Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT3L3PCU)

• DOT Name: Protein ecdysoneless homolog (ECD)
• Synonyms: Human suppressor of GCR two; hSGT1
• Gene Name: ECD
• Related Disease:
  Primary progressive aphasia
  Alzheimer disease
  Breast carcinoma
  Cardiac failure
  Chromosomal disorder
  Congestive heart failure
  Fatty liver disease
  Gerstmann-Straussler-Scheinker syndrome
  Graves disease
  leukaemia
  Leukemia
  Major depressive disorder
  Moyamoya disease
  Neoplasm
  Non-alcoholic fatty liver disease
  Pantothenate kinase-associated neurodegeneration
  Advanced cancer
  Gastric cancer
  Hashimoto thyroiditis
  HER2/NEU overexpressing breast cancer
  Influenza
  Metastatic malignant neoplasm
  Stomach cancer
  Crohn disease
  Lewy body dementia
  Myasthenia gravis
  Parkinson disease
• UniProt ID: ECD_HUMAN
• Pfam ID: PF07093
• Sequence:
  MEETMKLATMEDTVEYCLFLIPDESRDSDKHKEILQKYIERIITRFAPMLVPYIWQNQPF
  NLKYKPGKGGVPAHMFGVTKFGDNIEDEWFIVYVIKQITKEFPELVARIEDNDGEFLLIE
  AADFLPKWLDPENSTNRVFFCHGELCIIPAPRKSGAESWLPTTPPTIPQALNIITAHSEK
  ILASESIRAAVNRRIRGYPEKIQASLHRAHCFLPAGIVAVLKQRPRLVAAAVQAFYLRDP
  IDLRACRVFKTFLPETRIMTSVTFTKCLYAQLVQQRFVPDRRSGYRLPPPSDPQYRAHEL
  GMKLAHGFEILCSKCSPHFSDCKKSLVTASPLWASFLESLKKNDYFKGLIEGSAQYRERL
  EMAENYFQLSVDWPESSLAMSPGEEILTLLQTIPFDIEDLKKEAANLPPEDDDQWLDLSP
  DQLDQLLQEAVGKKESESVSKEEKEQNYDLTEVSESMKAFISKVSTHKGAELPREPSEAP
  ITFDADSFLNYFDKILGPRPNESDSDDLDDEDFECLDSDDDLDFETHEPGEEASLKGTLD
  NLKSYMAQMDQELAHTCISKSFTTRNQVEPVSQTTDNNSDEEDSGTGESVMAPVDVDLNL
  VSNILESYSSQAGLAGPASNLLQSMGVQLPDNTDHRPTSKPTKN
• Function: Regulator of p53/TP53 stability and function. Inhibits MDM2-mediated degradation of p53/TP53 possibly by cooperating in part with TXNIP. May be involved transcriptional regulation. In vitro has intrinsic transactivation activity enhanced by EP300. May be a transcriptional activator required for the expression of glycolytic genes. Involved in regulation of cell cycle progression. Proposed to disrupt Rb-E2F binding leading to transcriptional activation of E2F proteins. The cell cycle -regulating function may depend on its RUVBL1-mediated association with the R2TP complex. May play a role in regulation of pre-mRNA splicing.
• Tissue Specificity: Highly expressed in muscle and heart. Over-expressed in pancreatic and breast cancers.

Molecular Interaction Atlas (MIA) of This DOT

27 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Primary progressive aphasia	DISLRYFE	Definitive	Biomarker	[1]
Alzheimer disease	DISF8S70	Strong	Genetic Variation	[2]
Breast carcinoma	DIS2UE88	Strong	Altered Expression	[3]
Cardiac failure	DISDC067	Strong	Biomarker	[4]
Chromosomal disorder	DISM5BB5	Strong	Biomarker	[5]
Congestive heart failure	DIS32MEA	Strong	Biomarker	[4]
Fatty liver disease	DIS485QZ	Strong	Altered Expression	[6]
Gerstmann-Straussler-Scheinker syndrome	DISIO6KC	Strong	Genetic Variation	[7]
Graves disease	DISU4KOQ	Strong	Biomarker	[8]
leukaemia	DISS7D1V	Strong	Altered Expression	[9]
Leukemia	DISNAKFL	Strong	Altered Expression	[9]
Major depressive disorder	DIS4CL3X	Strong	Biomarker	[10]
Moyamoya disease	DISO62CA	Strong	Biomarker	[11]
Neoplasm	DISZKGEW	Strong	Biomarker	[12]
Non-alcoholic fatty liver disease	DISDG1NL	Strong	Biomarker	[13]
Pantothenate kinase-associated neurodegeneration	DIS50V55	Strong	Biomarker	[14]
Advanced cancer	DISAT1Z9	moderate	Genetic Variation	[15]
Gastric cancer	DISXGOUK	moderate	Biomarker	[16]
Hashimoto thyroiditis	DIS77CDF	moderate	Biomarker	[17]
HER2/NEU overexpressing breast cancer	DISYKID5	moderate	Biomarker	[18]
Influenza	DIS3PNU3	moderate	Altered Expression	[19]
Metastatic malignant neoplasm	DIS86UK6	moderate	Biomarker	[18]
Stomach cancer	DISKIJSX	moderate	Biomarker	[16]
Crohn disease	DIS2C5Q8	Limited	Altered Expression	[20]
Lewy body dementia	DISAE66J	Limited	Altered Expression	[21]
Myasthenia gravis	DISELRCI	Limited	Biomarker	[22]
Parkinson disease	DISQVHKL	Limited	Altered Expression	[21]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Protein ecdysoneless homolog (ECD).	[23]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Protein ecdysoneless homolog (ECD).	[24]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of Protein ecdysoneless homolog (ECD).	[25]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of Protein ecdysoneless homolog (ECD).	[27]
Temozolomide	DMKECZD	Approved	Temozolomide decreases the expression of Protein ecdysoneless homolog (ECD).	[28]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide decreases the expression of Protein ecdysoneless homolog (ECD).	[29]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of Protein ecdysoneless homolog (ECD).	[30]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the expression of Protein ecdysoneless homolog (ECD).	[32]

2 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 Protein ecdysoneless homolog (ECD).	[26]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 decreases the phosphorylation of Protein ecdysoneless homolog (ECD).	[33]

1 Drug(s) Affected the Protein Interaction/Cellular Processes of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
DNCB	DMDTVYC	Phase 2	DNCB affects the binding of Protein ecdysoneless homolog (ECD).	[31]

References

• [1] The Value of 99mTc ECD SPECT With Statistical Image Analysis on Enhancing the Early Diagnosis of Primary Progressive Aphasia.Clin Nucl Med. 2017 Feb;42(2):e117-e120. doi: 10.1097/RLU.0000000000001475.
• [2] Cerebral Perfusion Insufficiency and Relationships with Cognitive Deficits in Alzheimer's Disease: A Multiparametric Neuroimaging Study.Sci Rep. 2018 Jan 24;8(1):1541. doi: 10.1038/s41598-018-19387-x.
• [3] 8-hydroxydeoxyguanosine levels in DNA of human breast cancer are not significantly different from those of non-cancerous breast tissues by the HPLC-ECD method.Cancer Lett. 1995 Apr 14;90(2):157-62. doi: 10.1016/0304-3835(95)03698-v.
• [4] A systematic review of large scale and heterogeneous gene array data in heart failure.J Mol Cell Cardiol. 2005 Mar;38(3):425-32. doi: 10.1016/j.yjmcc.2004.12.016.
• [5] The epidemiology of cardiovascular defects, part 2: a study based on data from three large registries of congenital malformations.Pediatr Cardiol. 2003 May-Jun;24(3):222-35. doi: 10.1007/s00246-002-9402-5. Epub 2003 Mar 17.
• [6] Soluble FGFR4 extracellular domain inhibits FGF19-induced activation of FGFR4 signaling and prevents nonalcoholic fatty liver disease.Biochem Biophys Res Commun. 2011 Jun 17;409(4):651-6. doi: 10.1016/j.bbrc.2011.05.059. Epub 2011 May 17.
• [7] Thalamic involvement determined using VSRAD advance on MRI and easy Z-score analysis of (99m)Tc-ECD-SPECT in Gerstmann-Strussler-Scheinker syndrome with P102L mutation.J Neurol Sci. 2017 Feb 15;373:27-30. doi: 10.1016/j.jns.2016.12.021. Epub 2016 Dec 15.
• [8] T-cell recognition of residue 158-176 in thyrotropin receptor confers risk for development of thyroid autoimmunity in siblings in a family with Graves' disease.Thyroid. 1996 Dec;6(6):545-51. doi: 10.1089/thy.1996.6.545.
• [9] Increased oxidative DNA damage, inducible nitric oxide synthase, nuclear factor kappaB expression and enhanced antiapoptosis-related proteins in Helicobacter pylori-infected non-cardiac gastric adenocarcinoma.World J Gastroenterol. 2004 Aug 1;10(15):2232-40. doi: 10.3748/wjg.v10.i15.2232.
• [10] Towards characterizing the regional cerebral perfusion in evaluating the severity of major depression disorder with SPECT/CT.BMC Psychiatry. 2018 Mar 21;18(1):70. doi: 10.1186/s12888-018-1654-6.
• [11] Evaluation of 99mTC-ECD SPECT/CT brain Imaging with NeuroGam analysis in Moyamoya disease after surgical revascularization.Medicine (Baltimore). 2019 Nov;98(46):e16525. doi: 10.1097/MD.0000000000016525.
• [12] Immunization with HER2 extracellular subdomain proteins induces cellular response and tumor growth inhibition in mice.Immunotherapy. 2018 Mar 1;10(6):511-524. doi: 10.2217/imt-2017-0181.
• [13] Impact of SchisandraChinensis Bee Pollen on Nonalcoholic Fatty Liver Disease and Gut Microbiota in HighFat Diet Induced Obese Mice.Nutrients. 2019 Feb 6;11(2):346. doi: 10.3390/nu11020346.
• [14] Pantothenate kinase-associated neurodegeneration with increased lentiform nuclei cerebral blood flow.AJNR Am J Neuroradiol. 2006 Jan;27(1):212-3.
• [15] Immunogenicity and therapeutic efficacy of a dual-component genetic cancer vaccine cotargeting carcinoembryonic antigen and HER2/neu in preclinical models.Hum Gene Ther. 2014 Feb;25(2):121-31. doi: 10.1089/hum.2013.103. Epub 2013 Dec 21.
• [16] Trastuzumab-Based Photoimmunotherapy Integrated with Viral HER2 Transduction Inhibits Peritoneally Disseminated HER2-Negative Cancer.Mol Cancer Ther. 2016 Mar;15(3):402-11. doi: 10.1158/1535-7163.MCT-15-0644. Epub 2016 Feb 1.
• [17] T-cells recognize multiple epitopes in the human thyrotropin receptor extracellular domain.J Clin Endocrinol Metab. 1995 Mar;80(3):905-14. doi: 10.1210/jcem.80.3.7533773.
• [18] A prospective study to assess the clinical utility of serum HER2 extracellular domain in breast cancer with HER2 overexpression.Breast Cancer Res Treat. 2016 Nov;160(2):249-259. doi: 10.1007/s10549-016-4000-z. Epub 2016 Oct 5.
• [19] Optimized Expression, Purification, and Rapid Detection of Recombinant Influenza Nucleoproteins Expressed in Sf9 Insect Cells.J Microbiol Biotechnol. 2018 Oct 28;28(10):1683-1690. doi: 10.4014/jmb.1805.05053.
• [20] Gastric medullary carcinoma, a distinct entity associated with microsatellite instability-H, prominent intraepithelial lymphocytes and improved prognosis.Histopathology. 2004 Nov;45(5):485-92. doi: 10.1111/j.1365-2559.2004.01998.x.
• [21] HSP90 and Its Novel Co-Chaperones, SGT1 and CHP-1, in Brain of Patients with Parkinson's Disease and Dementia with Lewy Bodies.J Parkinsons Dis. 2019;9(1):97-107. doi: 10.3233/JPD-181443.
• [22] Expression of extracellular domains of muscle specific kinase (MuSK) and use as immunoadsorbents for the development of an antigen-specific therapy.J Neuroimmunol. 2014 Nov 15;276(1-2):150-8. doi: 10.1016/j.jneuroim.2014.09.013. Epub 2014 Sep 19.
• [23] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [24] 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.
• [25] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [26] 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.
• [27] 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.
• [28] 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.
• [29] Systems analysis of transcriptome and proteome in retinoic acid/arsenic trioxide-induced cell differentiation/apoptosis of promyelocytic leukemia. Proc Natl Acad Sci U S A. 2005 May 24;102(21):7653-8.
• [30] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [31] Proteomic analysis of the cellular response to a potent sensitiser unveils the dynamics of haptenation in living cells. Toxicology. 2020 Dec 1;445:152603. doi: 10.1016/j.tox.2020.152603. Epub 2020 Sep 28.
• [32] Gene expression changes associated with altered growth and differentiation in benzo[a]pyrene or arsenic exposed normal human epidermal keratinocytes. J Appl Toxicol. 2008 May;28(4):491-508.
• [33] Quantitative phosphoproteomics reveal cellular responses from caffeine, coumarin and quercetin in treated HepG2 cells. Toxicol Appl Pharmacol. 2022 Aug 15;449:116110. doi: 10.1016/j.taap.2022.116110. Epub 2022 Jun 7.