr 15.
27	Relapse to cocaine seeking increases activity-regulated gene expression differentially in the prefrontal cortex of abstinent rats.Psychopharmacology (Berl). 2008 May;198(1):77-91. doi: 10.1007/s00213-008-1090-2. Epub 2008 Mar 3.
28	Differential sensitivity of human colon cancer cell lines to the nucleoside analogs ARC and DRB.Int J Cancer. 2008 Mar 15;122(6):1426-9. doi: 10.1002/ijc.23239.
29	Ubiquitination and degradation of the anti-apoptotic protein ARC by MDM2.J Biol Chem. 2007 Feb 23;282(8):5529-35. doi: 10.1074/jbc.M609046200. Epub 2006 Dec 2.
30	Systematic understanding of the mechanism and effects of Arctigenin attenuates inflammation in dextran sulfate sodium-induced acute colitis through suppression of NLRP3 inflammasome by SIRT1.Am J Transl Res. 2019 Jul 15;11(7):3992-4009. eCollection 2019.
31	Major histocompatibility complex class I to III allotypes in patients with AIDS-related complex/Walter-Reed 5, disseminated Kaposi's sarcoma and in normal controls. The ARC-IVIG Study Group.Vox Sang. 1990;59 Suppl 1:15-20. doi: 10.1111/j.1423-0410.1990.tb01638.x.
32	ARC is essential for maintaining pancreatic islet structure and -cell viability during type 2 diabetes.Sci Rep. 2017 Aug 1;7(1):7019. doi: 10.1038/s41598-017-07107-w.
33	Detergent fractionation with subsequent subtractive suppression hybridization as a tool for identifying genes coding for plasma membrane proteins.Exp Dermatol. 2009 Jun;18(6):527-35. doi: 10.1111/j.1600-0625.2008.00821.x. Epub 2009 Jan 18.
34	Analysis of the candidate gene NRAMP1 in the first 61 ARC National Repository families for rheumatoid arthritis.J Rheumatol. 1997 Jan;24(1):212-4.
35	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.
36	Phenotypic characterization of retinoic acid differentiated SH-SY5Y cells by transcriptional profiling. PLoS One. 2013 May 28;8(5):e63862.
37	Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
38	Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
39	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.
40	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.
41	Characterizing the genetic basis for nicotine induced cancer development: a transcriptome sequencing study. PLoS One. 2013 Jun 18;8(6):e67252.
42	Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
43	Identification by automated screening of a small molecule that selectively eliminates neural stem cells derived from hESCs but not dopamine neurons. PLoS One. 2009 Sep 23;4(9):e7155.
44	Comprehensive transcriptome profiling of BET inhibitor-treated HepG2 cells. PLoS One. 2022 Apr 29;17(4):e0266966. doi: 10.1371/journal.pone.0266966. eCollection 2022.
45	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.
46	Synergistic effect of JQ1 and rapamycin for treatment of human osteosarcoma. Int J Cancer. 2015 May 1;136(9):2055-64.
47	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.
48	Gene expression changes in primary human nasal epithelial cells exposed to formaldehyde in vitro. Toxicol Lett. 2010 Oct 5;198(2):289-95.
49	Transcriptome profile analysis of saturated aliphatic aldehydes reveals carbon number-specific molecules involved in pulmonary toxicity. Chem Res Toxicol. 2014 Aug 18;27(8):1362-70.