Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTN8SD5W)

• DOT Name: Nuclear autoantigen Sp-100 (SP100)
• Synonyms: Nuclear dot-associated Sp100 protein; Speckled 100 kDa
• Gene Name: SP100
• Related Disease:
  Neoplasm
  Adult glioblastoma
  Advanced cancer
  Autoimmune disease
  Brain neoplasm
  Cytomegalovirus infection
  Glioblastoma multiforme
  leukaemia
  Meningioma
  Primary hyperoxaluria type 1
  Progressive multifocal leukoencephalopathy
  Promyelocytic leukaemia
  Leukemia
• UniProt ID: SP100_HUMAN
• PDB ID: 1H5P ; 4PTB ; 5FB0 ; 5FB1 ; 5PWE ; 5PWF ; 5PWG ; 5PWH ; 5PWI ; 5PWJ ; 5PWK ; 5PWL ; 5PWM ; 5PWN ; 5PWO ; 5PWP ; 5PWQ ; 5PWR ; 5PWS ; 5PWT ; 5PWU ; 5PWV ; 5PWW ; 5PWX ; 5PWY ; 5PWZ ; 5PX0 ; 5PX1 ; 5PX2 ; 5PX3 ; 5PX4 ; 5PX5 ; 5PX6 ; 5PX7 ; 5PX8 ; 5PX9 ; 5PXA ; 5PXB ; 5PXC ; 5PXD ; 5PXE ; 5PXF ; 5PXG ; 5PXH ; 5PXI ; 5PXJ ; 5PXK ; 5PXL ; 5PXM ; 5PXN ; 5PXO ; 5PXP ; 5PXQ ; 5PXR ; 5PXS ; 5PXT ; 5PXU ; 5PXV ; 5PXW ; 5PXX ; 5PXY ; 5PXZ ; 5PY0 ; 5PY1 ; 5PY2 ; 5PY3 ; 5PY4 ; 5PY5 ; 5PY6 ; 5PY7 ; 5PY8 ; 5PY9 ; 5PYA ; 5PYB ; 5PYC ; 5PYD ; 5PYE ; 5PYF ; 5PYG ; 5PYH ; 5PYI ; 5PYJ ; 5PYK ; 5PYL ; 5PYM ; 5PYN ; 5PYO ; 5PYP ; 5PYQ ; 5PYR ; 5PYS ; 5PYT ; 5PYU ; 5PYV ; 5PYW ; 5PYX ; 5PYY ; 5PYZ ; 5PZ0 ; 5PZ1 ; 5PZ2 ; 5PZ3 ; 5PZ4 ; 5PZ5 ; 5PZ6 ; 5PZ7 ; 5PZ8 ; 5PZ9 ; 5PZA ; 5PZB ; 5PZC ; 5PZD ; 5PZE ; 5PZF ; 5PZG ; 5PZH ; 5PZI ; 5PZJ ; 6G5N ; 6G5P
• Pfam ID: PF00505 ; PF09011 ; PF03172 ; PF01342
• Sequence:
  MAGGGGDLSTRRLNECISPVANEMNHLPAHSHDLQRMFTEDQGVDDRLLYDIVFKHFKRN
  KVEISNAIKKTFPFLEGLRDRDLITNKMFEDSQDSCRNLVPVQRVVYNVLSELEKTFNLP
  VLEALFSDVNMQEYPDLIHIYKGFENVIHDKLPLQESEEEEREERSGLQLSLEQGTGENS
  FRSLTWPPSGSPSHAGTTPPENGLSEHPCETEQINAKRKDTTSDKDDSLGSQQTNEQCAQ
  KAEPTESCEQIAVQVNNGDAGREMPCPLPCDEESPEAELHNHGIQINSCSVRLVDIKKEK
  PFSNSKVECQAQARTHHNQASDIIVISSEDSEGSTDVDEPLEVFISAPRSEPVINNDNPL
  ESNDEKEGQEATCSRPQIVPEPMDFRKLSTFRESFKKRVIGQDHDFSESSEEEAPAEASS
  GALRSKHGEKAPMTSRSTSTWRIPSRKRRFSSSDFSDLSNGEELQETCSSSLRRGSGSQP
  QEPENKKCSCVMCFPKGVPRSQEARTESSQASDMMDTMDVENNSTLEKHSGKRRKKRRHR
  SKVNGLQRGRKKDRPRKHLTLNNKVQKKRWQQRGRKANTRPLKRRRKRGPRIPKDENINF
  KQSELPVTCGEVKGTLYKERFKQGTSKKCIQSEDKKWFTPREFEIEGDRGASKNWKLSIR
  CGGYTLKVLMENKFLPEPPSTRKKRILESHNNTLVDPCEEHKKKNPDASVKFSEFLKKCS
  ETWKTIFAKEKGKFEDMAKADKAHYEREMKTYIPPKGEKKKKFKDPNAPKRPPLAFFLFC
  SEYRPKIKGEHPGLSIDDVVKKLAGMWNNTAAADKQFYEKKAAKLKEKYKKDIAAYRAKG
  KPNSAKKRVVKAEKSKKKKEEEEDEEDEQEEENEEDDDK
• Function: Together with PML, this tumor suppressor is a major constituent of the PML bodies, a subnuclear organelle involved in a large number of physiological processes including cell growth, differentiation and apoptosis. Functions as a transcriptional coactivator of ETS1 and ETS2 according to PubMed:11909962. Under certain conditions, it may also act as a corepressor of ETS1 preventing its binding to DNA according to PubMed:15247905. Through the regulation of ETS1 it may play a role in angiogenesis, controlling endothelial cell motility and invasion. Through interaction with the MRN complex it may be involved in the regulation of telomeres lengthening. May also regulate TP53-mediated transcription and through CASP8AP2, regulate FAS-mediated apoptosis. Also plays a role in infection by viruses, including human cytomegalovirus and Epstein-Barr virus, through mechanisms that may involve chromatin and/or transcriptional regulation.
• Tissue Specificity: Widely expressed. Sp100-B is expressed only in spleen, tonsil, thymus, mature B-cell line and some T-cell line, but not in brain, liver, muscle or non-lymphoid cell lines.
• KEGG Pathway:
  Herpes simplex virus 1 infection (hsa05168)
  Viral carcinogenesis (hsa05203)
• Reactome Pathway:
  Interferon gamma signaling (R-HSA-877300)
  SUMOylation of DNA damage response and repair proteins (R-HSA-3108214)

Molecular Interaction Atlas (MIA) of This DOT

13 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Neoplasm	DISZKGEW	Definitive	Biomarker	[1]
Adult glioblastoma	DISVP4LU	Strong	Altered Expression	[2]
Advanced cancer	DISAT1Z9	Strong	Altered Expression	[2]
Autoimmune disease	DISORMTM	Strong	Biomarker	[3]
Brain neoplasm	DISY3EKS	Strong	Altered Expression	[2]
Cytomegalovirus infection	DISCEMGC	Strong	Altered Expression	[4]
Glioblastoma multiforme	DISK8246	Strong	Altered Expression	[2]
leukaemia	DISS7D1V	Strong	Biomarker	[5]
Meningioma	DISPT4TG	Strong	Altered Expression	[2]
Primary hyperoxaluria type 1	DISS210K	Strong	Biomarker	[6]
Progressive multifocal leukoencephalopathy	DISX02WS	Strong	Biomarker	[7]
Promyelocytic leukaemia	DISYGG13	Strong	Biomarker	[8]
Leukemia	DISNAKFL	Limited	Biomarker	[9]

This DOT Affected the Drug Response of 1 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Cisplatin	DMRHGI9	Approved	Nuclear autoantigen Sp-100 (SP100) decreases the response to substance of Cisplatin.	[28]

18 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 Nuclear autoantigen Sp-100 (SP100).	[10]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Nuclear autoantigen Sp-100 (SP100).	[11]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Nuclear autoantigen Sp-100 (SP100).	[12]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Nuclear autoantigen Sp-100 (SP100).	[13]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Nuclear autoantigen Sp-100 (SP100).	[14]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of Nuclear autoantigen Sp-100 (SP100).	[15]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Nuclear autoantigen Sp-100 (SP100).	[16]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Nuclear autoantigen Sp-100 (SP100).	[17]
Vorinostat	DMWMPD4	Approved	Vorinostat increases the expression of Nuclear autoantigen Sp-100 (SP100).	[20]
Triclosan	DMZUR4N	Approved	Triclosan increases the expression of Nuclear autoantigen Sp-100 (SP100).	[21]
Selenium	DM25CGV	Approved	Selenium decreases the expression of Nuclear autoantigen Sp-100 (SP100).	[22]
Demecolcine	DMCZQGK	Approved	Demecolcine increases the expression of Nuclear autoantigen Sp-100 (SP100).	[23]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of Nuclear autoantigen Sp-100 (SP100).	[20]
Tocopherol	DMBIJZ6	Phase 2	Tocopherol decreases the expression of Nuclear autoantigen Sp-100 (SP100).	[22]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Nuclear autoantigen Sp-100 (SP100).	[24]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of Nuclear autoantigen Sp-100 (SP100).	[25]
Nickel chloride	DMI12Y8	Investigative	Nickel chloride decreases the expression of Nuclear autoantigen Sp-100 (SP100).	[26]
geraniol	DMS3CBD	Investigative	geraniol increases the expression of Nuclear autoantigen Sp-100 (SP100).	[27]

4 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 Nuclear autoantigen Sp-100 (SP100).	[18]
Quercetin	DM3NC4M	Approved	Quercetin affects the phosphorylation of Nuclear autoantigen Sp-100 (SP100).	[19]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 decreases the phosphorylation of Nuclear autoantigen Sp-100 (SP100).	[19]
Coumarin	DM0N8ZM	Investigative	Coumarin decreases the phosphorylation of Nuclear autoantigen Sp-100 (SP100).	[19]

References

• [1] The contribution of SP100 to cottontail rabbit papillomavirus transcription and replication.J Gen Virol. 2018 Mar;99(3):344-354. doi: 10.1099/jgv.0.001012.
• [2] SP100 reduces malignancy of human glioma cells.Int J Oncol. 2011 Apr;38(4):1023-30. doi: 10.3892/ijo.2011.927. Epub 2011 Jan 27.
• [3] Autoantibodies against "nuclear dots" in primary biliary cirrhosis.Semin Liver Dis. 1997 Feb;17(1):71-8. doi: 10.1055/s-2007-1007184.
• [4] Nuclear domain 10 components upregulated via interferon during human cytomegalovirus infection potently regulate viral infection.J Gen Virol. 2017 Jul;98(7):1795-1805. doi: 10.1099/jgv.0.000858.
• [5] The PML nuclear bodies: actors or extras?.Curr Opin Genet Dev. 1999 Jun;9(3):362-7. doi: 10.1016/s0959-437x(99)80054-9.
• [6] Subcellular distribution of HP1 proteins is altered in ICF syndrome.Eur J Hum Genet. 2005 Jan;13(1):41-51. doi: 10.1038/sj.ejhg.5201293.
• [7] PML nuclear body-residing proteins sequentially associate with HPV genome after infectious nuclear delivery.PLoS Pathog. 2019 Feb 25;15(2):e1007590. doi: 10.1371/journal.ppat.1007590. eCollection 2019 Feb.
• [8] PML-like subnuclear bodies, containing XRCC1, juxtaposed to DNA replication-based single-strand breaks.FASEB J. 2019 Feb;33(2):2301-2313. doi: 10.1096/fj.201801379R. Epub 2018 Sep 27.
• [9] Diagnostic and clinical utility of antibodies against the nuclear body promyelocytic leukaemia and Sp100 antigens in patients with primary biliary cirrhosis.Clin Chim Acta. 2012 Aug 16;413(15-16):1211-6. doi: 10.1016/j.cca.2012.03.020. Epub 2012 Apr 3.
• [10] Stem cell transcriptome responses and corresponding biomarkers that indicate the transition from adaptive responses to cytotoxicity. Chem Res Toxicol. 2017 Apr 17;30(4):905-922.
• [11] Cyclosporine A--induced oxidative stress in human renal mesangial cells: a role for ERK 1/2 MAPK signaling. Toxicol Sci. 2012 Mar;126(1):101-13.
• [12] Transcriptional and Metabolic Dissection of ATRA-Induced Granulocytic Differentiation in NB4 Acute Promyelocytic Leukemia Cells. Cells. 2020 Nov 5;9(11):2423. doi: 10.3390/cells9112423.
• [13] 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.
• [14] 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.
• [15] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [16] Long-term estrogen exposure promotes carcinogen bioactivation, induces persistent changes in gene expression, and enhances the tumorigenicity of MCF-7 human breast cancer cells. Toxicol Appl Pharmacol. 2009 Nov 1;240(3):355-66.
• [17] 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.
• [18] 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.
• [19] 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.
• [20] Definition of transcriptome-based indices for quantitative characterization of chemically disturbed stem cell development: introduction of the STOP-Toxukn and STOP-Toxukk tests. Arch Toxicol. 2017 Feb;91(2):839-864.
• [21] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [22] 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.
• [23] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [24] Inhibition of BRD4 attenuates tumor cell self-renewal and suppresses stem cell signaling in MYC driven medulloblastoma. Oncotarget. 2014 May 15;5(9):2355-71.
• [25] Identification of mechanisms of action of bisphenol a-induced human preadipocyte differentiation by transcriptional profiling. Obesity (Silver Spring). 2014 Nov;22(11):2333-43.
• [26] Nickel-induced down-regulation of Np63 and its role in the proliferation of keratinocytes. Toxicol Appl Pharmacol. 2011 Jun 15;253(3):235-43. doi: 10.1016/j.taap.2011.03.024. Epub 2011 Apr 3.
• [27] Geraniol suppresses prostate cancer growth through down-regulation of E2F8. Cancer Med. 2016 Oct;5(10):2899-2908.
• [28] Gene expression analysis using human cancer xenografts to identify novel predictive marker genes for the efficacy of 5-fluorouracil-based drugs. Cancer Sci. 2006 Jun;97(6):510-22. doi: 10.1111/j.1349-7006.2006.00204.x.