Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTDI85I5)

• DOT Name: Nucleotide exchange factor SIL1 (SIL1)
• Synonyms: BiP-associated protein; BAP
• Gene Name: SIL1
• Related Disease:
  Bacteremia
  Marinesco-Sjogren syndrome
  Melanoma
  Multiple sclerosis
  Atrial fibrillation
  Breast carcinoma
  Breast neoplasm
  Cerebellar ataxia
  Cerebellar disorder
  Dandy-Walker syndrome
  Glioma
  Movement disorder
  Myopathy
  Neoplasm
  Prostate cancer
  Prostate neoplasm
  Uveal Melanoma
  Alzheimer disease
  Amyotrophic lateral sclerosis
  Autosomal dominant polycystic liver disease
  Anxiety
  Anxiety disorder
  Atrial septal defect
  Breast cancer
  Intellectual disability
  Small lymphocytic lymphoma
  Tuberculosis
• UniProt ID: SIL1_HUMAN
• PDB ID: 6LBN; 6LEY
• Pfam ID: PF08609
• Sequence:
  MAPQSLPSSRMAPLGMLLGLLMAACFTFCLSHQNLKEFALTNPEKSSTKETERKETKAEE
  ELDAEVLEVFHPTHEWQALQPGQAVPAGSHVRLNLQTGEREAKLQYEDKFRNNLKGKRLD
  INTNTYTSQDLKSALAKFKEGAEMESSKEDKARQAEVKRLFRPIEELKKDFDELNVVIET
  DMQIMVRLINKFNSSSSSLEEKIAALFDLEYYVHQMDNAQDLLSFGGLQVVINGLNSTEP
  LVKEYAAFVLGAAFSSNPKVQVEAIEGGALQKLLVILATEQPLTAKKKVLFALCSLLRHF
  PYAQRQFLKLGGLQVLRTLVQEKGTEVLAVRVVTLLYDLVTEKMFAEEEAELTQEMSPEK
  LQQYRQVHLLPGLWEQGWCEITAHLLALPEHDAREKVLQTLGVLLTTCRDRYRQDPQLGR
  TLASLQAEYQVLASLELQDGEDEGYFQELLGSVNSLLKELR
• Function: Required for protein translocation and folding in the endoplasmic reticulum (ER). Functions as a nucleotide exchange factor for the ER lumenal chaperone HSPA5.
• Tissue Specificity: Highly expressed in tissues which produce large amounts of secreted proteins such as kidney, liver and placenta. Also expressed in colon, heart, lung, ovary, pancreas, peripheral leukocyte, prostate, spleen and thymus. Expressed at low levels throughout the brain.
• KEGG Pathway: Protein processing in endoplasmic reticulum (hsa04141)

Molecular Interaction Atlas (MIA) of This DOT

27 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Bacteremia	DIS6N9RZ	Definitive	Genetic Variation	[1]
Marinesco-Sjogren syndrome	DISKEU0B	Definitive	Autosomal recessive	[2]
Melanoma	DIS1RRCY	Definitive	Altered Expression	[3]
Multiple sclerosis	DISB2WZI	Definitive	Genetic Variation	[4]
Atrial fibrillation	DIS15W6U	Strong	Biomarker	[5]
Breast carcinoma	DIS2UE88	Strong	Biomarker	[6]
Breast neoplasm	DISNGJLM	Strong	Biomarker	[7]
Cerebellar ataxia	DIS9IRAV	Strong	Biomarker	[8]
Cerebellar disorder	DIS2O7WM	Strong	Genetic Variation	[9]
Dandy-Walker syndrome	DIS4HC6W	Strong	Genetic Variation	[10]
Glioma	DIS5RPEH	Strong	Biomarker	[11]
Movement disorder	DISOJJ2D	Strong	Biomarker	[12]
Myopathy	DISOWG27	Strong	Genetic Variation	[13]
Neoplasm	DISZKGEW	Strong	Altered Expression	[14]
Prostate cancer	DISF190Y	Strong	Biomarker	[15]
Prostate neoplasm	DISHDKGQ	Strong	Biomarker	[15]
Uveal Melanoma	DISA7ZGL	Strong	Biomarker	[16]
Alzheimer disease	DISF8S70	moderate	Biomarker	[17]
Amyotrophic lateral sclerosis	DISF7HVM	moderate	Biomarker	[17]
Autosomal dominant polycystic liver disease	DISJS005	Disputed	Genetic Variation	[18]
Anxiety	DISIJDBA	Limited	Biomarker	[19]
Anxiety disorder	DISBI2BT	Limited	Biomarker	[19]
Atrial septal defect	DISJT76B	Limited	Biomarker	[20]
Breast cancer	DIS7DPX1	Limited	Biomarker	[6]
Intellectual disability	DISMBNXP	Limited	Biomarker	[21]
Small lymphocytic lymphoma	DIS30POX	Limited	Genetic Variation	[22]
Tuberculosis	DIS2YIMD	Limited	Biomarker	[23]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the expression of Nucleotide exchange factor SIL1 (SIL1).	[24]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Nucleotide exchange factor SIL1 (SIL1).	[25]
Doxorubicin	DMVP5YE	Approved	Doxorubicin increases the expression of Nucleotide exchange factor SIL1 (SIL1).	[26]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Nucleotide exchange factor SIL1 (SIL1).	[27]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Nucleotide exchange factor SIL1 (SIL1).	[28]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Nucleotide exchange factor SIL1 (SIL1).	[29]
Temozolomide	DMKECZD	Approved	Temozolomide increases the expression of Nucleotide exchange factor SIL1 (SIL1).	[31]
Decitabine	DMQL8XJ	Approved	Decitabine affects the expression of Nucleotide exchange factor SIL1 (SIL1).	[32]
THAPSIGARGIN	DMDMQIE	Preclinical	THAPSIGARGIN increases the expression of Nucleotide exchange factor SIL1 (SIL1).	[34]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of Nucleotide exchange factor SIL1 (SIL1).	[35]
[3H]methyltrienolone	DMTSGOW	Investigative	[3H]methyltrienolone increases the expression of Nucleotide exchange factor SIL1 (SIL1).	[36]

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 Nucleotide exchange factor SIL1 (SIL1).	[30]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Nucleotide exchange factor SIL1 (SIL1).	[33]

References

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• [8] An unexpected role for the yeast nucleotide exchange factor Sil1 as a reductant acting on the molecular chaperone BiP.Elife. 2017 Mar 3;6:e24141. doi: 10.7554/eLife.24141.
• [9] SIL1 mutations and clinical spectrum in patients with Marinesco-Sjogren syndrome.Brain. 2013 Dec;136(Pt 12):3634-44. doi: 10.1093/brain/awt283. Epub 2013 Oct 30.
• [10] Novel SIL1 nonstop mutation in a Chinese consanguineous family with Marinesco-Sjgren syndrome and Dandy-Walker syndrome.Clin Chim Acta. 2016 Jul 1;458:1-4. doi: 10.1016/j.cca.2016.04.018. Epub 2016 Apr 19.
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• [15] Identification of genes potentially involved in the acquisition of androgen-independent and metastatic tumor growth in an autochthonous genetically engineered mouse prostate cancer model.Prostate. 2007 Jan 1;67(1):83-106. doi: 10.1002/pros.20505.
• [16] PARP Inhibition Increases the Response to Chemotherapy in Uveal Melanoma.Cancers (Basel). 2019 May 29;11(6):751. doi: 10.3390/cancers11060751.
• [17] Tracking Effects of SIL1 Increase: Taking a Closer Look Beyond the Consequences of Elevated Expression Level.Mol Neurobiol. 2018 Mar;55(3):2524-2546. doi: 10.1007/s12035-017-0494-6. Epub 2017 Apr 11.
• [18] Protein transport into the endoplasmic reticulum: mechanisms and pathologies.Trends Mol Med. 2006 Dec;12(12):567-73. doi: 10.1016/j.molmed.2006.10.004. Epub 2006 Oct 30.
• [19] Mid-childhood outcomes of infant siblings at familial high-risk of autism spectrum disorder.Autism Res. 2017 Mar;10(3):546-557. doi: 10.1002/aur.1733. Epub 2016 Nov 29.
• [20] Predictors of Pragmatic Communication in School-Age Siblings of Children with ASD and Low-Risk Controls.J Autism Dev Disord. 2019 Apr;49(4):1352-1365. doi: 10.1007/s10803-018-3837-x.
• [21] Functional Role of SIL1 in Neurodevelopment and Learning.Neural Plast. 2019 Aug 18;2019:9653024. doi: 10.1155/2019/9653024. eCollection 2019.
• [22] Prognostic relevance of oxidative stress measurement in chronic lymphocytic leukaemia.Eur J Haematol. 2017 Oct;99(4):306-314. doi: 10.1111/ejh.12918. Epub 2017 Aug 3.
• [23] Performance assessment of a nested-PCR assay (the RAPID BAP-MTB) and the BD ProbeTec ET system for detection of Mycobacterium tuberculosis in clinical specimens.J Clin Microbiol. 2004 Oct;42(10):4599-603. doi: 10.1128/JCM.42.10.4599-4603.2004.
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• [25] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [26] 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.
• [27] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [28] Characterisation of cisplatin-induced transcriptomics responses in primary mouse hepatocytes, HepG2 cells and mouse embryonic stem cells shows conservation of regulating transcription factor networks. Mutagenesis. 2014 Jan;29(1):17-26.
• [29] Quantitative proteomics reveals a broad-spectrum antiviral property of ivermectin, benefiting for COVID-19 treatment. J Cell Physiol. 2021 Apr;236(4):2959-2975. doi: 10.1002/jcp.30055. Epub 2020 Sep 22.
• [30] 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.
• [31] 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.
• [32] Acute hypersensitivity of pluripotent testicular cancer-derived embryonal carcinoma to low-dose 5-aza deoxycytidine is associated with global DNA Damage-associated p53 activation, anti-pluripotency and DNA demethylation. PLoS One. 2012;7(12):e53003. doi: 10.1371/journal.pone.0053003. Epub 2012 Dec 27.
• [33] 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.
• [34] Endoplasmic reticulum stress impairs insulin signaling through mitochondrial damage in SH-SY5Y cells. Neurosignals. 2012;20(4):265-80.
• [35] 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.
• [36] Evaluation of an in vitro model of androgen ablation and identification of the androgen responsive proteome in LNCaP cells. Proteomics. 2007 Jan;7(1):47-63.