Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTNW7YPK)

• DOT Name: LIM domain-containing protein ajuba (AJUBA)
• Gene Name: AJUBA
• Related Disease:
  Adult glioblastoma
  Cervical cancer
  Cervical carcinoma
  Colorectal carcinoma
  Esophageal squamous cell carcinoma
  Glioblastoma multiforme
  Glioma
  Prostate cancer
  Prostate carcinoma
  Head-neck squamous cell carcinoma
  Small-cell lung cancer
  Advanced cancer
  Malignant mesothelioma
  Neoplasm
  Neurofibromatosis type 2
• UniProt ID: AJUBA_HUMAN
• Pfam ID: PF00412
• Sequence:
  MERLGEKASRLLEKFGRRKGESSRSGSDGTPGPGKGRLSGLGGPRKSGPRGATGGPGDEP
  LEPAREQGSLDAERNQRGSFEAPRYEGSFPAGPPPTRALPLPQSLPPDFRLEPTAPALSP
  RSSFASSSASDASKPSSPRGSLLLDGAGAGGAGGSRPCSNRTSGISMGYDQRHGSPLPAG
  PCLFGPPLAGAPAGYSPGGVPSAYPELHAALDRLYAQRPAGFGCQESRHSYPPALGSPGA
  LAGAGVGAAGPLERRGAQPGRHSVTGYGDCAVGARYQDELTALLRLTVGTGGREAGARGE
  PSGIEPSGLEEPPGPFVPEAARARMREPEAREDYFGTCIKCNKGIYGQSNACQALDSLYH
  TQCFVCCSCGRTLRCKAFYSVNGSVYCEEDYLFSGFQEAAEKCCVCGHLILEKILQAMGK
  SYHPGCFRCIVCNKCLDGIPFTVDFSNQVYCVTDYHKNYAPKCAACGQPILPSEGCEDIV
  RVISMDRDYHFECYHCEDCRMQLSDEEGCCCFPLDGHLLCHGCHMQRLNARQPPANYI
• Function: Adapter or scaffold protein which participates in the assembly of numerous protein complexes and is involved in several cellular processes such as cell fate determination, cytoskeletal organization, repression of gene transcription, mitosis, cell-cell adhesion, cell differentiation, proliferation and migration. Contributes to the linking and/or strengthening of epithelia cell-cell junctions in part by linking adhesive receptors to the actin cytoskeleton. May be involved in signal transduction from cell adhesion sites to the nucleus. Plays an important role in regulation of the kinase activity of AURKA for mitotic commitment. Also a component of the IL-1 signaling pathway modulating IL-1-induced NFKB1 activation by influencing the assembly and activity of the PRKCZ-SQSTM1-TRAF6 multiprotein signaling complex. Functions as an HDAC-dependent corepressor for a subset of GFI1 target genes. Acts as a transcriptional corepressor for SNAI1 and SNAI2/SLUG-dependent repression of E-cadherin transcription. Acts as a hypoxic regulator by bridging an association between the prolyl hydroxylases and VHL enabling efficient degradation of HIF1A. Positively regulates microRNA (miRNA)-mediated gene silencing. Negatively regulates the Hippo signaling pathway and antagonizes phosphorylation of YAP1.
• KEGG Pathway:
  Hippo sig.ling pathway (hsa04390)
  Hippo sig.ling pathway - multiple species (hsa04392)
• Reactome Pathway:
  Regulation of PLK1 Activity at G2/M Transition (R-HSA-2565942)
  Activation of anterior HOX genes in hindbrain development during early embryogenesis (R-HSA-5617472)
  Oxygen-dependent proline hydroxylation of Hypoxia-inducible Factor Alpha (R-HSA-1234176)

Molecular Interaction Atlas (MIA) of This DOT

15 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Adult glioblastoma	DISVP4LU	Strong	Altered Expression	[1]
Cervical cancer	DISFSHPF	Strong	Altered Expression	[2]
Cervical carcinoma	DIST4S00	Strong	Altered Expression	[2]
Colorectal carcinoma	DIS5PYL0	Strong	Altered Expression	[3]
Esophageal squamous cell carcinoma	DIS5N2GV	Strong	Genetic Variation	[4]
Glioblastoma multiforme	DISK8246	Strong	Altered Expression	[1]
Glioma	DIS5RPEH	Strong	Biomarker	[1]
Prostate cancer	DISF190Y	Strong	Biomarker	[5]
Prostate carcinoma	DISMJPLE	Strong	Biomarker	[5]
Head-neck squamous cell carcinoma	DISF7P24	moderate	Genetic Variation	[6]
Small-cell lung cancer	DISK3LZD	moderate	Biomarker	[7]
Advanced cancer	DISAT1Z9	Limited	Biomarker	[8]
Malignant mesothelioma	DISTHJGH	Limited	Altered Expression	[9]
Neoplasm	DISZKGEW	Limited	Altered Expression	[5]
Neurofibromatosis type 2	DISI8ECS	Limited	Genetic Variation	[9]

15 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 LIM domain-containing protein ajuba (AJUBA).	[10]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of LIM domain-containing protein ajuba (AJUBA).	[11]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of LIM domain-containing protein ajuba (AJUBA).	[12]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of LIM domain-containing protein ajuba (AJUBA).	[13]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of LIM domain-containing protein ajuba (AJUBA).	[15]
Testosterone	DM7HUNW	Approved	Testosterone increases the expression of LIM domain-containing protein ajuba (AJUBA).	[16]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of LIM domain-containing protein ajuba (AJUBA).	[17]
Phenobarbital	DMXZOCG	Approved	Phenobarbital affects the expression of LIM domain-containing protein ajuba (AJUBA).	[18]
Sodium phenylbutyrate	DMXLBCQ	Approved	Sodium phenylbutyrate decreases the expression of LIM domain-containing protein ajuba (AJUBA).	[19]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of LIM domain-containing protein ajuba (AJUBA).	[20]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 decreases the expression of LIM domain-containing protein ajuba (AJUBA).	[21]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of LIM domain-containing protein ajuba (AJUBA).	[22]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A affects the expression of LIM domain-containing protein ajuba (AJUBA).	[23]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of LIM domain-containing protein ajuba (AJUBA).	[21]
Coumestrol	DM40TBU	Investigative	Coumestrol decreases the expression of LIM domain-containing protein ajuba (AJUBA).	[24]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Quercetin	DM3NC4M	Approved	Quercetin decreases the phosphorylation of LIM domain-containing protein ajuba (AJUBA).	[14]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 affects the phosphorylation of LIM domain-containing protein ajuba (AJUBA).	[14]
Coumarin	DM0N8ZM	Investigative	Coumarin affects the phosphorylation of LIM domain-containing protein ajuba (AJUBA).	[14]

References

• [1] siRNA-mediated knockdown of JUB expression suppresses the proliferation of glioblastoma cells.Cancer Biomark. 2015;15(4):477-84. doi: 10.3233/CBM-150491.
• [2] AJUBA increases the cisplatin resistance through hippo pathway in cervical cancer.Gene. 2018 Feb 20;644:148-154. doi: 10.1016/j.gene.2017.11.017. Epub 2017 Nov 7.
• [3] NFATC2 is a novel therapeutic target for colorectal cancer stem cells.Onco Targets Ther. 2018 Oct 15;11:6911-6924. doi: 10.2147/OTT.S169129. eCollection 2018.
• [4] Comprehensive genomic analysis of Oesophageal Squamous Cell Carcinoma reveals clinical relevance.Sci Rep. 2017 Nov 10;7(1):15324. doi: 10.1038/s41598-017-14909-5.
• [5] Androgen receptor-regulated miRNA-193a-3p targets AJUBA to promote prostate cancer cell migration.Prostate. 2017 Jun;77(9):1000-1011. doi: 10.1002/pros.23356. Epub 2017 Apr 19.
• [6] Distinct pattern of TP53 mutations in human immunodeficiency virus-related head and neck squamous cell carcinoma.Cancer. 2018 Jan 1;124(1):84-94. doi: 10.1002/cncr.31063. Epub 2017 Oct 20.
• [7] PRC2 overexpression and PRC2-target gene repression relating to poorer prognosis in small cell lung cancer.Sci Rep. 2013;3:1911. doi: 10.1038/srep01911.
• [8] AJUBA promotes the migration and invasion of esophageal squamous cell carcinoma cells through upregulation of MMP10 and MMP13 expression.Oncotarget. 2016 Jun 14;7(24):36407-36418. doi: 10.18632/oncotarget.9239.
• [9] LIM-domain protein AJUBA suppresses malignant mesothelioma cell proliferation via Hippo signaling cascade.Oncogene. 2015 Jan 2;34(1):73-83. doi: 10.1038/onc.2013.528. Epub 2013 Dec 16.
• [10] Design principles of concentration-dependent transcriptome deviations in drug-exposed differentiating stem cells. Chem Res Toxicol. 2014 Mar 17;27(3):408-20.
• [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] Gene expression analysis of precision-cut human liver slices indicates stable expression of ADME-Tox related genes. Toxicol Appl Pharmacol. 2011 May 15;253(1):57-69.
• [13] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [14] 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.
• [15] Global gene expression analysis reveals differences in cellular responses to hydroxyl- and superoxide anion radical-induced oxidative stress in caco-2 cells. Toxicol Sci. 2010 Apr;114(2):193-203. doi: 10.1093/toxsci/kfp309. Epub 2009 Dec 31.
• [16] The exosome-like vesicles derived from androgen exposed-prostate stromal cells promote epithelial cells proliferation and epithelial-mesenchymal transition. Toxicol Appl Pharmacol. 2021 Jan 15;411:115384. doi: 10.1016/j.taap.2020.115384. Epub 2020 Dec 25.
• [17] Gene Expression Regulation and Pathway Analysis After Valproic Acid and Carbamazepine Exposure in a Human Embryonic Stem Cell-Based Neurodevelopmental Toxicity Assay. Toxicol Sci. 2015 Aug;146(2):311-20. doi: 10.1093/toxsci/kfv094. Epub 2015 May 15.
• [18] Reproducible chemical-induced changes in gene expression profiles in human hepatoma HepaRG cells under various experimental conditions. Toxicol In Vitro. 2009 Apr;23(3):466-75. doi: 10.1016/j.tiv.2008.12.018. Epub 2008 Dec 30.
• [19] Gene expression profile analysis of 4-phenylbutyrate treatment of IB3-1 bronchial epithelial cell line demonstrates a major influence on heat-shock proteins. Physiol Genomics. 2004 Jan 15;16(2):204-11.
• [20] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [21] A transcriptome-based classifier to identify developmental toxicants by stem cell testing: design, validation and optimization for histone deacetylase inhibitors. Arch Toxicol. 2015 Sep;89(9):1599-618.
• [22] New insights into BaP-induced toxicity: role of major metabolites in transcriptomics and contribution to hepatocarcinogenesis. Arch Toxicol. 2016 Jun;90(6):1449-58.
• [23] Comprehensive analysis of transcriptomic changes induced by low and high doses of bisphenol A in HepG2 spheroids in vitro and rat liver in vivo. Environ Res. 2019 Jun;173:124-134. doi: 10.1016/j.envres.2019.03.035. Epub 2019 Mar 18.
• [24] Pleiotropic combinatorial transcriptomes of human breast cancer cells exposed to mixtures of dietary phytoestrogens. Food Chem Toxicol. 2009 Apr;47(4):787-95.