Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT20EAPR)

• DOT Name: LIM domain-binding protein 1 (LDB1)
• Synonyms: LDB-1; Carboxyl-terminal LIM domain-binding protein 2; CLIM-2; LIM domain-binding factor CLIM2; hLdb1; Nuclear LIM interactor
• Gene Name: LDB1
• Related Disease:
  Paralysis
  Acute leukaemia
  Advanced cancer
  Breast cancer
  Colorectal carcinoma
  leukaemia
  Leukemia
  Nail-patella syndrome
  Neoplasm
  Obesity
  Squamous cell carcinoma
  T-cell acute lymphoblastic leukaemia
  T-cell leukaemia
  Nephropathy
• UniProt ID: LDB1_HUMAN
• PDB ID: 2XJY; 2XJZ; 2YPA; 6TYD; 7OB5; 7OB8; 8HIB; 8SSU
• Pfam ID: PF17916 ; PF01803
• Sequence:
  MSVGCACPGCSSKSFKLYSPKEPPNGNAFPPFHPGTMLDRDVGPTPMYPPTYLEPGIGRH
  TPYGNQTDYRIFELNKRLQNWTEECDNLWWDAFTTEFFEDDAMLTITFCLEDGPKRYTIG
  RTLIPRYFRSIFEGGATELYYVLKHPKEAFHSNFVSLDCDQGSMVTQHGKPMFTQVCVEG
  RLYLEFMFDDMMRIKTWHFSIRQHRELIPRSILAMHAQDPQMLDQLSKNITRCGLSNSTL
  NYLRLCVILEPMQELMSRHKTYSLSPRDCLKTCLFQKWQRMVAPPAEPTRQQPSKRRKRK
  MSGGSTMSSGGGNTNNSNSKKKSPASTFALSSQVPDVMVVGEPTLMGGEFGDEDERLITR
  LENTQFDAANGIDDEDSFNNSPALGANSPWNSKPPSSQESKSENPTSQASQ
• Function: Binds to the LIM domain of a wide variety of LIM domain-containing transcription factors. May regulate the transcriptional activity of LIM-containing proteins by determining specific partner interactions. Plays a role in the development of interneurons and motor neurons in cooperation with LHX3 and ISL1. Acts synergistically with LHX1/LIM1 in axis formation and activation of gene expression. Acts with LMO2 in the regulation of red blood cell development, maintaining erythroid precursors in an immature state.
• Tissue Specificity: Expressed in a wide range of adult tissues including brain, heart, skeletal muscle, colon, thymus, spleen, kidney, liver, small intestine, lung and peripheral blood leukocytes.
• KEGG Pathway: Transcriptio.l misregulation in cancer (hsa05202)
• Reactome Pathway:
  Regulation of expression of SLITs and ROBOs (R-HSA-9010553)
  Cardiogenesis (R-HSA-9733709)
  Expression and translocation of olfactory receptors (R-HSA-9752946)
  RUNX1 regulates transcription of genes involved in differentiation of HSCs (R-HSA-8939236)

Molecular Interaction Atlas (MIA) of This DOT

14 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Paralysis	DISF9I3O	Definitive	Genetic Variation	[1]
Acute leukaemia	DISDQFDI	Strong	Altered Expression	[2]
Advanced cancer	DISAT1Z9	Strong	Biomarker	[3]
Breast cancer	DIS7DPX1	Strong	Altered Expression	[4]
Colorectal carcinoma	DIS5PYL0	Strong	Biomarker	[5]
leukaemia	DISS7D1V	Strong	Biomarker	[6]
Leukemia	DISNAKFL	Strong	Biomarker	[6]
Nail-patella syndrome	DIS8C4CT	Strong	Biomarker	[7]
Neoplasm	DISZKGEW	Strong	Altered Expression	[5]
Obesity	DIS47Y1K	Strong	Biomarker	[8]
Squamous cell carcinoma	DISQVIFL	Strong	Altered Expression	[9]
T-cell acute lymphoblastic leukaemia	DIS17AI2	Strong	Altered Expression	[10]
T-cell leukaemia	DISJ6YIF	Strong	Biomarker	[6]
Nephropathy	DISXWP4P	Disputed	Genetic Variation	[11]

7 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-binding protein 1 (LDB1).	[12]
Doxorubicin	DMVP5YE	Approved	Doxorubicin increases the expression of LIM domain-binding protein 1 (LDB1).	[13]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of LIM domain-binding protein 1 (LDB1).	[14]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of LIM domain-binding protein 1 (LDB1).	[15]
Sulindac	DM2QHZU	Approved	Sulindac increases the expression of LIM domain-binding protein 1 (LDB1).	[17]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of LIM domain-binding protein 1 (LDB1).	[18]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde increases the expression of LIM domain-binding protein 1 (LDB1).	[21]

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 LIM domain-binding protein 1 (LDB1).	[16]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the methylation of LIM domain-binding protein 1 (LDB1).	[19]
TAK-243	DM4GKV2	Phase 1	TAK-243 increases the sumoylation of LIM domain-binding protein 1 (LDB1).	[20]

References

• [1] The graded redefined assessment of strength sensibility and prehension version 2 (GV2): Psychometric properties.J Spinal Cord Med. 2019 Oct;42(sup1):149-157. doi: 10.1080/10790268.2019.1616950.
• [2] The LMO1 and LDB1 proteins interact in human T cell acute leukaemia with the chromosomal translocation t(11;14)(p15;q11).Oncogene. 1998 Dec 17;17(24):3199-202. doi: 10.1038/sj.onc.1202353.
• [3] Enhancer long-range contacts: The multi-adaptor protein LDB1 is the tie that binds.Biochim Biophys Acta Gene Regul Mech. 2019 Jun;1862(6):625-633. doi: 10.1016/j.bbagrm.2019.04.003. Epub 2019 Apr 22.
• [4] The LIM domain binding protein 1, Ldb1, has distinct roles in Neu-induced mammary tumorigenesis.Biochim Biophys Acta Mol Cell Res. 2018 Nov;1865(11 Pt A):1590-1597. doi: 10.1016/j.bbamcr.2018.08.013. Epub 2018 Aug 23.
• [5] LDB1 overexpression is a negative prognostic factor in colorectal cancer.Oncotarget. 2016 Dec 20;7(51):84258-84270. doi: 10.18632/oncotarget.12481.
• [6] LMO2 Oncoprotein Stability in T-Cell Leukemia Requires Direct LDB1 Binding.Mol Cell Biol. 2015 Nov 23;36(3):488-506. doi: 10.1128/MCB.00901-15. Print 2016 Feb 1.
• [7] The podocyte-specific inactivation of Lmx1b, Ldb1 and E2a yields new insight into a transcriptional network in podocytes.Dev Biol. 2007 Apr 15;304(2):701-12. doi: 10.1016/j.ydbio.2007.01.020. Epub 2007 Jan 18.
• [8] LDB1 Regulates Energy Homeostasis During Diet-Induced Obesity.Endocrinology. 2017 May 1;158(5):1289-1297. doi: 10.1210/en.2016-1791.
• [9] The LIM-only protein, LMO4, and the LIM domain-binding protein, LDB1, expression in squamous cell carcinomas of the oral cavity.Br J Cancer. 2003 May 19;88(10):1543-8. doi: 10.1038/sj.bjc.6600952.
• [10] Overexpression of Lhx2 suppresses proliferation of human T cell acute lymphoblastic leukemia-derived cells, partly by reducing LMO2 protein levels.Biochem Biophys Res Commun. 2018 Jan 15;495(3):2310-2316. doi: 10.1016/j.bbrc.2017.12.135. Epub 2017 Dec 24.
• [11] Confirmation of CLIM2/LMX1B interaction by yeast two-hybrid screening and analysis of its involvement in nail-patella syndrome.Int J Mol Med. 2003 Jul;12(1):79-82.
• [12] 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.
• [13] 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.
• [14] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [15] Genistein and bisphenol A exposure cause estrogen receptor 1 to bind thousands of sites in a cell type-specific manner. Genome Res. 2012 Nov;22(11):2153-62.
• [16] 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.
• [17] Expression profile analysis of colon cancer cells in response to sulindac or aspirin. Biochem Biophys Res Commun. 2002 Mar 29;292(2):498-512.
• [18] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [19] 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.
• [20] Inhibiting ubiquitination causes an accumulation of SUMOylated newly synthesized nuclear proteins at PML bodies. J Biol Chem. 2019 Oct 18;294(42):15218-15234. doi: 10.1074/jbc.RA119.009147. Epub 2019 Jul 8.
• [21] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.