Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTLEDM2S)

• DOT Name: Splicing factor 1 (SF1)
• Synonyms: Mammalian branch point-binding protein; BBP; mBBP; Transcription factor ZFM1; Zinc finger gene in MEN1 locus; Zinc finger protein 162
• Gene Name: SF1
• Related Disease:
  Multiple endocrine neoplasia type 1
  Non-insulin dependent diabetes
  Adenoma
  Adrenocortical carcinoma
  Aplasia cutis congenita
  Carcinoma
  Corpus callosum, agenesis of
  Hypospadias
  Melanoma
  Ovarian dysgenesis 1
  Ovarian neoplasm
  46,XY disorder of sex development
  Adrenocortical insufficiency
  Type-1/2 diabetes
  Ischemia
  Neoplasm
  Osteomyelitis
• UniProt ID: SF01_HUMAN
• PDB ID: 1K1G; 1O0P; 1OPI; 2M09; 2M0G; 4FXW; 4FXX; 7VH9; 7VPX
• Pfam ID: PF00013 ; PF16275 ; PF00098
• Sequence:
  MATGANATPLDFPSKKRKRSRWNQDTMEQKTVIPGMPTVIPPGLTREQERAYIVQLQIED
  LTRKLRTGDLGIPPNPEDRSPSPEPIYNSEGKRLNTREFRTRKKLEEERHNLITEMVALN
  PDFKPPADYKPPATRVSDKVMIPQDEYPEINFVGLLIGPRGNTLKNIEKECNAKIMIRGK
  GSVKEGKVGRKDGQMLPGEDEPLHALVTANTMENVKKAVEQIRNILKQGIETPEDQNDLR
  KMQLRELARLNGTLREDDNRILRPWQSSETRSITNTTVCTKCGGAGHIASDCKFQRPGDP
  QSAQDKARMDKEYLSLMAELGEAPVPASVGSTSGPATTPLASAPRPAAPANNPPPPSLMS
  TTQSRPPWMNSGPSESRPYHGMHGGGPGGPGGGPHSFPHPLPSLTGGHGGHPMQHNPNGP
  PPPWMQPPPPPMNQGPHPPGHHGPPPMDQYLGSTPVGSGVYRLHQGKGMMPPPPMGMMPP
  PPPPPSGQPPPPPSGPLPPWQQQQQQPPPPPPPSSSMASSTPLPWQQNTTTTTTSAGTGS
  IPPWQQQQAAAAASPGAPQMQGNPTMVPLPPGVQPPLPPGAPPPPPPPPPGSAGMMYAPP
  PPPPPPMDPSNFVTMMGMGVAGMPPFGMPPAPPPPPPQN
• Function: Necessary for the ATP-dependent first step of spliceosome assembly. Binds to the intron branch point sequence (BPS) 5'-UACUAAC-3' of the pre-mRNA. May act as transcription repressor.
• Tissue Specificity: Detected in lung, ovary, adrenal gland, colon, kidney, muscle, pancreas, thyroid, placenta, brain, liver and heart.
• Reactome Pathway: mRNA Splicing - Major Pathway (R-HSA-72163)

Molecular Interaction Atlas (MIA) of This DOT

17 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Multiple endocrine neoplasia type 1	DIS0RJRK	Definitive	Genetic Variation	[1]
Non-insulin dependent diabetes	DISK1O5Z	Definitive	Genetic Variation	[2]
Adenoma	DIS78ZEV	Strong	Altered Expression	[3]
Adrenocortical carcinoma	DISZF4HX	Strong	Biomarker	[4]
Aplasia cutis congenita	DISMDAYM	Strong	Biomarker	[5]
Carcinoma	DISH9F1N	Strong	Altered Expression	[3]
Corpus callosum, agenesis of	DISO9P40	Strong	Biomarker	[5]
Hypospadias	DIS48CCP	Strong	Genetic Variation	[6]
Melanoma	DIS1RRCY	Strong	Biomarker	[7]
Ovarian dysgenesis 1	DISXIXHW	Strong	Genetic Variation	[8]
Ovarian neoplasm	DISEAFTY	Strong	Biomarker	[9]
46,XY disorder of sex development	DIS78CGG	moderate	Genetic Variation	[10]
Adrenocortical insufficiency	DISZ0CPT	moderate	Genetic Variation	[11]
Type-1/2 diabetes	DISIUHAP	Disputed	Biomarker	[12]
Ischemia	DIS5XOOY	Limited	Biomarker	[13]
Neoplasm	DISZKGEW	Limited	Altered Expression	[14]
Osteomyelitis	DIS0VUZL	Limited	Biomarker	[15]

This DOT Affected the Drug Response of 2 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Temozolomide	DMKECZD	Approved	Splicing factor 1 (SF1) affects the response to substance of Temozolomide.	[32]
DTI-015	DMXZRW0	Approved	Splicing factor 1 (SF1) affects the response to substance of DTI-015.	[32]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Doxorubicin	DMVP5YE	Approved	Doxorubicin affects the expression of Splicing factor 1 (SF1).	[16]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Splicing factor 1 (SF1).	[17]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Splicing factor 1 (SF1).	[18]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Splicing factor 1 (SF1).	[19]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Splicing factor 1 (SF1).	[20]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide decreases the expression of Splicing factor 1 (SF1).	[21]
Selenium	DM25CGV	Approved	Selenium decreases the expression of Splicing factor 1 (SF1).	[22]
Benzatropine	DMF7EXL	Approved	Benzatropine decreases the expression of Splicing factor 1 (SF1).	[23]
Hydrocortisone	DMGEMB7	Approved	Hydrocortisone decreases the expression of Splicing factor 1 (SF1).	[24]
Hydroxyflutamide	DMGIZF5	Approved	Hydroxyflutamide decreases the expression of Splicing factor 1 (SF1).	[26]
Dihydrotestosterone	DM3S8XC	Phase 4	Dihydrotestosterone decreases the expression of Splicing factor 1 (SF1).	[26]
Tocopherol	DMBIJZ6	Phase 2	Tocopherol decreases the expression of Splicing factor 1 (SF1).	[22]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A affects the expression of Splicing factor 1 (SF1).	[29]
methyl p-hydroxybenzoate	DMO58UW	Investigative	methyl p-hydroxybenzoate increases the expression of Splicing factor 1 (SF1).	[30]
CATECHIN	DMY38SB	Investigative	CATECHIN decreases the expression of Splicing factor 1 (SF1).	[31]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Dihydroartemisinin	DMBXVMZ	Approved	Dihydroartemisinin affects the binding of Splicing factor 1 (SF1).	[25]

2 Drug(s) Affected the Post-Translational Modifications of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the methylation of Splicing factor 1 (SF1).	[27]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 affects the phosphorylation of Splicing factor 1 (SF1).	[28]

References

• [1] Diverse modes of alternative splicing of human splicing factor SF1 deduced from the exon-intron structure of the gene.Gene. 1998 Apr 28;211(1):29-37. doi: 10.1016/s0378-1119(98)00058-4.
• [2] The Gly146Ala variation in human SF-1 gene: its association with insulin resistance and type 2 diabetes in Chinese.Diabetes Res Clin Pract. 2006 Sep;73(3):322-8. doi: 10.1016/j.diabres.2006.02.007. Epub 2006 Mar 27.
• [3] DAX1 Overexpression in Pediatric Adrenocortical Tumors: A Synergic Role with SF1 in Tumorigenesis.Horm Metab Res. 2015 Aug;47(9):656-61. doi: 10.1055/s-0034-1398560. Epub 2015 May 18.
• [4] Knockdown of SF-1 and RNF31 affects components of steroidogenesis, TGFbeta, and Wnt/beta-catenin signaling in adrenocortical carcinoma cells. PLoS One. 2012;7(3):e32080.
• [5] High diagnostic and prognostic value of steroidogenic factor-1 expression in adrenal tumors.J Clin Endocrinol Metab. 2010 Oct;95(10):E161-71. doi: 10.1210/jc.2010-0653. Epub 2010 Jul 21.
• [6] Mutation analysis of the SRD5A2, AR and SF-1 genes in 52 Chinese boys with hypospadias.J Pediatr Endocrinol Metab. 2013;26(9-10):887-93. doi: 10.1515/jpem-2012-0316.
• [7] Aggressiveness of human melanoma xenograft models is promoted by aneuploidy-driven gene expression deregulation.Oncotarget. 2012 Apr;3(4):399-413. doi: 10.18632/oncotarget.473.
• [8] Preserved fertility in a patient with a 46,XY disorder of sex development due to a new heterozygous mutation in the NR5A1/SF-1 gene: evidence of 46,XY and 46,XX gonadal dysgenesis phenotype variability in multiple members of an affected kindred.Horm Res Paediatr. 2012;78(2):119-26. doi: 10.1159/000338346. Epub 2012 Aug 14.
• [9] Genetic and epigenetic alterations of steroidogenic factor? in ovarian tumors.Int J Oncol. 2013 Feb;42(2):627-34. doi: 10.3892/ijo.2012.1758. Epub 2012 Dec 28.
• [10] Three new SF-1 (NR5A1) gene mutations in two unrelated families with multiple affected members: within-family variability in 46,XY subjects and low ovarian reserve in fertile 46,XX subjects.Horm Res Paediatr. 2011;75(1):70-7. doi: 10.1159/000320029. Epub 2010 Sep 22.
• [11] In cases of familial primary ovarian insufficiency and disorders of gonadal development, consider NR5A1/SF-1 sequence variants.Reprod Biomed Online. 2020 Jan;40(1):151-159. doi: 10.1016/j.rbmo.2019.10.002. Epub 2019 Oct 10.
• [12] Insulin Treatment Forces Arteriogenesis in Diabetes Mellitus by Upregulation of the Early Growth Response-1 (Egr-1) Pathway in Mice.Int J Mol Sci. 2019 Jul 5;20(13):3320. doi: 10.3390/ijms20133320.
• [13] ZFM1/SF1 mRNA in rat and gerbil brain after global ischaemia.Eur J Neurosci. 1999 Mar;11(3):781-7. doi: 10.1046/j.1460-9568.1999.00485.x.
• [14] Steroidogenic factor 1 overexpression and gene amplification are more frequent in adrenocortical tumors from children than from adults.J Clin Endocrinol Metab. 2010 Mar;95(3):1458-62. doi: 10.1210/jc.2009-2040. Epub 2010 Jan 15.
• [15] A bone sialoprotein-binding protein from Staphylococcus aureus: a member of the staphylococcal Sdr family.Biochem J. 2000 Feb 1;345 Pt 3(Pt 3):611-9.
• [16] 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.
• [17] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [18] 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.
• [19] 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.
• [20] 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.
• [21] Microarray analysis of H2O2-, HNE-, or tBH-treated ARPE-19 cells. Free Radic Biol Med. 2002 Nov 15;33(10):1419-32.
• [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] Cannabidiol Displays Proteomic Similarities to Antipsychotics in Cuprizone-Exposed Human Oligodendrocytic Cell Line MO3.13. Front Mol Neurosci. 2021 May 28;14:673144. doi: 10.3389/fnmol.2021.673144. eCollection 2021.
• [24] Intergenerational genetic programming mechanism and sex differences of the adrenal corticosterone synthesis dysfunction in offspring induced by prenatal ethanol exposure. Toxicol Lett. 2021 Oct 15;351:78-88. doi: 10.1016/j.toxlet.2021.08.007. Epub 2021 Aug 25.
• [25] Untargeted Proteomics and Systems-Based Mechanistic Investigation of Artesunate in Human Bronchial Epithelial Cells. Chem Res Toxicol. 2015 Oct 19;28(10):1903-13. doi: 10.1021/acs.chemrestox.5b00105. Epub 2015 Sep 21.
• [26] Androgen receptor modulation following combination exposure to brominated flame-retardants. Sci Rep. 2018 Mar 19;8(1):4843. doi: 10.1038/s41598-018-23181-0.
• [27] 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.
• [28] 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.
• [29] Comprehensive analysis of transcriptomic changes induced by low and high doses of bisphenol A in HepG2 spheroids in vitro and rat liver in vivo. Environ Res. 2019 Jun;173:124-134. doi: 10.1016/j.envres.2019.03.035. Epub 2019 Mar 18.
• [30] Transcriptome dynamics of alternative splicing events revealed early phase of apoptosis induced by methylparaben in H1299 human lung carcinoma cells. Arch Toxicol. 2020 Jan;94(1):127-140. doi: 10.1007/s00204-019-02629-w. Epub 2019 Nov 20.
• [31] Epicatechin and a cocoa polyphenolic extract modulate gene expression in human Caco-2 cells. J Nutr. 2004 Oct;134(10):2509-16.
• [32] Tumor necrosis factor-alpha-induced protein 3 as a putative regulator of nuclear factor-kappaB-mediated resistance to O6-alkylating agents in human glioblastomas. J Clin Oncol. 2006 Jan 10;24(2):274-87. doi: 10.1200/JCO.2005.02.9405. Epub 2005 Dec 19.