Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT1RDKR9)

• DOT Name: RNA-binding protein with multiple splicing (RBPMS)
• Synonyms: RBP-MS; RBPMS; Heart and RRM expressed sequence; Hermes
• Gene Name: RBPMS
• Related Disease:
  Advanced cancer
  Diabetic retinopathy
  Measles
  Neoplasm
  Stroke
  Plasma cell myeloma
  Werner syndrome
• UniProt ID: RBPMS_HUMAN
• PDB ID: 5CYJ; 5DET
• Pfam ID: PF00076
• Sequence:
  MNNGGKAEKENTPSEANLQEEEVRTLFVSGLPLDIKPRELYLLFRPFKGYEGSLIKLTSK
  QPVGFVSFDSRSEAEAAKNALNGIRFDPEIPQTLRLEFAKANTKMAKNKLVGTPNPSTPL
  PNTVPQFIAREPYELTVPALYPSSPEVWAPYPLYPAELAPALPPPAFTYPASLHAQMRWL
  PPSEATSQGWKSRQFC
• Function: [Isoform A]: RNA binding protein that mediates the regulation of pre-mRNA alternative splicing (AS). Acts either as activator (FLNB, HSPG2, LIPA1, MYOCD, PTPRF and PPFIBP1) or repressor (TPM1, ACTN1, ITGA7, PIEZO1, LSM14B, MBNL1 and MBML2) of splicing events on specific pre-mRNA targets. Together with RNA binding proteins RBFOX2 and MBNL1/2, activates a splicing program associated with differentiated contractile vascular smooth muscle cells (SMC) by regulating AS of numerous pre-mRNA involved in actin cytoskeleton and focal adhesion machineries, suggesting a role in promoting a cell differentiated state. Binds to introns, exons and 3'-UTR associated with tandem CAC trinucleotide motifs separated by a variable spacer region, at a minimum as a dimer. The minimal length of RNA required for RBPMS-binding tandem CAC motifs is 15 nt, with spacing ranging from 1 to 9 nt. Can also bind to CA dinucleotide repeats. Mediates repression of TPM1 exon 3 by binding to CAC tandem repeats in the flanking intronic regions, followed by higher-order oligomerization and heterotypic interactions with other splicing regulators including MBNL1 and RBFOX2, which prevents assembly of ATP-dependent splicing complexes; [Isoform C]: Acts as a regulator of pre-mRNA alternative splicing (AS). Binds mRNA. Regulates AS of ACTN1, FLNB, although with lower efficiency than isoform A / RBPMSA. Acts as coactivator of SMAD transcriptional activity in a TGFB1-dependent manner, possibly through increased phosphorylation of SMAD2 and SMAD3 at the C-terminal SSXS regions and promotion of the nuclear accumulation of SMAD proteins.
• Tissue Specificity: Ubiquitously expressed, at various levels depending on the isoform and the tissue . Strongly expressed in the heart, prostate, small intestine, large intestine, and ovary; moderately expressed in the placenta, lung, liver, kidney, pancreas, and testis; and poorly expressed in the skeletal muscle, spleen, thymus and peripheral leukocytes .

Molecular Interaction Atlas (MIA) of This DOT

7 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Advanced cancer	DISAT1Z9	Strong	Biomarker	[1]
Diabetic retinopathy	DISHGUJM	Strong	Biomarker	[2]
Measles	DISXSUID	Strong	Biomarker	[3]
Neoplasm	DISZKGEW	Strong	Biomarker	[4]
Stroke	DISX6UHX	Strong	Genetic Variation	[5]
Plasma cell myeloma	DIS0DFZ0	moderate	Biomarker	[6]
Werner syndrome	DISZY45W	moderate	Genetic Variation	[7]

4 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 RNA-binding protein with multiple splicing (RBPMS).	[8]
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of RNA-binding protein with multiple splicing (RBPMS).	[13]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the methylation of RNA-binding protein with multiple splicing (RBPMS).	[21]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of RNA-binding protein with multiple splicing (RBPMS).	[22]

13 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 RNA-binding protein with multiple splicing (RBPMS).	[9]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of RNA-binding protein with multiple splicing (RBPMS).	[10]
Doxorubicin	DMVP5YE	Approved	Doxorubicin increases the expression of RNA-binding protein with multiple splicing (RBPMS).	[11]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of RNA-binding protein with multiple splicing (RBPMS).	[12]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide increases the expression of RNA-binding protein with multiple splicing (RBPMS).	[14]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of RNA-binding protein with multiple splicing (RBPMS).	[15]
Selenium	DM25CGV	Approved	Selenium increases the expression of RNA-binding protein with multiple splicing (RBPMS).	[16]
Isotretinoin	DM4QTBN	Approved	Isotretinoin increases the expression of RNA-binding protein with multiple splicing (RBPMS).	[17]
Cyclophosphamide	DM4O2Z7	Approved	Cyclophosphamide increases the expression of RNA-binding protein with multiple splicing (RBPMS).	[18]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of RNA-binding protein with multiple splicing (RBPMS).	[19]
Amiodarone	DMUTEX3	Phase 2/3 Trial	Amiodarone increases the expression of RNA-binding protein with multiple splicing (RBPMS).	[20]
Tocopherol	DMBIJZ6	Phase 2	Tocopherol increases the expression of RNA-binding protein with multiple splicing (RBPMS).	[16]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of RNA-binding protein with multiple splicing (RBPMS).	[23]

References

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• [7] A unique human gene that spans over 230 kb in the human chromosome 8p11-12 and codes multiple family proteins sharing RNA-binding motifs.Proc Natl Acad Sci U S A. 1996 Oct 1;93(20):10913-7. doi: 10.1073/pnas.93.20.10913.
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• [18] Comparative gene expression analysis of a chronic myelogenous leukemia cell line resistant to cyclophosphamide using oligonucleotide arrays and response to tyrosine kinase inhibitors. Leuk Res. 2007 Nov;31(11):1511-20.
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• [20] Identification by automated screening of a small molecule that selectively eliminates neural stem cells derived from hESCs but not dopamine neurons. PLoS One. 2009 Sep 23;4(9):e7155.
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