Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTLK3K4U)

• DOT Name: Protein CASC3 (CASC3)
• Synonyms: Cancer susceptibility candidate gene 3 protein; Metastatic lymph node gene 51 protein; MLN 51; Protein barentsz; Btz
• Gene Name: CASC3
• Related Disease:
  Acute lymphocytic leukaemia
  Advanced cancer
  Breast cancer
  Breast carcinoma
  Melanoma
  Osteoarthritis
  Rheumatoid arthritis
  Plasma cell myeloma
• UniProt ID: CASC3_HUMAN
• PDB ID: 2HYI; 2J0Q; 2J0S; 2J0U; 2XB2; 3EX7; 5XJC; 5YZG; 6ICZ; 7W59; 7W5A; 7W5B
• Pfam ID: PF09405
• Sequence:
  MADRRRQRASQDTEDEESGASGSDSGGSPLRGGGSCSGSAGGGGSGSLPSQRGGRTGALH
  LRRVESGGAKSAEESECESEDGIEGDAVLSDYESAEDSEGEEGEYSEEENSKVELKSEAN
  DAVNSSTKEEKGEEKPDTKSTVTGERQSGDGQESTEPVENKVGKKGPKHLDDDEDRKNPA
  YIPRKGLFFEHDLRGQTQEEEVRPKGRQRKLWKDEGRWEHDKFREDEQAPKSRQELIALY
  GYDIRSAHNPDDIKPRRIRKPRYGSPPQRDPNWNGERLNKSHRHQGLGGTLPPRTFINRN
  AAGTGRMSAPRNYSRSGGFKEGRAGFRPVEAGGQHGGRSGETVKHEISYRSRRLEQTSVR
  DPSPEADAPVLGSPEKEEAASEPPAAAPDAAPPPPDRPIEKKSYSRARRTRTKVGDAVKL
  AEEVPPPPEGLIPAPPVPETTPTPPTKTGTWEAPVDSSTSGLEQDVAQLNIAEQNWSPGQ
  PSFLQPRELRGMPNHIHMGAGPPPQFNRMEEMGVQGGRAKRYSSQRQRPVPEPPAPPVHI
  SIMEGHYYDPLQFQGPIYTHGDSPAPLPPQGMLVQPGMNLPHPGLHPHQTPAPLPNPGLY
  PPPVSMSPGQPPPQQLLAPTYFSAPGVMNFGNPSYPYAPGALPPPPPPHLYPNTQAPSQV
  YGGVTYYNPAQQQVQPKPSPPRRTPQPVTIKPPPPEVVSRGSS
• Function: Required for pre-mRNA splicing as component of the spliceosome. Core component of the splicing-dependent multiprotein exon junction complex (EJC) deposited at splice junctions on mRNAs. The EJC is a dynamic structure consisting of core proteins and several peripheral nuclear and cytoplasmic associated factors that join the complex only transiently either during EJC assembly or during subsequent mRNA metabolism. The EJC marks the position of the exon-exon junction in the mature mRNA for the gene expression machinery and the core components remain bound to spliced mRNAs throughout all stages of mRNA metabolism thereby influencing downstream processes including nuclear mRNA export, subcellular mRNA localization, translation efficiency and nonsense-mediated mRNA decay (NMD). Stimulates the ATPase and RNA-helicase activities of EIF4A3. Plays a role in the stress response by participating in cytoplasmic stress granules assembly and by favoring cell recovery following stress. Component of the dendritic ribonucleoprotein particles (RNPs) in hippocampal neurons. May play a role in mRNA transport. Binds spliced mRNA in sequence-independent manner, 20-24 nucleotides upstream of mRNA exon-exon junctions. Binds poly(G) and poly(U) RNA homomer.
• Tissue Specificity: Widely expressed. Overexpressed in breast cancers and metastasis, as well as in gastric cancers.
• KEGG Pathway:
  Nucleocytoplasmic transport (hsa03013)
  mR. surveillance pathway (hsa03015)
• Reactome Pathway:
  mRNA Splicing - Major Pathway (R-HSA-72163)
  mRNA 3'-end processing (R-HSA-72187)
  RNA Polymerase II Transcription Termination (R-HSA-73856)
  Regulation of expression of SLITs and ROBOs (R-HSA-9010553)
  Nonsense Mediated Decay (NMD) enhanced by the Exon Junction Complex (EJC) (R-HSA-975957)
  Transport of Mature mRNA derived from an Intron-Containing Transcript (R-HSA-159236)

Molecular Interaction Atlas (MIA) of This DOT

8 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Acute lymphocytic leukaemia	DISPX75S	Strong	Biomarker	[1]
Advanced cancer	DISAT1Z9	Strong	Biomarker	[2]
Breast cancer	DIS7DPX1	Strong	Biomarker	[3]
Breast carcinoma	DIS2UE88	Strong	Genetic Variation	[4]
Melanoma	DIS1RRCY	Strong	Altered Expression	[5]
Osteoarthritis	DIS05URM	Strong	Altered Expression	[6]
Rheumatoid arthritis	DISTSB4J	Strong	Altered Expression	[7]
Plasma cell myeloma	DIS0DFZ0	Disputed	Biomarker	[8]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Mitoxantrone	DMM39BF	Approved	Protein CASC3 (CASC3) affects the response to substance of Mitoxantrone.	[14]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the expression of Protein CASC3 (CASC3).	[9]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Protein CASC3 (CASC3).	[10]
Vorinostat	DMWMPD4	Approved	Vorinostat decreases the expression of Protein CASC3 (CASC3).	[11]
[3H]methyltrienolone	DMTSGOW	Investigative	[3H]methyltrienolone increases the expression of Protein CASC3 (CASC3).	[13]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 decreases the phosphorylation of Protein CASC3 (CASC3).	[12]
Coumarin	DM0N8ZM	Investigative	Coumarin affects the phosphorylation of Protein CASC3 (CASC3).	[12]

References

• [1] Synergistic activity of bortezomib and HDACi in preclinical models of B-cell precursor acute lymphoblastic leukemia via modulation of p53, PI3K/AKT, and NF-B.Clin Cancer Res. 2013 Mar 15;19(6):1445-57. doi: 10.1158/1078-0432.CCR-12-1511. Epub 2013 Jan 28.
• [2] The exon-junction-complex-component metastatic lymph node 51 functions in stress-granule assembly.J Cell Sci. 2007 Aug 15;120(Pt 16):2774-84. doi: 10.1242/jcs.009225. Epub 2007 Jul 24.
• [3] Genomic analysis of the HER2/TOP2A amplicon in breast cancer and breast cancer cell lines.Lab Invest. 2008 May;88(5):491-503. doi: 10.1038/labinvest.2008.19. Epub 2008 Mar 10.
• [4] MLN51 and GM-CSF involvement in the proliferation of fibroblast-like synoviocytes in the pathogenesis of rheumatoid arthritis.Arthritis Res Ther. 2006;8(6):R170. doi: 10.1186/ar2079.
• [5] Identification of robust reference genes for studies of gene expression in FFPE melanoma samples and melanoma cell lines.Melanoma Res. 2020 Feb;30(1):26-38. doi: 10.1097/CMR.0000000000000644.
• [6] Identification of suitable reference genes in bone marrow stromal cells from osteoarthritic donors.Stem Cell Res. 2013 Nov;11(3):1288-98. doi: 10.1016/j.scr.2013.08.015. Epub 2013 Sep 9.
• [7] FLIP and MAPK play crucial roles in the MLN51-mediated hyperproliferation of fibroblast-like synoviocytes in the pathogenesis of rheumatoid arthritis.FEBS J. 2008 Jul;275(14):3546-55. doi: 10.1111/j.1742-4658.2008.06500.x.
• [8] LncRNA H19 overexpression induces bortezomib resistance in multiple myeloma by targeting MCL-1 via miR-29b-3p.Cell Death Dis. 2019 Feb 6;10(2):106. doi: 10.1038/s41419-018-1219-0.
• [9] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [10] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [11] 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.
• [12] 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.
• [13] Analysis of the prostate cancer cell line LNCaP transcriptome using a sequencing-by-synthesis approach. BMC Genomics. 2006 Sep 29;7:246. doi: 10.1186/1471-2164-7-246.
• [14] Prediction of doxorubicin sensitivity in breast tumors based on gene expression profiles of drug-resistant cell lines correlates with patient survival. Oncogene. 2005 Nov 17;24(51):7542-51. doi: 10.1038/sj.onc.1208908.