Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT94R6M1)

• DOT Name: EMILIN-1 (EMILIN1)
• Synonyms: Elastin microfibril interface-located protein 1; Elastin microfibril interfacer 1
• Gene Name: EMILIN1
• Related Disease:
  Aortic valve disorder
  Bone osteosarcoma
  Colitis
  Colon cancer
  Colon carcinoma
  Colorectal neoplasm
  Congenital diaphragmatic hernia
  Connective tissue disorder
  Essential hypertension
  Inflammatory bowel disease
  Neoplasm
  Neuronopathy, distal hereditary motor, autosomal dominant 10
  Osteosarcoma
  Ovarian cancer
  Gastric cancer
  Stomach cancer
• UniProt ID: EMIL1_HUMAN
• PDB ID: 2KA3; 2OII
• Pfam ID: PF00386 ; PF01391 ; PF07546
• Sequence:
  MAPRTLWSCYLCCLLTAAAGAASYPPRGFSLYTGSSGALSPGGPQAQIAPRPASRHRNWC
  AYVVTRTVSCVLEDGVETYVKYQPCAWGQPQCPQSIMYRRFLRPRYRVAYKTVTDMEWRC
  CQGYGGDDCAESPAPALGPASSTPRPLARPARPNLSGSSAGSPLSGLGGEGPGESEKVQQ
  LEEQVQSLTKELQGLRGVLQGLSGRLAEDVQRAVETAFNGRQQPADAAARPGVHETLNEI
  QHQLQLLDTRVSTHDQELGHLNNHHGGSSSSGGSRAPAPASAPPGPSEELLRQLEQRLQE
  SCSVCLAGLDGFRRQQQEDRERLRAMEKLLASVEERQRHLAGLAVGRRPPQECCSPELGR
  RLAELERRLDVVAGSVTVLSGRRGTELGGAAGQGGHPPGYTSLASRLSRLEDRFNSTLGP
  SEEQEESWPGAPGGLSHWLPAARGRLEQLGGLLANVSGELGGRLDLLEEQVAGAMQACGQ
  LCSGAPGEQDSQVSEILSALERRVLDSEGQLRLVGSGLHTVEAAGEARQATLEGLQEVVG
  RLQDRVDAQDETAAEFTLRLNLTAARLGQLEGLLQAHGDEGCGACGGVQEELGRLRDGVE
  RCSCPLLPPRGPGAGPGVGGPSRGPLDGFSVFGGSSGSALQALQGELSEVILSFSSLNDS
  LNELQTTVEGQGADLADLGATKDRIISEINRLQQEATEHATESEERFRGLEEGQAQAGQC
  PSLEGRLGRLEGVCERLDTVAGGLQGLREGLSRHVAGLWAGLRETNTTSQMQAALLEKLV
  GGQAGLGRRLGALNSSLQLLEDRLHQLSLKDLTGPAGEAGPPGPPGLQGPPGPAGPPGSP
  GKDGQEGPIGPPGPQGEQGVEGAPAAPVPQVAFSAALSLPRSEPGTVPFDRVLLNDGGYY
  DPETGVFTAPLAGRYLLSAVLTGHRHEKVEAVLSRSNQGVARVDSGGYEPEGLENKPVAE
  SQPSPGTLGVFSLILPLQAGDTVCVDLVMGQLAHSEEPLTIFSGALLYGDPELEHA
• Function: May be responsible for anchoring smooth muscle cells to elastic fibers, and may be involved not only in the formation of the elastic fiber, but also in the processes that regulate vessel assembly. Has cell adhesive capacity.
• Tissue Specificity: Distributed in tissues where resilience and elastic recoil are prominent. Highest levels in the adult small intestine, aorta, lung, uterus, and appendix and in the fetal spleen, kidney, lung, and heart; intermediate expression was detected in adult liver, ovary, colon, stomach, lymph node and spleen; adult heart, bladder, prostate, adrenal gland, mammary gland, placenta and kidney showed low expression whereas a series of other adult tissues, including skeletal muscle and different regions of adult brain show no expression. Detected in intramuscular nerve bundles, where it particularly localizes in the epineurium, the most external layer of dense connective tissue enclosing the nerve .
• Reactome Pathway: Molecules associated with elastic fibres (R-HSA-2129379)

Molecular Interaction Atlas (MIA) of This DOT

16 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Aortic valve disorder	DISKLYD7	Strong	Genetic Variation	[1]
Bone osteosarcoma	DIST1004	Strong	Biomarker	[2]
Colitis	DISAF7DD	Strong	Biomarker	[3]
Colon cancer	DISVC52G	Strong	Altered Expression	[3]
Colon carcinoma	DISJYKUO	Strong	Altered Expression	[3]
Colorectal neoplasm	DISR1UCN	Strong	Altered Expression	[4]
Congenital diaphragmatic hernia	DIS0IPVU	Strong	Altered Expression	[5]
Connective tissue disorder	DISKXBS3	Strong	Genetic Variation	[6]
Essential hypertension	DIS7WI98	Strong	Biomarker	[7]
Inflammatory bowel disease	DISGN23E	Strong	Biomarker	[3]
Neoplasm	DISZKGEW	Strong	Altered Expression	[3]
Neuronopathy, distal hereditary motor, autosomal dominant 10	DISEH4ER	Strong	Autosomal dominant	[6]
Osteosarcoma	DISLQ7E2	Strong	Biomarker	[2]
Ovarian cancer	DISZJHAP	Strong	Biomarker	[8]
Gastric cancer	DISXGOUK	Limited	Biomarker	[9]
Stomach cancer	DISKIJSX	Limited	Biomarker	[9]

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 EMILIN-1 (EMILIN1).	[10]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the methylation of EMILIN-1 (EMILIN1).	[15]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of EMILIN-1 (EMILIN1).	[11]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of EMILIN-1 (EMILIN1).	[12]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of EMILIN-1 (EMILIN1).	[13]
Selenium	DM25CGV	Approved	Selenium increases the expression of EMILIN-1 (EMILIN1).	[14]
Menadione	DMSJDTY	Approved	Menadione affects the expression of EMILIN-1 (EMILIN1).	[13]
Tocopherol	DMBIJZ6	Phase 2	Tocopherol increases the expression of EMILIN-1 (EMILIN1).	[14]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of EMILIN-1 (EMILIN1).	[16]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of EMILIN-1 (EMILIN1).	[17]

References

• [1] Proteomic Alterations Associated with Biomechanical Dysfunction are Early Processes in the Emilin1 Deficient Mouse Model of Aortic Valve Disease.Ann Biomed Eng. 2017 Nov;45(11):2548-2562. doi: 10.1007/s10439-017-1899-0. Epub 2017 Aug 15.
• [2] Distinct profiles of oxidative stress-related and matrix proteins in adult bone and soft tissue osteosarcoma and desmoid tumors: a proteomics study.Hum Pathol. 2013 May;44(5):725-33. doi: 10.1016/j.humpath.2012.06.023. Epub 2012 Oct 11.
• [3] Abrogation of EMILIN1-1 integrin interaction promotes experimental colitis and colon carcinogenesis.Matrix Biol. 2019 Oct;83:97-115. doi: 10.1016/j.matbio.2019.08.006. Epub 2019 Aug 31.
• [4] A chemical genetics approach identifies PTP4A3 as a regulator of colon cancer cell adhesion.FASEB J. 2018 Oct;32(10):5661-5673. doi: 10.1096/fj.201701446R. Epub 2018 May 10.
• [5] Downregulated Elastin Microfibril Interfacer 1 Expression in the Pulmonary Vasculature of Experimental Congenital Diaphragmatic Hernia.Eur J Pediatr Surg. 2018 Feb;28(1):115-119. doi: 10.1055/s-0037-1604026. Epub 2017 Jul 12.
• [6] Diagnostic Exome Sequencing Identifies a Novel Gene, EMILIN1, Associated with Autosomal-Dominant Hereditary Connective Tissue Disease. Hum Mutat. 2016 Jan;37(1):84-97. doi: 10.1002/humu.22920. Epub 2015 Nov 4.
• [7] Association of intronic single-nucleotide polymorphisms in the EMILIN1 gene with essential hypertension in a Chinese population.J Hum Hypertens. 2012 Sep;26(9):553-61. doi: 10.1038/jhh.2011.68. Epub 2011 Jul 14.
• [8] Neutrophil elastase-dependent cleavage compromises the tumor suppressor role of EMILIN1.Matrix Biol. 2014 Feb;34:22-32. doi: 10.1016/j.matbio.2014.01.018. Epub 2014 Feb 7.
• [9] TSPAN9 and EMILIN1 synergistically inhibit the migration and invasion of gastric cancer cells by increasing TSPAN9 expression.BMC Cancer. 2019 Jun 26;19(1):630. doi: 10.1186/s12885-019-5810-2.
• [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] 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.
• [12] Low doses of cisplatin induce gene alterations, cell cycle arrest, and apoptosis in human promyelocytic leukemia cells. Biomark Insights. 2016 Aug 24;11:113-21.
• [13] Time series analysis of oxidative stress response patterns in HepG2: a toxicogenomics approach. Toxicology. 2013 Apr 5;306:24-34.
• [14] Selenium and vitamin E: cell type- and intervention-specific tissue effects in prostate cancer. J Natl Cancer Inst. 2009 Mar 4;101(5):306-20.
• [15] 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.
• [16] Targeting MYCN in neuroblastoma by BET bromodomain inhibition. Cancer Discov. 2013 Mar;3(3):308-23.
• [17] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.