Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTV2KFZH)

• DOT Name: Nucleolysin TIAR (TIAL1)
• Synonyms: TIA-1-related protein
• Gene Name: TIAL1
• Related Disease:
  Breast cancer
  Breast carcinoma
  Parkinson disease
  Breast neoplasm
  Idiopathic interstitial pneumonia
  Inflammatory bowel disease
  Lung squamous cell carcinoma
  Neoplasm
  Ulcerative colitis
  Neurofibromatosis type 1
• UniProt ID: TIAR_HUMAN
• PDB ID: 1X4G; 2CQI; 2DH7
• Pfam ID: PF00076
• Sequence:
  MMEDDGQPRTLYVGNLSRDVTEVLILQLFSQIGPCKSCKMITEHTSNDPYCFVEFYEHRD
  AAAALAAMNGRKILGKEVKVNWATTPSSQKKDTSNHFHVFVGDLSPEITTEDIKSAFAPF
  GKISDARVVKDMATGKSKGYGFVSFYNKLDAENAIVHMGGQWLGGRQIRTNWATRKPPAP
  KSTQENNTKQLRFEDVVNQSSPKNCTVYCGGIASGLTDQLMRQTFSPFGQIMEIRVFPEK
  GYSFVRFSTHESAAHAIVSVNGTTIEGHVVKCYWGKESPDMTKNFQQVDYSQWGQWSQVY
  GNPQQYGQYMANGWQVPPYGVYGQPWNQQGFGVDQSPSAAWMGGFGAQPPQGQAPPPVIP
  PPNQAGYGMASYQTQ
• Function: RNA-binding protein involved in alternative pre-RNA splicing and in cytoplasmic stress granules formation. Shows a preference for uridine-rich RNAs. Activates splicing of alternative exons with weak 5' splice sites followed by a U-rich stretch on its own pre-mRNA and on TIA1 mRNA. Promotes the inclusion of TIA1 exon 5 to give rise to the long isoform (isoform a) of TIA1. Acts downstream of the stress-induced phosphorylation of EIF2S1/EIF2A to promote the recruitment of untranslated mRNAs to cytoplasmic stress granules (SG). Possesses nucleolytic activity against cytotoxic lymphocyte target cells. May be involved in apoptosis.
• Tissue Specificity: Expressed in brain, heart, kidney, lung and skeletal muscle.
• Reactome Pathway: FGFR2 alternative splicing (R-HSA-6803529)

Molecular Interaction Atlas (MIA) of This DOT

10 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Breast cancer	DIS7DPX1	Definitive	Biomarker	[1]
Breast carcinoma	DIS2UE88	Definitive	Biomarker	[1]
Parkinson disease	DISQVHKL	Definitive	Altered Expression	[2]
Breast neoplasm	DISNGJLM	Strong	Genetic Variation	[3]
Idiopathic interstitial pneumonia	DISH7LPY	Strong	Altered Expression	[4]
Inflammatory bowel disease	DISGN23E	Strong	Biomarker	[5]
Lung squamous cell carcinoma	DISXPIBD	Strong	Altered Expression	[6]
Neoplasm	DISZKGEW	Strong	Biomarker	[7]
Ulcerative colitis	DIS8K27O	Strong	Genetic Variation	[8]
Neurofibromatosis type 1	DIS53JH9	moderate	Biomarker	[9]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Fluorouracil	DMUM7HZ	Approved	Nucleolysin TIAR (TIAL1) affects the response to substance of Fluorouracil.	[21]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the expression of Nucleolysin TIAR (TIAL1).	[10]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Nucleolysin TIAR (TIAL1).	[11]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Nucleolysin TIAR (TIAL1).	[12]
Menthol	DMG2KW7	Approved	Menthol decreases the expression of Nucleolysin TIAR (TIAL1).	[14]
Tocopherol	DMBIJZ6	Phase 2	Tocopherol decreases the expression of Nucleolysin TIAR (TIAL1).	[15]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Nucleolysin TIAR (TIAL1).	[17]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A affects the expression of Nucleolysin TIAR (TIAL1).	[19]
methyl p-hydroxybenzoate	DMO58UW	Investigative	methyl p-hydroxybenzoate decreases the expression of Nucleolysin TIAR (TIAL1).	[20]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of Nucleolysin TIAR (TIAL1).	[13]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Nucleolysin TIAR (TIAL1).	[16]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the methylation of Nucleolysin TIAR (TIAL1).	[18]

References

• [1] Genome-wide analysis of alternative transcripts in human breast cancer.Breast Cancer Res Treat. 2015 Jun;151(2):295-307. doi: 10.1007/s10549-015-3395-2. Epub 2015 Apr 26.
• [2] Discovering the 3' UTR-mediated regulation of alpha-synuclein.Nucleic Acids Res. 2017 Dec 15;45(22):12888-12903. doi: 10.1093/nar/gkx1048.
• [3] IL-1beta induces stabilization of IL-8 mRNA in malignant breast cancer cells via the 3' untranslated region: Involvement of divergent RNA-binding factors HuR, KSRP and TIAR.Int J Cancer. 2005 Mar 1;113(6):911-9. doi: 10.1002/ijc.20675.
• [4] Expression Profile of Six RNA-Binding Proteins in Pulmonary Sarcoidosis.PLoS One. 2016 Aug 30;11(8):e0161669. doi: 10.1371/journal.pone.0161669. eCollection 2016.
• [5] Contribution of TIA-1+ and granzyme B+ cytotoxic T lymphocytes to cryptal apoptosis and ulceration in active inflammatory bowel disease.Pathol Res Pract. 2007;203(10):717-23. doi: 10.1016/j.prp.2007.06.007. Epub 2007 Sep 14.
• [6] T-cell intracellular antigens function as tumor suppressor genes.Cell Death Dis. 2015 Mar 5;6(3):e1669. doi: 10.1038/cddis.2015.43.
• [7] LncRNA MT1JP functions as a tumor suppressor by interacting with TIAR to modulate the p53 pathway.Oncotarget. 2016 Mar 29;7(13):15787-800. doi: 10.18632/oncotarget.7487.
• [8] Transcriptome meta-analysis identifies immune signature comprising of RNA binding proteins in ulcerative colitis patients.Cell Immunol. 2018 Dec;334:42-48. doi: 10.1016/j.cellimm.2018.09.003. Epub 2018 Sep 21.
• [9] Alternative splicing of the neurofibromatosis type 1 pre-mRNA is regulated by the muscleblind-like proteins and the CUG-BP and ELAV-like factors.BMC Mol Biol. 2012 Dec 10;13:35. doi: 10.1186/1471-2199-13-35.
• [10] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [11] The retinoid anticancer signal: mechanisms of target gene regulation. Br J Cancer. 2005 Aug 8;93(3):310-8. doi: 10.1038/sj.bjc.6602700.
• [12] 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.
• [13] Prenatal arsenic exposure and the epigenome: identifying sites of 5-methylcytosine alterations that predict functional changes in gene expression in newborn cord blood and subsequent birth outcomes. Toxicol Sci. 2015 Jan;143(1):97-106. doi: 10.1093/toxsci/kfu210. Epub 2014 Oct 10.
• [14] Repurposing L-menthol for systems medicine and cancer therapeutics? L-menthol induces apoptosis through caspase 10 and by suppressing HSP90. OMICS. 2016 Jan;20(1):53-64.
• [15] 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.
• [16] 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.
• [17] 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.
• [18] DNA methylome-wide alterations associated with estrogen receptor-dependent effects of bisphenols in breast cancer. Clin Epigenetics. 2019 Oct 10;11(1):138. doi: 10.1186/s13148-019-0725-y.
• [19] A trichostatin A expression signature identified by TempO-Seq targeted whole transcriptome profiling. PLoS One. 2017 May 25;12(5):e0178302. doi: 10.1371/journal.pone.0178302. eCollection 2017.
• [20] 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.
• [21] Mechanistic and predictive profiling of 5-Fluorouracil resistance in human cancer cells. Cancer Res. 2004 Nov 15;64(22):8167-76. doi: 10.1158/0008-5472.CAN-04-0970.