Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT23LZYY)

• DOT Name: PDZ and LIM domain protein 4 (PDLIM4)
• Synonyms: LIM protein RIL; Reversion-induced LIM protein
• Gene Name: PDLIM4
• Related Disease:
  Advanced cancer
  Autoimmune disease
  Bipolar disorder
  Breast adenocarcinoma
  Cervical cancer
  Cervical carcinoma
  Colon carcinoma
  Epithelial ovarian cancer
  Esophageal squamous cell carcinoma
  Hepatocellular carcinoma
  Lung cancer
  Lung neoplasm
  Neoplasm
  Osteoporosis
  Ovarian cancer
  Ovarian neoplasm
  Polycystic ovarian syndrome
  Prostate cancer
  Prostate carcinoma
  Thyroid tumor
  Acute myelogenous leukaemia
  Breast cancer
  Breast carcinoma
  Colon cancer
  Malignant mesothelioma
  Myelodysplastic syndrome
• UniProt ID: PDLI4_HUMAN
• PDB ID: 2EEG; 2V1W; 4Q2O
• Pfam ID: PF15936 ; PF00412 ; PF00595
• Sequence:
  MPHSVTLRGPSPWGFRLVGGRDFSAPLTISRVHAGSKAALAALCPGDLIQAINGESTELM
  THLEAQNRIKGCHDHLTLSVSRPEGRSWPSAPDDSKAQAHRIHIDPEIQDGSPTTSRRPS
  GTGTGPEDGRPSLGSPYGQPPRFPVPHNGSSEATLPAQMSTLHVSPPPSADPARGLPRSR
  DCRVDLGSEVYRMLREPAEPVAAEPKQSGSFRYLQGMLEAGEGGDWPGPGGPRNLKPTAS
  KLGAPLSGLQGLPECTRCGHGIVGTIVKARDKLYHPECFMCSDCGLNLKQRGYFFLDERL
  YCESHAKARVKPPEGYDVVAVYPNAKVELV
• Function: [Isoform 1]: Suppresses SRC activation by recognizing and binding to active SRC and facilitating PTPN13-mediated dephosphorylation of SRC 'Tyr-419' leading to its inactivation. Inactivated SRC dissociates from this protein allowing the initiation of a new SRC inactivation cycle. Involved in reorganization of the actin cytoskeleton. In nonmuscle cells, binds to ACTN1 (alpha-actinin-1), increases the affinity of ACTN1 to F-actin (filamentous actin), and promotes formation of actin stress fibers. Involved in regulation of the synaptic AMPA receptor transport in dendritic spines of hippocampal pyramidal neurons directing the receptors toward an insertion at the postsynaptic membrane. Links endosomal surface-internalized GRIA1-containing AMPA receptors to the alpha-actinin/actin cytoskeleton. Increases AMPA receptor-mediated excitatory postsynaptic currents in neurons; [Isoform 2]: Involved in reorganization of the actin cytoskeleton and in regulation of cell migration. In response to oxidative stress, binds to NQO1, which stabilizes it and protects it from ubiquitin-independent degradation by the core 20S proteasome. Stabilized protein is able to heterodimerize with isoform 1 changing the subcellular location of it from cytoskeleton and nuclei to cytosol, leading to loss of isoforms 1 ability to induce formation of actin stress fibers. Counteracts the effects produced by isoform 1 on organization of actin cytoskeleton and cell motility to fine-tune actin cytoskeleton rearrangement and to attenuate cell migration.
• Tissue Specificity: .Found in brain.
• KEGG Pathway: Cytoskeleton in muscle cells (hsa04820)

Molecular Interaction Atlas (MIA) of This DOT

26 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Advanced cancer	DISAT1Z9	Strong	Posttranslational Modification	[1]
Autoimmune disease	DISORMTM	Strong	Biomarker	[2]
Bipolar disorder	DISAM7J2	Strong	Biomarker	[3]
Breast adenocarcinoma	DISMPHJ0	Strong	Biomarker	[4]
Cervical cancer	DISFSHPF	Strong	Biomarker	[5]
Cervical carcinoma	DIST4S00	Strong	Biomarker	[5]
Colon carcinoma	DISJYKUO	Strong	Biomarker	[6]
Epithelial ovarian cancer	DIS56MH2	Strong	Altered Expression	[7]
Esophageal squamous cell carcinoma	DIS5N2GV	Strong	Biomarker	[8]
Hepatocellular carcinoma	DIS0J828	Strong	Biomarker	[6]
Lung cancer	DISCM4YA	Strong	Biomarker	[9]
Lung neoplasm	DISVARNB	Strong	Biomarker	[9]
Neoplasm	DISZKGEW	Strong	Altered Expression	[7]
Osteoporosis	DISF2JE0	Strong	Genetic Variation	[10]
Ovarian cancer	DISZJHAP	Strong	Altered Expression	[7]
Ovarian neoplasm	DISEAFTY	Strong	Altered Expression	[7]
Polycystic ovarian syndrome	DISZ2BNG	Strong	Biomarker	[11]
Prostate cancer	DISF190Y	Strong	Altered Expression	[12]
Prostate carcinoma	DISMJPLE	Strong	Altered Expression	[12]
Thyroid tumor	DISLVKMD	Strong	Biomarker	[13]
Acute myelogenous leukaemia	DISCSPTN	Limited	Posttranslational Modification	[14]
Breast cancer	DIS7DPX1	Limited	Biomarker	[15]
Breast carcinoma	DIS2UE88	Limited	Biomarker	[15]
Colon cancer	DISVC52G	Limited	Altered Expression	[14]
Malignant mesothelioma	DISTHJGH	Limited	Biomarker	[16]
Myelodysplastic syndrome	DISYHNUI	Limited	Posttranslational Modification	[14]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the methylation of PDZ and LIM domain protein 4 (PDLIM4).	[17]
Decitabine	DMQL8XJ	Approved	Decitabine affects the methylation of PDZ and LIM domain protein 4 (PDLIM4).	[23]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of PDZ and LIM domain protein 4 (PDLIM4).	[28]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of PDZ and LIM domain protein 4 (PDLIM4).	[30]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of PDZ and LIM domain protein 4 (PDLIM4).	[18]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of PDZ and LIM domain protein 4 (PDLIM4).	[19]
Temozolomide	DMKECZD	Approved	Temozolomide increases the expression of PDZ and LIM domain protein 4 (PDLIM4).	[20]
Vorinostat	DMWMPD4	Approved	Vorinostat increases the expression of PDZ and LIM domain protein 4 (PDLIM4).	[21]
Triclosan	DMZUR4N	Approved	Triclosan increases the expression of PDZ and LIM domain protein 4 (PDLIM4).	[22]
Selenium	DM25CGV	Approved	Selenium increases the expression of PDZ and LIM domain protein 4 (PDLIM4).	[24]
Niclosamide	DMJAGXQ	Approved	Niclosamide increases the expression of PDZ and LIM domain protein 4 (PDLIM4).	[25]
Rosiglitazone	DMILWZR	Approved	Rosiglitazone decreases the expression of PDZ and LIM domain protein 4 (PDLIM4).	[26]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of PDZ and LIM domain protein 4 (PDLIM4).	[27]
Tocopherol	DMBIJZ6	Phase 2	Tocopherol increases the expression of PDZ and LIM domain protein 4 (PDLIM4).	[24]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of PDZ and LIM domain protein 4 (PDLIM4).	[29]
PMID27336223-Compound-5	DM6E50A	Patented	PMID27336223-Compound-5 decreases the expression of PDZ and LIM domain protein 4 (PDLIM4).	[26]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of PDZ and LIM domain protein 4 (PDLIM4).	[31]

References

• [1] An Sp1/Sp3 binding polymorphism confers methylation protection.PLoS Genet. 2008 Aug 22;4(8):e1000162. doi: 10.1371/journal.pgen.1000162.
• [2] Genetically Engineered Adipose Mesenchymal Stem Cells Using HIV-Based Lentiviral Vectors as Gene Therapy for Autoimmune Diseases.Cell Reprogram. 2018 Dec;20(6):337-346. doi: 10.1089/cell.2018.0006. Epub 2018 Oct 9.
• [3] Peripheral PDLIM5 expression in bipolar disorder and the effect of olanzapine administration.BMC Med Genet. 2012 Oct 2;13:91. doi: 10.1186/1471-2350-13-91.
• [4] The LIM domain protein FHL1C interacts with tight junction protein ZO-1 contributing to the epithelial-mesenchymal transition (EMT) of a breast adenocarcinoma cell line.Gene. 2014 Jun 1;542(2):182-9. doi: 10.1016/j.gene.2014.03.036. Epub 2014 Mar 19.
• [5] 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.
• [6] Enigma negatively regulates p53 through MDM2 and promotes tumor cell survival in mice.J Clin Invest. 2010 Dec;120(12):4493-506. doi: 10.1172/JCI42674. Epub 2010 Nov 8.
• [7] PDZ and LIM domain protein 4 suppresses the growth and invasion of ovarian cancer cells via inactivation of STAT3 signaling.Life Sci. 2019 Sep 15;233:116715. doi: 10.1016/j.lfs.2019.116715. Epub 2019 Jul 31.
• [8] The LIM domain protein, CRIP2, promotes apoptosis in esophageal squamous cell carcinoma.Cancer Lett. 2012 Mar;316(1):39-45. doi: 10.1016/j.canlet.2011.10.020. Epub 2011 Oct 20.
• [9] Bronchial airway gene expression signatures in mouse lung squamous cell carcinoma and their modulation by cancer chemopreventive agents.Oncotarget. 2017 Mar 21;8(12):18885-18900. doi: 10.18632/oncotarget.13806.
• [10] Association of genetic variation of the RIL gene, encoding a PDZ-LIM domain protein and localized in 5q31.1, with low bone mineral density in adult Japanese women.J Hum Genet. 2003;48(7):342-5. doi: 10.1007/s10038-003-0035-1. Epub 2003 Jun 6.
• [11] Progesterone resistance in PCOS endometrium: a microarray analysis in clomiphene citrate-treated and artificial menstrual cycles.J Clin Endocrinol Metab. 2011 Jun;96(6):1737-46. doi: 10.1210/jc.2010-2600. Epub 2011 Mar 16.
• [12] PDLIM4, an actin binding protein, suppresses prostate cancer cell growth.Cancer Invest. 2009 Mar;27(3):264-72. doi: 10.1080/07357900802406319.
• [13] Methylation of tumour suppressor genes associated with thyroid cancer.Cancer Biomark. 2019;25(1):53-65. doi: 10.3233/CBM-182265.
• [14] RIL, a LIM gene on 5q31, is silenced by methylation in cancer and sensitizes cancer cells to apoptosis.Cancer Res. 2007 Mar 1;67(5):1997-2005. doi: 10.1158/0008-5472.CAN-06-3093.
• [15] Methylation of HIN-1, RASSF1A, RIL and CDH13 in breast cancer is associated with clinical characteristics, but only RASSF1A methylation is associated with outcome.BMC Cancer. 2012 Jun 13;12:243. doi: 10.1186/1471-2407-12-243.
• [16] 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.
• [17] Integrative omics data analyses of repeated dose toxicity of valproic acid in vitro reveal new mechanisms of steatosis induction. Toxicology. 2018 Jan 15;393:160-170.
• [18] Cyclosporine A--induced oxidative stress in human renal mesangial cells: a role for ERK 1/2 MAPK signaling. Toxicol Sci. 2012 Mar;126(1):101-13.
• [19] Bringing in vitro analysis closer to in vivo: studying doxorubicin toxicity and associated mechanisms in 3D human microtissues with PBPK-based dose modelling. Toxicol Lett. 2018 Sep 15;294:184-192.
• [20] Temozolomide induces activation of Wnt/-catenin signaling in glioma cells via PI3K/Akt pathway: implications in glioma therapy. Cell Biol Toxicol. 2020 Jun;36(3):273-278. doi: 10.1007/s10565-019-09502-7. Epub 2019 Nov 22.
• [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] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [23] Effect of cytarabine and decitabine in combination in human leukemic cell lines. Clin Cancer Res. 2007 Jul 15;13(14):4225-32. doi: 10.1158/1078-0432.CCR-06-2762.
• [24] 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.
• [25] Mitochondrial Uncoupling Induces Epigenome Remodeling and Promotes Differentiation in Neuroblastoma. Cancer Res. 2023 Jan 18;83(2):181-194. doi: 10.1158/0008-5472.CAN-22-1029.
• [26] PPARgamma controls CD1d expression by turning on retinoic acid synthesis in developing human dendritic cells. J Exp Med. 2006 Oct 2;203(10):2351-62.
• [27] 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.
• [28] 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.
• [29] 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.
• [30] Global and region-specific post-transcriptional and post-translational modifications of bisphenol A in human prostate cancer cells. Environ Pollut. 2019 Dec;255(Pt 2):113318. doi: 10.1016/j.envpol.2019.113318. Epub 2019 Oct 2.
• [31] From transient transcriptome responses to disturbed neurodevelopment: role of histone acetylation and methylation as epigenetic switch between reversible and irreversible drug effects. Arch Toxicol. 2014 Jul;88(7):1451-68.