Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT4EGCPG)

• DOT Name: PDZ and LIM domain protein 1 (PDLIM1)
• Synonyms: C-terminal LIM domain protein 1; Elfin; LIM domain protein CLP-36
• Gene Name: PDLIM1
• Related Disease:
  Adult glioblastoma
  Advanced cancer
  Attention deficit hyperactivity disorder
  Focal segmental glomerulosclerosis
  Friedreich's ataxia
  Glioblastoma multiforme
  Glioma
  Hepatocellular carcinoma
  Metastatic malignant neoplasm
  Neoplasm
  Osteoarthritis
  Breast cancer
  Breast carcinoma
  Supravalvular aortic stenosis
• UniProt ID: PDLI1_HUMAN
• PDB ID: 1X62; 2PKT
• Pfam ID: PF15936 ; PF00412 ; PF00595
• Sequence:
  MTTQQIDLQGPGPWGFRLVGGKDFEQPLAISRVTPGSKAALANLCIGDVITAIDGENTSN
  MTHLEAQNRIKGCTDNLTLTVARSEHKVWSPLVTEEGKRHPYKMNLASEPQEVLHIGSAH
  NRSAMPFTASPASSTTARVITNQYNNPAGLYSSENISNFNNALESKTAASGVEANSRPLD
  HAQPPSSLVIDKESEVYKMLQEKQELNEPPKQSTSFLVLQEILESEEKGDPNKPSGFRSV
  KAPVTKVAASIGNAQKLPMCDKCGTGIVGVFVKLRDRHRHPECYVCTDCGTNLKQKGHFF
  VEDQIYCEKHARERVTPPEGYEVVTVFPK
• Function: Cytoskeletal protein that may act as an adapter that brings other proteins (like kinases) to the cytoskeleton. Involved in assembly, disassembly and directioning of stress fibers in fibroblasts. Required for the localization of ACTN1 and PALLD to stress fibers. Required for cell migration and in maintaining cell polarity of fibroblasts.
• Tissue Specificity: Strongly expressed in the heart and skeletal muscle, moderately expressed in the spleen, small intestine, colon, placenta, and lung. A lower level expression is seen in liver, thymus, kidney, prostate and pancreas and is not found in the brain, testis, ovary, and peripheral blood leukocytes.
• KEGG Pathway: Cytoskeleton in muscle cells (hsa04820)

Molecular Interaction Atlas (MIA) of This DOT

14 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Adult glioblastoma	DISVP4LU	Strong	Biomarker	[1]
Advanced cancer	DISAT1Z9	Strong	Altered Expression	[2]
Attention deficit hyperactivity disorder	DISL8MX9	Strong	Biomarker	[3]
Focal segmental glomerulosclerosis	DISJNHH0	Strong	Genetic Variation	[4]
Friedreich's ataxia	DIS5DV35	Strong	Biomarker	[5]
Glioblastoma multiforme	DISK8246	Strong	Biomarker	[1]
Glioma	DIS5RPEH	Strong	Biomarker	[1]
Hepatocellular carcinoma	DIS0J828	Strong	Biomarker	[6]
Metastatic malignant neoplasm	DIS86UK6	Strong	Biomarker	[6]
Neoplasm	DISZKGEW	Strong	Biomarker	[7]
Osteoarthritis	DIS05URM	Strong	Genetic Variation	[8]
Breast cancer	DIS7DPX1	moderate	Biomarker	[9]
Breast carcinoma	DIS2UE88	moderate	Biomarker	[9]
Supravalvular aortic stenosis	DIS8FSJD	Limited	Genetic Variation	[10]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the methylation of PDZ and LIM domain protein 1 (PDLIM1).	[11]
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of PDZ and LIM domain protein 1 (PDLIM1).	[19]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of PDZ and LIM domain protein 1 (PDLIM1).	[27]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 decreases the phosphorylation of PDZ and LIM domain protein 1 (PDLIM1).	[29]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of PDZ and LIM domain protein 1 (PDLIM1).	[30]
Coumarin	DM0N8ZM	Investigative	Coumarin increases the phosphorylation of PDZ and LIM domain protein 1 (PDLIM1).	[29]

24 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 1 (PDLIM1).	[12]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of PDZ and LIM domain protein 1 (PDLIM1).	[13]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of PDZ and LIM domain protein 1 (PDLIM1).	[14]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of PDZ and LIM domain protein 1 (PDLIM1).	[15]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of PDZ and LIM domain protein 1 (PDLIM1).	[16]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of PDZ and LIM domain protein 1 (PDLIM1).	[17]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of PDZ and LIM domain protein 1 (PDLIM1).	[18]
Temozolomide	DMKECZD	Approved	Temozolomide decreases the expression of PDZ and LIM domain protein 1 (PDLIM1).	[20]
Decitabine	DMQL8XJ	Approved	Decitabine affects the expression of PDZ and LIM domain protein 1 (PDLIM1).	[21]
Progesterone	DMUY35B	Approved	Progesterone decreases the expression of PDZ and LIM domain protein 1 (PDLIM1).	[22]
Panobinostat	DM58WKG	Approved	Panobinostat increases the expression of PDZ and LIM domain protein 1 (PDLIM1).	[23]
Dexamethasone	DMMWZET	Approved	Dexamethasone increases the expression of PDZ and LIM domain protein 1 (PDLIM1).	[24]
Cidofovir	DMA13GD	Approved	Cidofovir increases the expression of PDZ and LIM domain protein 1 (PDLIM1).	[16]
Clodronate	DM9Y6X7	Approved	Clodronate increases the expression of PDZ and LIM domain protein 1 (PDLIM1).	[16]
Ibuprofen	DM8VCBE	Approved	Ibuprofen decreases the expression of PDZ and LIM domain protein 1 (PDLIM1).	[16]
Prednisolone	DMQ8FR2	Approved	Prednisolone increases the expression of PDZ and LIM domain protein 1 (PDLIM1).	[25]
Adefovir dipivoxil	DMMAWY1	Approved	Adefovir dipivoxil increases the expression of PDZ and LIM domain protein 1 (PDLIM1).	[16]
Gamolenic acid	DMQN30Z	Approved	Gamolenic acid decreases the expression of PDZ and LIM domain protein 1 (PDLIM1).	[26]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of PDZ and LIM domain protein 1 (PDLIM1).	[23]
Belinostat	DM6OC53	Phase 2	Belinostat increases the expression of PDZ and LIM domain protein 1 (PDLIM1).	[23]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of PDZ and LIM domain protein 1 (PDLIM1).	[28]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of PDZ and LIM domain protein 1 (PDLIM1).	[31]
Coumestrol	DM40TBU	Investigative	Coumestrol decreases the expression of PDZ and LIM domain protein 1 (PDLIM1).	[17]
Sulforaphane	DMQY3L0	Investigative	Sulforaphane decreases the expression of PDZ and LIM domain protein 1 (PDLIM1).	[32]

References

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• [2] Exosomes Derived from Human Primary and Metastatic Colorectal Cancer Cells Contribute to Functional Heterogeneity of Activated Fibroblasts by Reprogramming Their Proteome.Proteomics. 2019 Apr;19(8):e1800148. doi: 10.1002/pmic.201800148. Epub 2019 Jan 31.
• [3] Parent-of-origin effects of FAS and PDLIM1 in attention-deficit/hyperactivity disorder.J Psychiatry Neurosci. 2012 Jan;37(1):46-52. doi: 10.1503/jpn.100173.
• [4] Alpha-actinin-4 and CLP36 protein deficiencies contribute to podocyte defects in multiple human glomerulopathies.J Biol Chem. 2011 Sep 2;286(35):30795-30805. doi: 10.1074/jbc.M111.255984. Epub 2011 Jun 16.
• [5] Lymphoblast Oxidative Stress Genes as Potential Biomarkers of Disease Severity and Drug Effect in Friedreich's Ataxia.PLoS One. 2016 Apr 14;11(4):e0153574. doi: 10.1371/journal.pone.0153574. eCollection 2016.
• [6] PDLIM1 Inhibits Tumor Metastasis Through Activating Hippo Signaling in Hepatocellular Carcinoma.Hepatology. 2020 May;71(5):1643-1659. doi: 10.1002/hep.30930. Epub 2020 Jan 21.
• [7] PDZ and LIM domain protein 1(PDLIM1)/CLP36 promotes breast cancer cell migration, invasion and metastasis through interaction with -actinin.Oncogene. 2015 Mar 5;34(10):1300-11. doi: 10.1038/onc.2014.64. Epub 2014 Mar 24.
• [8] Protein interaction and microRNA network analysis in osteoarthritis meniscal cells.Genet Mol Res. 2013 Mar 13;12(1):738-46. doi: 10.4238/2013.March.13.2.
• [9] Autoantibodies against TYMS and PDLIM1 proteins detected as circulatory signatures in Indian breast cancer patients.Proteomics Clin Appl. 2016 May;10(5):564-73. doi: 10.1002/prca.201500138.
• [10] The elastin gene is disrupted in a family with a balanced translocation t(7;16)(q11.23;q13) associated with a variable expression of the Williams-Beuren syndrome.Eur J Hum Genet. 2002 Jun;10(6):351-61. doi: 10.1038/sj.ejhg.5200812.
• [11] 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.
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• [15] 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.
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• [17] Pleiotropic combinatorial transcriptomes of human breast cancer cells exposed to mixtures of dietary phytoestrogens. Food Chem Toxicol. 2009 Apr;47(4):787-95.
• [18] 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.
• [19] 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.
• [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] Acute hypersensitivity of pluripotent testicular cancer-derived embryonal carcinoma to low-dose 5-aza deoxycytidine is associated with global DNA Damage-associated p53 activation, anti-pluripotency and DNA demethylation. PLoS One. 2012;7(12):e53003. doi: 10.1371/journal.pone.0053003. Epub 2012 Dec 27.
• [22] Coordinate up-regulation of TMEM97 and cholesterol biosynthesis genes in normal ovarian surface epithelial cells treated with progesterone: implications for pathogenesis of ovarian cancer. BMC Cancer. 2007 Dec 11;7:223.
• [23] 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.
• [24] Identification of mechanisms of action of bisphenol a-induced human preadipocyte differentiation by transcriptional profiling. Obesity (Silver Spring). 2014 Nov;22(11):2333-43.
• [25] Gene expression profiling of rheumatoid arthritis synovial cells treated with antirheumatic drugs. J Biomol Screen. 2007 Apr;12(3):328-40. doi: 10.1177/1087057107299261. Epub 2007 Mar 22.
• [26] Antineoplastic effects of gamma linolenic Acid on hepatocellular carcinoma cell lines. J Clin Biochem Nutr. 2010 Jul;47(1):81-90.
• [27] 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.
• [28] 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.
• [29] 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.
• [30] 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.
• [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.
• [32] Sulforaphane-induced apoptosis in human leukemia HL-60 cells through extrinsic and intrinsic signal pathways and altering associated genes expression assayed by cDNA microarray. Environ Toxicol. 2017 Jan;32(1):311-328.