Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTOFT707)

• DOT Name: Serine/arginine-rich splicing factor 3 (SRSF3)
• Synonyms: Pre-mRNA-splicing factor SRP20; Splicing factor, arginine/serine-rich 3
• Gene Name: SRSF3
• Related Disease:
  Adult glioblastoma
  Advanced cancer
  Alzheimer disease
  Bipolar disorder
  Bone osteosarcoma
  Cervical carcinoma
  Colon cancer
  Colon carcinoma
  Colorectal carcinoma
  Epithelial ovarian cancer
  Follicular lymphoma
  Frontotemporal dementia
  Glioblastoma multiforme
  Glioma
  Haematological malignancy
  Head-neck squamous cell carcinoma
  Hepatitis B virus infection
  Hepatocellular carcinoma
  Hereditary myopathy with lactic acidosis due to ISCU deficiency
  Influenza
  Liver cirrhosis
  Myocardial infarction
  Neoplasm
  Non-alcoholic fatty liver disease
  Non-alcoholic steatohepatitis
  Osteosarcoma
  Ovarian cancer
  Ovarian neoplasm
  Retinoblastoma
  Squamous cell carcinoma
  Tuberculosis
  Benign neoplasm
  Picornaviridae infectious disease
  Stroke
  Breast cancer
  Breast carcinoma
  Neuroblastoma
  Ocular hypertension
  OPTN-related open angle glaucoma
  Triple negative breast cancer
• UniProt ID: SRSF3_HUMAN
• PDB ID: 2I2Y; 2I38
• Pfam ID: PF00076
• Sequence:
  MHRDSCPLDCKVYVGNLGNNGNKTELERAFGYYGPLRSVWVARNPPGFAFVEFEDPRDAA
  DAVRELDGRTLCGCRVRVELSNGEKRSRNRGPPPSWGRRPRDDYRRRSPPPRRRSPRRRS
  FSRSRSRSLSRDRRRERSLSRERNHKPSRSFSRSRSRSRSNERK
• Function: Splicing factor, which binds the consensus motif 5'-C[ACU][AU]C[ACU][AC]C-3' within pre-mRNA and promotes specific exons inclusion during alternative splicing. Interaction with YTHDC1, a RNA-binding protein that recognizes and binds N6-methyladenosine (m6A)-containing RNAs, promotes recruitment of SRSF3 to its mRNA-binding elements adjacent to m6A sites within exons. Also functions as an adapter involved in mRNA nuclear export. Binds mRNA which is thought to be transferred to the NXF1-NXT1 heterodimer for export (TAP/NXF1 pathway); enhances NXF1-NXT1 RNA-binding activity. Involved in nuclear export of m6A-containing mRNAs via interaction with YTHDC1: interaction with YTHDC1 facilitates m6A-containing mRNA-binding to both SRSF3 and NXF1, promoting mRNA nuclear export.
• KEGG Pathway:
  Spliceosome (hsa03040)
  Amyotrophic lateral sclerosis (hsa05014)
  Herpes simplex virus 1 infection (hsa05168)
• Reactome Pathway:
  mRNA Splicing - Major Pathway (R-HSA-72163)
  mRNA 3'-end processing (R-HSA-72187)
  Processing of Capped Intron-Containing Pre-mRNA (R-HSA-72203)
  RNA Polymerase II Transcription Termination (R-HSA-73856)
  Transport of Mature mRNA derived from an Intron-Containing Transcript (R-HSA-159236)

Molecular Interaction Atlas (MIA) of This DOT

40 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Adult glioblastoma	DISVP4LU	Strong	Biomarker	[1]
Advanced cancer	DISAT1Z9	Strong	Altered Expression	[2]
Alzheimer disease	DISF8S70	Strong	Altered Expression	[3]
Bipolar disorder	DISAM7J2	Strong	Biomarker	[4]
Bone osteosarcoma	DIST1004	Strong	Biomarker	[5]
Cervical carcinoma	DIST4S00	Strong	Genetic Variation	[6]
Colon cancer	DISVC52G	Strong	Altered Expression	[7]
Colon carcinoma	DISJYKUO	Strong	Altered Expression	[7]
Colorectal carcinoma	DIS5PYL0	Strong	Biomarker	[8]
Epithelial ovarian cancer	DIS56MH2	Strong	Biomarker	[9]
Follicular lymphoma	DISVEUR6	Strong	Genetic Variation	[10]
Frontotemporal dementia	DISKYHXL	Strong	Genetic Variation	[11]
Glioblastoma multiforme	DISK8246	Strong	Biomarker	[1]
Glioma	DIS5RPEH	Strong	Altered Expression	[1]
Haematological malignancy	DISCDP7W	Strong	Genetic Variation	[10]
Head-neck squamous cell carcinoma	DISF7P24	Strong	Biomarker	[12]
Hepatitis B virus infection	DISLQ2XY	Strong	Biomarker	[13]
Hepatocellular carcinoma	DIS0J828	Strong	Biomarker	[13]
Hereditary myopathy with lactic acidosis due to ISCU deficiency	DISJHOGS	Strong	Biomarker	[14]
Influenza	DIS3PNU3	Strong	Biomarker	[15]
Liver cirrhosis	DIS4G1GX	Strong	Genetic Variation	[16]
Myocardial infarction	DIS655KI	Strong	Altered Expression	[17]
Neoplasm	DISZKGEW	Strong	Biomarker	[1]
Non-alcoholic fatty liver disease	DISDG1NL	Strong	Genetic Variation	[16]
Non-alcoholic steatohepatitis	DIST4788	Strong	Genetic Variation	[16]
Osteosarcoma	DISLQ7E2	Strong	Biomarker	[5]
Ovarian cancer	DISZJHAP	Strong	Biomarker	[9]
Ovarian neoplasm	DISEAFTY	Strong	Biomarker	[9]
Retinoblastoma	DISVPNPB	Strong	Biomarker	[18]
Squamous cell carcinoma	DISQVIFL	Strong	Biomarker	[19]
Tuberculosis	DIS2YIMD	Strong	Altered Expression	[20]
Benign neoplasm	DISDUXAD	moderate	Altered Expression	[21]
Picornaviridae infectious disease	DISC80MD	moderate	Biomarker	[22]
Stroke	DISX6UHX	moderate	Genetic Variation	[23]
Breast cancer	DIS7DPX1	Limited	Altered Expression	[19]
Breast carcinoma	DIS2UE88	Limited	Altered Expression	[19]
Neuroblastoma	DISVZBI4	Limited	Biomarker	[24]
Ocular hypertension	DISC2BT9	Limited	Genetic Variation	[25]
OPTN-related open angle glaucoma	DISDR98A	Limited	Genetic Variation	[26]
Triple negative breast cancer	DISAMG6N	Limited	Biomarker	[27]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the methylation of Serine/arginine-rich splicing factor 3 (SRSF3).	[28]
TAK-243	DM4GKV2	Phase 1	TAK-243 decreases the sumoylation of Serine/arginine-rich splicing factor 3 (SRSF3).	[39]
Paraquat	DMR8O3X	Investigative	Paraquat increases the phosphorylation of Serine/arginine-rich splicing factor 3 (SRSF3).	[45]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Serine/arginine-rich splicing factor 3 (SRSF3).	[29]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Serine/arginine-rich splicing factor 3 (SRSF3).	[30]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Serine/arginine-rich splicing factor 3 (SRSF3).	[31]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of Serine/arginine-rich splicing factor 3 (SRSF3).	[32]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Serine/arginine-rich splicing factor 3 (SRSF3).	[33]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of Serine/arginine-rich splicing factor 3 (SRSF3).	[34]
Marinol	DM70IK5	Approved	Marinol decreases the expression of Serine/arginine-rich splicing factor 3 (SRSF3).	[35]
Piroxicam	DMTK234	Approved	Piroxicam decreases the expression of Serine/arginine-rich splicing factor 3 (SRSF3).	[36]
Tamibarotene	DM3G74J	Phase 3	Tamibarotene affects the expression of Serine/arginine-rich splicing factor 3 (SRSF3).	[30]
Curcumin	DMQPH29	Phase 3	Curcumin increases the expression of Serine/arginine-rich splicing factor 3 (SRSF3).	[37]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Serine/arginine-rich splicing factor 3 (SRSF3).	[38]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Serine/arginine-rich splicing factor 3 (SRSF3).	[40]
THAPSIGARGIN	DMDMQIE	Preclinical	THAPSIGARGIN decreases the expression of Serine/arginine-rich splicing factor 3 (SRSF3).	[41]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Serine/arginine-rich splicing factor 3 (SRSF3).	[42]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde increases the expression of Serine/arginine-rich splicing factor 3 (SRSF3).	[43]
methyl p-hydroxybenzoate	DMO58UW	Investigative	methyl p-hydroxybenzoate decreases the expression of Serine/arginine-rich splicing factor 3 (SRSF3).	[44]
AHPN	DM8G6O4	Investigative	AHPN decreases the expression of Serine/arginine-rich splicing factor 3 (SRSF3).	[46]
PP-242	DM2348V	Investigative	PP-242 increases the expression of Serine/arginine-rich splicing factor 3 (SRSF3).	[47]
5'-(N-ethyl-N-isopropyl)amiloride	DM3TPMO	Investigative	5'-(N-ethyl-N-isopropyl)amiloride increases the expression of Serine/arginine-rich splicing factor 3 (SRSF3).	[48]

References

• [1] SRSF3-Regulated RNA Alternative Splicing Promotes Glioblastoma Tumorigenicity by Affecting Multiple Cellular Processes.Cancer Res. 2019 Oct 15;79(20):5288-5301. doi: 10.1158/0008-5472.CAN-19-1504. Epub 2019 Aug 28.
• [2] Oncogenic splicing factor SRSF3 regulates ILF3 alternative splicing to promote cancer cell proliferation and transformation.RNA. 2019 May;25(5):630-644. doi: 10.1261/rna.068619.118. Epub 2019 Feb 22.
• [3] Srp20 regulates TrkB pre-mRNA splicing to generate TrkB-Shc transcripts with implications for Alzheimer's disease.J Neurochem. 2012 Oct;123(1):159-71. doi: 10.1111/j.1471-4159.2012.07873.x. Epub 2012 Aug 16.
• [4] Increased expression of splicing factor SRp20 mRNA in bipolar disorder patients.J Affect Disord. 2008 Sep;110(1-2):62-9. doi: 10.1016/j.jad.2008.01.003. Epub 2008 Feb 20.
• [5] MicroRNA-1908-5p contributes to the oncogenic function of the splicing factor SRSF3.Oncotarget. 2017 Jan 31;8(5):8342-8355. doi: 10.18632/oncotarget.14184.
• [6] HNRNPA1, a Splicing Regulator, Is an Effective Target Protein for Cervical Cancer Detection: Comparison With Conventional Tumor Markers.Int J Gynecol Cancer. 2017 Feb;27(2):326-331. doi: 10.1097/IGC.0000000000000868.
• [7] Oxidative stress-inducible truncated serine/arginine-rich splicing factor 3 regulates interleukin-8 production in human colon cancer cells.Am J Physiol Cell Physiol. 2014 Feb 1;306(3):C250-62. doi: 10.1152/ajpcell.00091.2013. Epub 2013 Nov 27.
• [8] RBM4-SRSF3-MAP4K4 splicing cascade modulates the metastatic signature of colorectal cancer cell.Biochim Biophys Acta Mol Cell Res. 2018 Feb;1865(2):259-272. doi: 10.1016/j.bbamcr.2017.11.005. Epub 2017 Nov 11.
• [9] Serine/arginine-rich splicing factor 3 (SRSF3) regulates homologous recombination-mediated DNA repair.Mol Cancer. 2015 Aug 19;14:158. doi: 10.1186/s12943-015-0422-1.
• [10] Splicing factor SRP20 is a novel partner of BCL6 in a t(3;6)(q27;p21) translocation in transformed follicular lymphoma.Genes Chromosomes Cancer. 2001 Nov;32(3):281-4. doi: 10.1002/gcc.1191.
• [11] A minimal length between tau exon 10 and 11 is required for correct splicing of exon 10.J Neurochem. 2004 Jul;90(1):164-72. doi: 10.1111/j.1471-4159.2004.02477.x.
• [12] Inclusion of hnRNP L Alternative Exon 7 Is Associated with Good Prognosis and Inhibited by Oncogene SRSF3 in Head and Neck Squamous Cell Carcinoma.Biomed Res Int. 2019 Nov 13;2019:9612425. doi: 10.1155/2019/9612425. eCollection 2019.
• [13] A Coiled-Coil Domain Containing 50 Splice Variant Is Modulated by Serine/Arginine-Rich Splicing Factor 3 and Promotes Hepatocellular Carcinoma in Mice by the Ras Signaling Pathway.Hepatology. 2019 Jan;69(1):179-195. doi: 10.1002/hep.30147. Epub 2018 Dec 22.
• [14] The High Level of Aberrant Splicing of ISCU in Slow-Twitch Muscle May Involve the Splicing Factor SRSF3.PLoS One. 2016 Oct 26;11(10):e0165453. doi: 10.1371/journal.pone.0165453. eCollection 2016.
• [15] Highly pathogenic avian influenza virus nucleoprotein interacts with TREX complex adaptor protein Aly/REF.PLoS One. 2013 Sep 20;8(9):e72429. doi: 10.1371/journal.pone.0072429. eCollection 2013.
• [16] Degradation of splicing factor SRSF3 contributes to progressive liver disease.J Clin Invest. 2019 Aug 8;129(10):4477-4491. doi: 10.1172/JCI127374.
• [17] Loss of SRSF3 in Cardiomyocytes Leads to Decapping of Contraction-Related mRNAs and Severe Systolic Dysfunction.Circ Res. 2019 Jul 5;125(2):170-183. doi: 10.1161/CIRCRESAHA.118.314515. Epub 2019 May 30.
• [18] Genomic landscape of retinoblastoma in Rb(-/-) p130(-/-) mice resembles human retinoblastoma.Genes Chromosomes Cancer. 2017 Mar;56(3):231-242. doi: 10.1002/gcc.22429. Epub 2016 Nov 21.
• [19] Downregulation of SRSF3 by antisense oligonucleotides sensitizes oral squamous cell carcinoma and breast cancer cells to paclitaxel treatment.Cancer Chemother Pharmacol. 2019 Nov;84(5):1133-1143. doi: 10.1007/s00280-019-03945-9. Epub 2019 Sep 12.
• [20] Expression Profile of Three Splicing Factors in Pleural Cells Based on the Underlying Etiology and Its Clinical Values in Patients with Pleural Effusion.Transl Oncol. 2018 Feb;11(1):147-156. doi: 10.1016/j.tranon.2017.12.005. Epub 2017 Dec 27.
• [21] Knockdown of splicing factor SRp20 causes apoptosis in ovarian cancer cells and its expression is associated with malignancy of epithelial ovarian cancer.Oncogene. 2011 Jan 20;30(3):356-65. doi: 10.1038/onc.2010.426. Epub 2010 Sep 20.
• [22] Viral proteinase requirements for the nucleocytoplasmic relocalization of cellular splicing factor SRp20 during picornavirus infections.J Virol. 2013 Mar;87(5):2390-400. doi: 10.1128/JVI.02396-12. Epub 2012 Dec 19.
• [23] BRG1 variant rs1122608 on chromosome 19p13.2 confers protection against stroke and regulates expression of pre-mRNA-splicing factor SFRS3.Hum Genet. 2014 May;133(5):499-508. doi: 10.1007/s00439-013-1389-x. Epub 2013 Nov 5.
• [24] Re-localization of cellular protein SRp20 during poliovirus infection: bridging a viral IRES to the host cell translation apparatus.PLoS Pathog. 2011 Jul;7(7):e1002127. doi: 10.1371/journal.ppat.1002127. Epub 2011 Jul 14.
• [25] Analysis of single nucleotide polymorphisms in the SFRS3 and FKBP4 genes in corticosteroid-induced ocular hypertension.Ophthalmic Genet. 2012 Dec;33(4):221-4. doi: 10.3109/13816810.2012.716488. Epub 2012 Aug 27.
• [26] Assessment of SNPs associated with the human glucocorticoid receptor in primary open-angle glaucoma and steroid responders.Mol Vis. 2010 Apr 3;16:596-601.
• [27] Cortisol-induced SRSF3 expression promotes GR splicing, RACK1 expression and breast cancer cells migration.Pharmacol Res. 2019 May;143:17-26. doi: 10.1016/j.phrs.2019.03.008. Epub 2019 Mar 9.
• [28] 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.
• [29] 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.
• [30] Differential modulation of PI3-kinase/Akt pathway during all-trans retinoic acid- and Am80-induced HL-60 cell differentiation revealed by DNA microarray analysis. Biochem Pharmacol. 2004 Dec 1;68(11):2177-86.
• [31] 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.
• [32] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [33] 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.
• [34] Global gene expression analysis reveals differences in cellular responses to hydroxyl- and superoxide anion radical-induced oxidative stress in caco-2 cells. Toxicol Sci. 2010 Apr;114(2):193-203. doi: 10.1093/toxsci/kfp309. Epub 2009 Dec 31.
• [35] JunD is involved in the antiproliferative effect of Delta9-tetrahydrocannabinol on human breast cancer cells. Oncogene. 2008 Aug 28;27(37):5033-44.
• [36] Apoptosis induced by piroxicam plus cisplatin combined treatment is triggered by p21 in mesothelioma. PLoS One. 2011;6(8):e23569.
• [37] Gene-expression profiling during curcumin-induced apoptosis reveals downregulation of CXCR4. Exp Hematol. 2007 Jan;35(1):84-95.
• [38] Comparison of HepG2 and HepaRG by whole-genome gene expression analysis for the purpose of chemical hazard identification. Toxicol Sci. 2010 May;115(1):66-79.
• [39] Inhibiting ubiquitination causes an accumulation of SUMOylated newly synthesized nuclear proteins at PML bodies. J Biol Chem. 2019 Oct 18;294(42):15218-15234. doi: 10.1074/jbc.RA119.009147. Epub 2019 Jul 8.
• [40] Cell-based two-dimensional morphological assessment system to predict cancer drug-induced cardiotoxicity using human induced pluripotent stem cell-derived cardiomyocytes. Toxicol Appl Pharmacol. 2019 Nov 15;383:114761. doi: 10.1016/j.taap.2019.114761. Epub 2019 Sep 15.
• [41] Endoplasmic reticulum stress impairs insulin signaling through mitochondrial damage in SH-SY5Y cells. Neurosignals. 2012;20(4):265-80.
• [42] 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.
• [43] Gene expression changes in primary human nasal epithelial cells exposed to formaldehyde in vitro. Toxicol Lett. 2010 Oct 5;198(2):289-95.
• [44] 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.
• [45] Paraquat modulates alternative pre-mRNA splicing by modifying the intracellular distribution of SRPK2. PLoS One. 2013 Apr 16;8(4):e61980. doi: 10.1371/journal.pone.0061980. Print 2013.
• [46] ST1926, a novel and orally active retinoid-related molecule inducing apoptosis in myeloid leukemia cells: modulation of intracellular calcium homeostasis. Blood. 2004 Jan 1;103(1):194-207.
• [47] Marine biogenics in sea spray aerosols interact with the mTOR signaling pathway. Sci Rep. 2019 Jan 24;9(1):675.
• [48] 5-(N-ethyl-N-isopropyl)-amiloride enhances SMN2 exon 7 inclusion and protein expression in spinal muscular atrophy cells. Ann Neurol. 2008 Jan;63(1):26-34. doi: 10.1002/ana.21241.