Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTWG2LAB)

• DOT Name: Eukaryotic translation initiation factor 1A, X-chromosomal (EIF1AX)
• Synonyms: eIF-1A X isoform; eIF1A X isoform; Eukaryotic translation initiation factor 4C; eIF-4C
• Gene Name: EIF1AX
• Related Disease:
  Thyroid gland carcinoma
  Thyroid tumor
  Carcinoma
  Metastatic malignant neoplasm
  Neoplasm
  Thyroid cancer
  Thyroid gland papillary carcinoma
  Thyroid gland undifferentiated (anaplastic) carcinoma
  Uveal Melanoma
  Adult lymphoma
  Cutaneous melanoma
  Lymphoma
  Melanoma
  Metastatic melanoma
  Pediatric lymphoma
• UniProt ID: IF1AX_HUMAN
• PDB ID: 1D7Q; 3ZJY; 4KZY; 4KZZ; 6YBW; 6ZMW; 6ZP4; 7A09; 7QP6; 7QP7; 7SYQ; 7SYR; 7SYS; 7SYV; 7SYW; 7SYX; 7TQL; 8PPL
• Pfam ID: PF01176
• Sequence:
  MPKNKGKGGKNRRRGKNENESEKRELVFKEDGQEYAQVIKMLGNGRLEAMCFDGVKRLCH
  IRGKLRKKVWINTSDIILVGLRDYQDNKADVILKYNADEARSLKAYGELPEHAKINETDT
  FGPGDDDEIQFDDIGDDDEDIDDI
• Function: Component of the 43S pre-initiation complex (43S PIC), which binds to the mRNA cap-proximal region, scans mRNA 5'-untranslated region, and locates the initiation codon. This protein enhances formation of the cap-proximal complex. Together with EIF1, facilitates scanning, start codon recognition, promotion of the assembly of 48S complex at the initiation codon (43S PIC becomes 48S PIC after the start codon is reached), and dissociation of aberrant complexes. After start codon location, together with EIF5B orients the initiator methionine-tRNA in a conformation that allows 60S ribosomal subunit joining to form the 80S initiation complex. Is released after 80S initiation complex formation, just after GTP hydrolysis by EIF5B, and before release of EIF5B. Its globular part is located in the A site of the 40S ribosomal subunit. Its interaction with EIF5 during scanning contribute to the maintenance of EIF1 within the open 43S PIC. In contrast to yeast orthologs, does not bind EIF1.
• Reactome Pathway:
  Translation initiation complex formation (R-HSA-72649)
  Formation of a pool of free 40S subunits (R-HSA-72689)
  Formation of the ternary complex, and subsequently, the 43S complex (R-HSA-72695)
  Ribosomal scanning and start codon recognition (R-HSA-72702)
  GTP hydrolysis and joining of the 60S ribosomal subunit (R-HSA-72706)
  L13a-mediated translational silencing of Ceruloplasmin expression (R-HSA-156827)

Molecular Interaction Atlas (MIA) of This DOT

15 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Thyroid gland carcinoma	DISMNGZ0	Definitive	Biomarker	[1]
Thyroid tumor	DISLVKMD	Definitive	Biomarker	[1]
Carcinoma	DISH9F1N	Strong	Genetic Variation	[2]
Metastatic malignant neoplasm	DIS86UK6	Strong	Biomarker	[3]
Neoplasm	DISZKGEW	Strong	Genetic Variation	[4]
Thyroid cancer	DIS3VLDH	Strong	Biomarker	[1]
Thyroid gland papillary carcinoma	DIS48YMM	Strong	Genetic Variation	[5]
Thyroid gland undifferentiated (anaplastic) carcinoma	DISYBB1W	Strong	Genetic Variation	[1]
Uveal Melanoma	DISA7ZGL	Strong	Genetic Variation	[6]
Adult lymphoma	DISK8IZR	Limited	Genetic Variation	[7]
Cutaneous melanoma	DIS3MMH9	Limited	Genetic Variation	[8]
Lymphoma	DISN6V4S	Limited	Genetic Variation	[7]
Melanoma	DIS1RRCY	Limited	Genetic Variation	[8]
Metastatic melanoma	DISSL43L	Limited	Genetic Variation	[9]
Pediatric lymphoma	DIS51BK2	Limited	Genetic Variation	[7]

17 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 Eukaryotic translation initiation factor 1A, X-chromosomal (EIF1AX).	[10]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Eukaryotic translation initiation factor 1A, X-chromosomal (EIF1AX).	[11]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Eukaryotic translation initiation factor 1A, X-chromosomal (EIF1AX).	[12]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Eukaryotic translation initiation factor 1A, X-chromosomal (EIF1AX).	[13]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Eukaryotic translation initiation factor 1A, X-chromosomal (EIF1AX).	[14]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Eukaryotic translation initiation factor 1A, X-chromosomal (EIF1AX).	[15]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of Eukaryotic translation initiation factor 1A, X-chromosomal (EIF1AX).	[16]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of Eukaryotic translation initiation factor 1A, X-chromosomal (EIF1AX).	[17]
Marinol	DM70IK5	Approved	Marinol decreases the expression of Eukaryotic translation initiation factor 1A, X-chromosomal (EIF1AX).	[18]
Diclofenac	DMPIHLS	Approved	Diclofenac affects the expression of Eukaryotic translation initiation factor 1A, X-chromosomal (EIF1AX).	[17]
Piroxicam	DMTK234	Approved	Piroxicam decreases the expression of Eukaryotic translation initiation factor 1A, X-chromosomal (EIF1AX).	[19]
Indomethacin	DMSC4A7	Approved	Indomethacin decreases the expression of Eukaryotic translation initiation factor 1A, X-chromosomal (EIF1AX).	[20]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Eukaryotic translation initiation factor 1A, X-chromosomal (EIF1AX).	[22]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of Eukaryotic translation initiation factor 1A, X-chromosomal (EIF1AX).	[23]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of Eukaryotic translation initiation factor 1A, X-chromosomal (EIF1AX).	[24]
Nickel chloride	DMI12Y8	Investigative	Nickel chloride decreases the expression of Eukaryotic translation initiation factor 1A, X-chromosomal (EIF1AX).	[25]
CH-223191	DMMJZYC	Investigative	CH-223191 decreases the expression of Eukaryotic translation initiation factor 1A, X-chromosomal (EIF1AX).	[26]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Eukaryotic translation initiation factor 1A, X-chromosomal (EIF1AX).	[21]

References

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• [2] Integrated genomic characterization of papillary thyroid carcinoma.Cell. 2014 Oct 23;159(3):676-90. doi: 10.1016/j.cell.2014.09.050.
• [3] Genetic Profiling of Primary Orbital Melanoma: An Analysis of 6 Cases with Clinicopathologic Correlation.Ophthalmology. 2019 Jul;126(7):1045-1052. doi: 10.1016/j.ophtha.2018.12.047. Epub 2018 Dec 31.
• [4] Poorly Differentiated Carcinoma of the Thyroid Gland: Current Status and Future Prospects.Thyroid. 2019 Mar;29(3):311-321. doi: 10.1089/thy.2018.0509.
• [5] MassARRAY-based simultaneous detection of hotspot somatic mutations and recurrent fusion genes in papillary thyroid carcinoma: the PTC-MA assay.Endocrine. 2018 Jul;61(1):36-41. doi: 10.1007/s12020-017-1483-2. Epub 2017 Dec 6.
• [6] eIF1A residues implicated in cancer stabilize translation preinitiation complexes and favor suboptimal initiation sites in yeast.Elife. 2017 Dec 5;6:e31250. doi: 10.7554/eLife.31250.
• [7] Methodology, Criteria, and Characterization of Patient-Matched Thyroid Cell Lines and Patient-Derived Tumor Xenografts.J Clin Endocrinol Metab. 2018 Sep 1;103(9):3169-3182. doi: 10.1210/jc.2017-01845.
• [8] SF3B1 and EIF1AX mutations occur in primary leptomeningeal melanocytic neoplasms; yet another similarity to uveal melanomas.Acta Neuropathol Commun. 2016 Jan 15;4:5. doi: 10.1186/s40478-016-0272-0.
• [9] Intraventricular melanocytoma diagnosis confirmed by gene mutation profile.Neuropathology. 2018 Jun;38(3):288-292. doi: 10.1111/neup.12443. Epub 2017 Dec 11.
• [10] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [11] 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.
• [12] Transcriptional and Metabolic Dissection of ATRA-Induced Granulocytic Differentiation in NB4 Acute Promyelocytic Leukemia Cells. Cells. 2020 Nov 5;9(11):2423. doi: 10.3390/cells9112423.
• [13] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [14] Low doses of cisplatin induce gene alterations, cell cycle arrest, and apoptosis in human promyelocytic leukemia cells. Biomark Insights. 2016 Aug 24;11:113-21.
• [15] 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.
• [16] Minimal peroxide exposure of neuronal cells induces multifaceted adaptive responses. PLoS One. 2010 Dec 17;5(12):e14352. doi: 10.1371/journal.pone.0014352.
• [17] Drug-induced endoplasmic reticulum and oxidative stress responses independently sensitize toward TNF-mediated hepatotoxicity. Toxicol Sci. 2014 Jul;140(1):144-59. doi: 10.1093/toxsci/kfu072. Epub 2014 Apr 20.
• [18] JunD is involved in the antiproliferative effect of Delta9-tetrahydrocannabinol on human breast cancer cells. Oncogene. 2008 Aug 28;27(37):5033-44.
• [19] Apoptosis induced by piroxicam plus cisplatin combined treatment is triggered by p21 in mesothelioma. PLoS One. 2011;6(8):e23569.
• [20] Mechanisms of indomethacin-induced alterations in the choline phospholipid metabolism of breast cancer cells. Neoplasia. 2006 Sep;8(9):758-71.
• [21] 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.
• [22] Environmental pollutant induced cellular injury is reflected in exosomes from placental explants. Placenta. 2020 Jan 1;89:42-49. doi: 10.1016/j.placenta.2019.10.008. Epub 2019 Oct 17.
• [23] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [24] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.
• [25] The contact allergen nickel triggers a unique inflammatory and proangiogenic gene expression pattern via activation of NF-kappaB and hypoxia-inducible factor-1alpha. J Immunol. 2007 Mar 1;178(5):3198-207.
• [26] Adaptive changes in global gene expression profile of lung carcinoma A549 cells acutely exposed to distinct types of AhR ligands. Toxicol Lett. 2018 Aug;292:162-174.