Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTUSWA74)

DOT Name	E3 ubiquitin-protein ligase TRIM63 (TRIM63)
Synonyms	EC 2.3.2.27; Iris RING finger protein; Muscle-specific RING finger protein 1; MuRF-1; MuRF1; RING finger protein 28; RING-type E3 ubiquitin transferase TRIM63; Striated muscle RING zinc finger protein; Tripartite motif-containing protein 63
Gene Name	TRIM63
Related Disease	Alveolar soft part sarcoma ( ) Cardiomyopathy ( ) Congenital myopathy 7A, myosin storage, autosomal dominant ( ) Head and neck cancer ( ) Head and neck carcinoma ( ) Hepatitis ( ) Hepatitis A virus infection ( ) Hepatocellular carcinoma ( ) Hyperinsulinemia ( ) Idiopathic cardiomyopathy ( ) Inflammatory bowel disease ( ) Liver cirrhosis ( ) Muscular dystrophy ( ) Myocardial ischemia ( ) Myopathy ( ) Myositis disease ( ) Neoplasm ( ) Osteoarthritis ( ) Peripheral arterial disease ( ) Peripheral vascular disease ( ) Plasma cell myeloma ( ) Postmenopausal osteoporosis ( ) Qualitative or quantitative defects of dysferlin ( ) Respiratory syncytial virus infection ( ) Systemic lupus erythematosus ( ) Type-1/2 diabetes ( ) Advanced cancer ( ) Breast cancer ( ) Breast carcinoma ( ) Chronic kidney disease ( ) Chronic obstructive pulmonary disease ( ) Coronary atherosclerosis ( ) Hypertrophic cardiomyopathy ( ) Pancreatic cancer ( ) Small lymphocytic lymphoma ( ) Gastrointestinal stromal tumour ( ) Leiomyosarcoma ( ) Tuberculosis ( )
UniProt ID	TRI63_HUMAN
3D Structure	Download 2D Sequence (FASTA) Download 3D Structure (PDB) Download
PDB ID	2D8U; 3DDT; 4M3L
EC Number	2.3.2.27
Pfam ID	PF00643 ; PF13445
Sequence	MDYKSSLIQDGNPMENLEKQLICPICLEMFTKPVVILPCQHNLCRKCANDIFQAANPYWT SRGSSVSMSGGRFRCPTCRHEVIMDRHGVYGLQRNLLVENIIDIYKQECSSRPLQKGSHP MCKEHEDEKINIYCLTCEVPTCSMCKVFGIHKACEVAPLQSVFQGQKTELNNCISMLVAG NDRVQTIITQLEDSRRVTKENSHQVKEELSQKFDTLYAILDEKKSELLQRITQEQEKKLS FIEALIQQYQEQLDKSTKLVETAIQSLDEPGGATFLLTAKQLIKSIVEASKGCQLGKTEQ GFENMDFFTLDLEHIADALRAIDFGTDEEEEEFIEEEDQEEEESTEGKEEGHQ
Function	E3 ubiquitin ligase. Mediates the ubiquitination and subsequent proteasomal degradation of CKM, GMEB1 and HIBADH. Regulates the proteasomal degradation of muscle proteins under amino acid starvation, where muscle protein is catabolized to provide other organs with amino acids. Inhibits de novo skeletal muscle protein synthesis under amino acid starvation. Regulates proteasomal degradation of cardiac troponin I/TNNI3 and probably of other sarcomeric-associated proteins. May play a role in striated muscle atrophy and hypertrophy by regulating an anti-hypertrophic PKC-mediated signaling pathway. May regulate the organization of myofibrils through TTN in muscle cells.
Tissue Specificity	Muscle specific. Selectively expressed in heart and skeletal muscle. Also expressed in the iris.
KEGG Pathway	Cytoskeleton in muscle cells (hsa04820 )
Reactome Pathway	Antigen processing (R-HSA-983168 ) FOXO-mediated transcription of oxidative stress, metabolic and neuronal genes (R-HSA-9615017 )

Molecular Interaction Atlas (MIA) of This DOT

38 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance
Alveolar soft part sarcoma	DISLKJKZ	Strong	Genetic Variation	[1]
Cardiomyopathy	DISUPZRG	Strong	Therapeutic	[2]
Congenital myopathy 7A, myosin storage, autosomal dominant	DISUV37B	Strong	Genetic Variation	[3]
Head and neck cancer	DISBPSQZ	Strong	Biomarker	[4]
Head and neck carcinoma	DISOU1DS	Strong	Biomarker	[4]
Hepatitis	DISXXX35	Strong	Altered Expression	[5]
Hepatitis A virus infection	DISUMFQV	Strong	Altered Expression	[5]
Hepatocellular carcinoma	DIS0J828	Strong	Biomarker	[6]
Hyperinsulinemia	DISIDWT6	Strong	Biomarker	[7]
Idiopathic cardiomyopathy	DISUGBZL	Strong	Therapeutic	[2]
Inflammatory bowel disease	DISGN23E	Strong	Altered Expression	[8]
Liver cirrhosis	DIS4G1GX	Strong	Altered Expression	[9]
Muscular dystrophy	DISJD6P7	Strong	Biomarker	[10]
Myocardial ischemia	DISFTVXF	Strong	Altered Expression	[11]
Myopathy	DISOWG27	Strong	Genetic Variation	[12]
Myositis disease	DISCIXF0	Strong	Biomarker	[13]
Neoplasm	DISZKGEW	Strong	Biomarker	[14]
Osteoarthritis	DIS05URM	Strong	Altered Expression	[15]
Peripheral arterial disease	DIS78WFB	Strong	Biomarker	[16]
Peripheral vascular disease	DISXSU1Y	Strong	Biomarker	[16]
Plasma cell myeloma	DIS0DFZ0	Strong	Biomarker	[17]
Postmenopausal osteoporosis	DISS0RQZ	Strong	Biomarker	[18]
Qualitative or quantitative defects of dysferlin	DIS59VEJ	Strong	Altered Expression	[19]
Respiratory syncytial virus infection	DIS7FWHY	Strong	Biomarker	[20]
Systemic lupus erythematosus	DISI1SZ7	Strong	Genetic Variation	[21]
Type-1/2 diabetes	DISIUHAP	Strong	Biomarker	[22]
Advanced cancer	DISAT1Z9	moderate	Biomarker	[23]
Breast cancer	DIS7DPX1	moderate	Biomarker	[24]
Breast carcinoma	DIS2UE88	moderate	Biomarker	[24]
Chronic kidney disease	DISW82R7	moderate	Altered Expression	[25]
Chronic obstructive pulmonary disease	DISQCIRF	moderate	Biomarker	[26]
Coronary atherosclerosis	DISKNDYU	moderate	Altered Expression	[11]
Hypertrophic cardiomyopathy	DISQG2AI	Moderate	Autosomal recessive	[27]
Pancreatic cancer	DISJC981	moderate	Biomarker	[28]
Small lymphocytic lymphoma	DIS30POX	moderate	Altered Expression	[29]
Gastrointestinal stromal tumour	DIS6TJYS	Limited	Altered Expression	[30]
Leiomyosarcoma	DIS6COXM	Limited	Altered Expression	[30]
Tuberculosis	DIS2YIMD	Limited	Biomarker	[31]
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Molecular Interaction Atlas (MIA)

MIA Detail

Jump to Detail Molecular Interaction Atlas of This DOT

2 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 E3 ubiquitin-protein ligase TRIM63 (TRIM63).	[32]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of E3 ubiquitin-protein ligase TRIM63 (TRIM63).	[36]
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3 Drug(s) Affected the Gene/Protein Processing of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Doxorubicin	DMVP5YE	Approved	Doxorubicin increases the expression of E3 ubiquitin-protein ligase TRIM63 (TRIM63).	[33]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of E3 ubiquitin-protein ligase TRIM63 (TRIM63).	[34]
Triclosan	DMZUR4N	Approved	Triclosan decreases the expression of E3 ubiquitin-protein ligase TRIM63 (TRIM63).	[35]
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References

1	ASPS-1, a novel cell line manifesting key features of alveolar soft part sarcoma.J Pediatr Hematol Oncol. 2011 Jul;33(5):360-8. doi: 10.1097/MPH.0b013e3182002f9f.
2	Muscle ring finger 1 mediates cardiac atrophy in vivo.Am J Physiol Heart Circ Physiol. 2009 Apr;296(4):H997-H1006. doi: 10.1152/ajpheart.00660.2008. Epub 2009 Jan 23.
3	New cardiac and skeletal protein aggregate myopathy associated with combined MuRF1 and MuRF3 mutations.Hum Mol Genet. 2015 Jul 1;24(13):3638-50. doi: 10.1093/hmg/ddv108. Epub 2015 Mar 23.
4	Differential regulation of NF-kB and IRF target genes as they relate to fatigue in patients with head and neck cancer.Brain Behav Immun. 2018 Nov;74:291-295. doi: 10.1016/j.bbi.2018.09.013. Epub 2018 Sep 11.
5	The E3 ubiquitin ligase MuRF2 attenuates LPS-induced macrophage activation by inhibiting production of inflammatory cytokines and migration.FEBS Open Bio. 2018 Jan 8;8(2):234-243. doi: 10.1002/2211-5463.12367. eCollection 2018 Feb.
6	Growth suppression of the hepatocellular carcinoma cell line Hepa1-6 by an activatable interferon regulatory factor-1 in mice.Cancer Res. 2001 Mar 15;61(6):2609-17.
7	MuRF1-dependent regulation of systemic carbohydrate metabolism as revealed from transgenic mouse studies.J Mol Biol. 2008 Jun 13;379(4):666-77. doi: 10.1016/j.jmb.2008.03.049. Epub 2008 Apr 3.
8	IRF4 regulates IL-17A promoter activity and controls RORt-dependent Th17 colitis in vivo.Inflamm Bowel Dis. 2011 Jun;17(6):1343-58. doi: 10.1002/ibd.21476. Epub 2011 Feb 8.
9	MuRF-1 and p-GSK3 expression in muscle atrophy of cirrhosis.Liver Int. 2013 May;33(5):714-21. doi: 10.1111/liv.12128. Epub 2013 Feb 24.
10	Noninvasive imaging of in vivo MuRF1 expression during muscle atrophy.PLoS One. 2014 Apr 7;9(4):e94032. doi: 10.1371/journal.pone.0094032. eCollection 2014.
11	Role of Toll-like receptors and interferon regulatory factors in different experimental heart failure models of diverse etiology: IRF7 as novel cardiovascular stress-inducible factor.PLoS One. 2018 Mar 14;13(3):e0193844. doi: 10.1371/journal.pone.0193844. eCollection 2018.
12	Muscle RING-finger protein-1 (MuRF1) functions and cellular localization are regulated by SUMO1 post-translational modification.J Mol Cell Biol. 2019 May 1;11(5):356-370. doi: 10.1093/jmcb/mjy036.
13	l-arginine modulates inflammation and muscle regulatory genes after a single session of resistance exercise in rats.Scand J Med Sci Sports. 2018 Feb;28(2):425-435. doi: 10.1111/sms.12935. Epub 2017 Aug 4.
14	Genetic pathways of multiple esophageal squamous cell carcinomas.Oncol Rep. 2011 Feb;25(2):453-9. doi: 10.3892/or.2010.1110. Epub 2010 Dec 14.
15	The Role of Interferon Regulatory Factor 5 in Macrophage Inflammation During Osteoarthritis.Inflammation. 2019 Oct;42(5):1821-1829. doi: 10.1007/s10753-019-01044-8.
16	TLR-4 and VEGF polymorphisms in chronic periaortitis.PLoS One. 2013 May 14;8(5):e62330. doi: 10.1371/journal.pone.0062330. Print 2013.
17	Interferon regulatory factor 4 (IRF-4) targets IRF-5 to regulate Epstein-Barr virus transformation.J Biol Chem. 2011 May 20;286(20):18261-7. doi: 10.1074/jbc.M110.210542. Epub 2011 Mar 24.
18	In silico analysis of the molecular mechanism of postmenopausal osteoporosis.Mol Med Rep. 2015 Nov;12(5):6584-90. doi: 10.3892/mmr.2015.4283. Epub 2015 Sep 2.
19	Muscle atrophy, ubiquitin-proteasome, and autophagic pathways in dysferlinopathy.Muscle Nerve. 2014 Sep;50(3):340-7. doi: 10.1002/mus.24167. Epub 2014 May 17.
20	BRD4 Couples NF-B/RelA with Airway Inflammation and the IRF-RIG-I Amplification Loop in Respiratory Syncytial Virus Infection.J Virol. 2017 Feb 28;91(6):e00007-17. doi: 10.1128/JVI.00007-17. Print 2017 Mar 15.
21	Association of an IRF5 gene functional polymorphism with Sjgren's syndrome.Arthritis Rheum. 2007 Dec;56(12):3989-94. doi: 10.1002/art.23142.
22	Insulin treatment reverses the increase in atrogin-1 expression in atrophied skeletal muscles of diabetic rats with acute joint inflammation.Ther Clin Risk Manag. 2018 Feb 14;14:275-286. doi: 10.2147/TCRM.S142948. eCollection 2018.
23	TLRs: linking inflammation and breast cancer.Cell Signal. 2014 Nov;26(11):2350-7. doi: 10.1016/j.cellsig.2014.07.035. Epub 2014 Aug 3.
24	A novel oncogene TRIM63 promotes cell proliferation and migration via activating Wnt/-catenin signaling pathway in breast cancer.Pathol Res Pract. 2019 Oct;215(10):152573. doi: 10.1016/j.prp.2019.152573. Epub 2019 Jul 31.
25	Long-noncoding RNA Atrolnc-1 promotes muscle wasting in mice with chronic kidney disease.J Cachexia Sarcopenia Muscle. 2018 Oct;9(5):962-974. doi: 10.1002/jcsm.12321. Epub 2018 Jul 24.
26	Atrophy and hypertrophy signalling of the quadriceps and diaphragm in COPD.Thorax. 2010 Nov;65(11):963-70. doi: 10.1136/thx.2009.133827.
27	Technical standards for the interpretation and reporting of constitutional copy-number variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics (ACMG) and the Clinical Genome Resource (ClinGen). Genet Med. 2020 Feb;22(2):245-257. doi: 10.1038/s41436-019-0686-8. Epub 2019 Nov 6.
28	TRIF is a key inflammatory mediator of acute sickness behavior and cancer cachexia.Brain Behav Immun. 2018 Oct;73:364-374. doi: 10.1016/j.bbi.2018.05.021. Epub 2018 May 28.
29	Toll-like receptor signaling pathway in chronic lymphocytic leukemia: distinct gene expression profiles of potential pathogenic significance in specific subsets of patients.Haematologica. 2011 Nov;96(11):1644-52. doi: 10.3324/haematol.2011.044792. Epub 2011 Jul 12.
30	A systems biological approach to identify key transcription factors and their genomic neighborhoods in human sarcomas.Chin J Cancer. 2011 Jan;30(1):27-40. doi: 10.5732/cjc.010.10541.
31	IRF and tuberculosis.J Interferon Cytokine Res. 2002 Jan;22(1):15-25. doi: 10.1089/107999002753452629.
32	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.
33	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.
34	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.
35	Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
36	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.