Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTGPN3P8)

• DOT Name: Cytotoxic granule associated RNA binding protein TIA1 (TIA1)
• Synonyms: Nucleolysin TIA-1 isoform p40; RNA-binding protein TIA-1; T-cell-restricted intracellular antigen-1; TIA-1; p40-TIA-1
• Gene Name: TIA1
• Related Disease:
  T-cell lymphoma
  Acquired immune deficiency syndrome
  Alzheimer disease
  Anaplastic large cell lymphoma
  Bone Paget disease
  Coeliac disease
  Colon cancer
  Colon carcinoma
  Colorectal carcinoma
  Distal myopathy, Welander type
  Hepatitis B virus infection
  Hepatocellular carcinoma
  Herpes simplex infection
  Lung squamous cell carcinoma
  Lymphoma, non-Hodgkin, familial
  Lymphoproliferative syndrome
  Motor neurone disease
  Myelodysplastic syndrome
  Myositis disease
  Non-hodgkin lymphoma
  Osteoarthritis
  Pick disease
  Polymyositis
  Primary cutaneous peripheral T-cell lymphoma not otherwise specified
  Rheumatoid arthritis
  Sarcoma
  Small lymphocytic lymphoma
  Thyroid gland undifferentiated (anaplastic) carcinoma
  Ulcerative colitis
  Advanced cancer
  Neurofibromatosis type 1
  Spinal muscular atrophy
  Extranodal NK/T-cell Lymphoma
  Adult respiratory distress syndrome
  Amyotrophic lateral sclerosis
  Amyotrophic lateral sclerosis 26 with or without frontotemporal dementia
  Anxiety
  Anxiety disorder
  Arthritis
  Follicular lymphoma
  Frontotemporal dementia
  Gastric cancer
  Gastric neoplasm
  Non-small-cell lung cancer
  Post-traumatic stress disorder
  Stomach cancer
  Tauopathy
• UniProt ID: TIA1_HUMAN
• PDB ID: 2MJN; 3BS9; 5ITH; 5O2V; 5O3J; 6ELD; 7VI4; 7VI5
• Pfam ID: PF00076
• Sequence:
  MEDEMPKTLYVGNLSRDVTEALILQLFSQIGPCKNCKMIMDTAGNDPYCFVEFHEHRHAA
  AALAAMNGRKIMGKEVKVNWATTPSSQKKDTSSSTVVSTQRSQDHFHVFVGDLSPEITTE
  DIKAAFAPFGRISDARVVKDMATGKSKGYGFVSFFNKWDAENAIQQMGGQWLGGRQIRTN
  WATRKPPAPKSTYESNTKQLSYDEVVNQSSPSNCTVYCGGVTSGLTEQLMRQTFSPFGQI
  MEIRVFPDKGYSFVRFNSHESAAHAIVSVNGTTIEGHVVKCYWGKETLDMINPVQQQNQI
  GYPQPYGQWGQWYGNAQQIGQYMPNGWQVPAYGMYGQAWNQQGFNQTQSSAPWMGPNYGV
  QPPQGQNGSMLPNQPSGYRVAGYETQ
• Function: RNA-binding protein involved in the regulation of alternative pre-RNA splicing and mRNA translation by binding to uridine-rich (U-rich) RNA sequences. Binds to U-rich sequences immediately downstream from a 5' splice sites in a uridine-rich small nuclear ribonucleoprotein (U snRNP)-dependent fashion, thereby modulating alternative pre-RNA splicing. Preferably binds to the U-rich IAS1 sequence in a U1 snRNP-dependent manner; this binding is optimal if a 5' splice site is adjacent to IAS1. Activates the use of heterologous 5' splice sites; the activation depends on the intron sequence downstream from the 5' splice site, with a preference for a downstream U-rich sequence. By interacting with SNRPC/U1-C, promotes recruitment and binding of spliceosomal U1 snRNP to 5' splice sites followed by U-rich sequences, thereby facilitating atypical 5' splice site recognition by U1 snRNP. Activates splicing of alternative exons with weak 5' splice sites followed by a U-rich stretch on its own pre-mRNA and on TIAR mRNA. Acts as a modulator of alternative splicing for the apoptotic FAS receptor, thereby promoting apoptosis. Binds to the 5' splice site region of FAS intron 5 to promote accumulation of transcripts that include exon 6 at the expense of transcripts in which exon 6 is skipped, thereby leading to the transcription of a membrane-bound apoptotic FAS receptor, which promotes apoptosis. Binds to a conserved AU-rich cis element in COL2A1 intron 2 and modulates alternative splicing of COL2A1 exon 2. Also binds to the equivalent AT-rich element in COL2A1 genomic DNA, and may thereby be involved in the regulation of transcription. Binds specifically to a polypyrimidine-rich controlling element (PCE) located between the weak 5' splice site and the intronic splicing silencer of CFTR mRNA to promote exon 9 inclusion, thereby antagonizing PTB1 and its role in exon skipping of CFTR exon 9. Involved in the repression of mRNA translation by binding to AU-rich elements (AREs) located in mRNA 3' untranslated regions (3' UTRs), including target ARE-bearing mRNAs encoding TNF and PTGS2. Also participates in the cellular response to environmental stress, by acting downstream of the stress-induced phosphorylation of EIF2S1/EIF2A to promote the recruitment of untranslated mRNAs to cytoplasmic stress granules (SGs), leading to stress-induced translational arrest. Formation and recruitment to SGs is regulated by Zn(2+). Possesses nucleolytic activity against cytotoxic lymphocyte target cells ; [Isoform Short]: Displays enhanced splicing regulatory activity compared with TIA isoform Long.
• Tissue Specificity: Expressed in heart, small intestine, kidney, liver, lung, skeletal muscle, testes, pancreas, and ovary (at protein level).
• Reactome Pathway: FGFR2 alternative splicing (R-HSA-6803529)

Molecular Interaction Atlas (MIA) of This DOT

47 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
T-cell lymphoma	DISSXRTQ	Definitive	Biomarker	[1]
Acquired immune deficiency syndrome	DISL5UOX	Strong	Altered Expression	[2]
Alzheimer disease	DISF8S70	Strong	Biomarker	[3]
Anaplastic large cell lymphoma	DISP4D1R	Strong	Altered Expression	[4]
Bone Paget disease	DISIPS4V	Strong	Biomarker	[5]
Coeliac disease	DISIY60C	Strong	Altered Expression	[6]
Colon cancer	DISVC52G	Strong	Altered Expression	[7]
Colon carcinoma	DISJYKUO	Strong	Altered Expression	[7]
Colorectal carcinoma	DIS5PYL0	Strong	Biomarker	[8]
Distal myopathy, Welander type	DISM5DNL	Strong	Autosomal dominant	[9]
Hepatitis B virus infection	DISLQ2XY	Strong	Altered Expression	[10]
Hepatocellular carcinoma	DIS0J828	Strong	Altered Expression	[11]
Herpes simplex infection	DISL1SAV	Strong	Biomarker	[12]
Lung squamous cell carcinoma	DISXPIBD	Strong	Altered Expression	[13]
Lymphoma, non-Hodgkin, familial	DISCXYIZ	Strong	Biomarker	[14]
Lymphoproliferative syndrome	DISMVL8O	Strong	Biomarker	[15]
Motor neurone disease	DISUHWUI	Strong	Biomarker	[16]
Myelodysplastic syndrome	DISYHNUI	Strong	Altered Expression	[17]
Myositis disease	DISCIXF0	Strong	Biomarker	[18]
Non-hodgkin lymphoma	DISS2Y8A	Strong	Biomarker	[14]
Osteoarthritis	DIS05URM	Strong	Altered Expression	[19]
Pick disease	DISP6X50	Strong	Genetic Variation	[20]
Polymyositis	DIS5DHFP	Strong	Biomarker	[18]
Primary cutaneous peripheral T-cell lymphoma not otherwise specified	DIS5OHQF	Strong	Biomarker	[21]
Rheumatoid arthritis	DISTSB4J	Strong	Biomarker	[22]
Sarcoma	DISZDG3U	Strong	Altered Expression	[23]
Small lymphocytic lymphoma	DIS30POX	Strong	Genetic Variation	[24]
Thyroid gland undifferentiated (anaplastic) carcinoma	DISYBB1W	Strong	Altered Expression	[25]
Ulcerative colitis	DIS8K27O	Strong	Altered Expression	[26]
Advanced cancer	DISAT1Z9	moderate	Biomarker	[8]
Neurofibromatosis type 1	DIS53JH9	moderate	Biomarker	[27]
Spinal muscular atrophy	DISTLKOB	moderate	Biomarker	[28]
Extranodal NK/T-cell Lymphoma	DIS72GCL	Disputed	Biomarker	[29]
Adult respiratory distress syndrome	DISIJV47	Limited	Genetic Variation	[30]
Amyotrophic lateral sclerosis	DISF7HVM	Limited	Genetic Variation	[31]
Amyotrophic lateral sclerosis 26 with or without frontotemporal dementia	DISQ2AM2	Limited	Autosomal dominant	[32]
Anxiety	DISIJDBA	Limited	Biomarker	[33]
Anxiety disorder	DISBI2BT	Limited	Biomarker	[33]
Arthritis	DIST1YEL	Limited	Biomarker	[34]
Follicular lymphoma	DISVEUR6	Limited	Biomarker	[35]
Frontotemporal dementia	DISKYHXL	Limited	Genetic Variation	[31]
Gastric cancer	DISXGOUK	Limited	Altered Expression	[36]
Gastric neoplasm	DISOKN4Y	Limited	Biomarker	[36]
Non-small-cell lung cancer	DIS5Y6R9	Limited	Biomarker	[37]
Post-traumatic stress disorder	DISHL1EY	Limited	Biomarker	[38]
Stomach cancer	DISKIJSX	Limited	Altered Expression	[36]
Tauopathy	DISY2IPA	Limited	Biomarker	[39]

This DOT Affected the Drug Response of 3 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Paclitaxel	DMLB81S	Approved	Cytotoxic granule associated RNA binding protein TIA1 (TIA1) affects the response to substance of Paclitaxel.	[60]
Topotecan	DMP6G8T	Approved	Cytotoxic granule associated RNA binding protein TIA1 (TIA1) affects the response to substance of Topotecan.	[60]
Mitoxantrone	DMM39BF	Approved	Cytotoxic granule associated RNA binding protein TIA1 (TIA1) affects the response to substance of Mitoxantrone.	[60]

21 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 Cytotoxic granule associated RNA binding protein TIA1 (TIA1).	[40]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Cytotoxic granule associated RNA binding protein TIA1 (TIA1).	[41]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Cytotoxic granule associated RNA binding protein TIA1 (TIA1).	[42]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Cytotoxic granule associated RNA binding protein TIA1 (TIA1).	[43]
Doxorubicin	DMVP5YE	Approved	Doxorubicin increases the expression of Cytotoxic granule associated RNA binding protein TIA1 (TIA1).	[44]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of Cytotoxic granule associated RNA binding protein TIA1 (TIA1).	[45]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Cytotoxic granule associated RNA binding protein TIA1 (TIA1).	[46]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of Cytotoxic granule associated RNA binding protein TIA1 (TIA1).	[47]
Temozolomide	DMKECZD	Approved	Temozolomide increases the expression of Cytotoxic granule associated RNA binding protein TIA1 (TIA1).	[48]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of Cytotoxic granule associated RNA binding protein TIA1 (TIA1).	[49]
Selenium	DM25CGV	Approved	Selenium decreases the expression of Cytotoxic granule associated RNA binding protein TIA1 (TIA1).	[50]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Cytotoxic granule associated RNA binding protein TIA1 (TIA1).	[51]
Genistein	DM0JETC	Phase 2/3	Genistein increases the expression of Cytotoxic granule associated RNA binding protein TIA1 (TIA1).	[52]
Tocopherol	DMBIJZ6	Phase 2	Tocopherol decreases the expression of Cytotoxic granule associated RNA binding protein TIA1 (TIA1).	[50]
Flupirtine	DMPBV9D	Phase 2	Flupirtine decreases the expression of Cytotoxic granule associated RNA binding protein TIA1 (TIA1).	[53]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Cytotoxic granule associated RNA binding protein TIA1 (TIA1).	[54]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Cytotoxic granule associated RNA binding protein TIA1 (TIA1).	[55]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Cytotoxic granule associated RNA binding protein TIA1 (TIA1).	[56]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of Cytotoxic granule associated RNA binding protein TIA1 (TIA1).	[57]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of Cytotoxic granule associated RNA binding protein TIA1 (TIA1).	[58]
Nickel chloride	DMI12Y8	Investigative	Nickel chloride decreases the expression of Cytotoxic granule associated RNA binding protein TIA1 (TIA1).	[59]

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