Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT5YLL7E)

• DOT Name: Death-associated protein 1 (DAP)
• Synonyms: DAP-1
• Gene Name: DAP
• Related Disease:
  B-cell neoplasm
  Acute lymphocytic leukaemia
  Acute myelogenous leukaemia
  B-cell lymphoma
  Bladder cancer
  Breast cancer
  Breast carcinoma
  Breast neoplasm
  Carcinoma of esophagus
  Colorectal carcinoma
  Endometrium adenocarcinoma
  Epilepsy
  Esophageal cancer
  Esophageal squamous cell carcinoma
  Follicular lymphoma
  Gastric cancer
  Hepatocellular carcinoma
  LambertEaton myasthenic syndrome
  Lung adenocarcinoma
  Lung cancer
  Lymphoma
  Metastatic malignant neoplasm
  Myelodysplastic syndrome
  Nasopharyngeal carcinoma
  Neoplasm of esophagus
  Non-small-cell lung cancer
  Pancreatic cancer
  Plasma cell myeloma
  Small lymphocytic lymphoma
  Squamous cell carcinoma
  Stomach cancer
  Triple negative breast cancer
  Ulcerative colitis
  Urinary bladder cancer
  Urinary bladder neoplasm
  Congenital myasthenic syndrome
  Inflammatory bowel disease
  Lung carcinoma
  Methicillin-resistant staphylococci infection
  Neuroblastoma
  Cervical cancer
  Cervical carcinoma
  Ankylosing spondylitis
  Carcinoma
  Crohn disease
  Psoriasis
  Sclerosing cholangitis
  Tuberculosis
• UniProt ID: DAP1_HUMAN
• Pfam ID: PF15228
• Sequence:
  MSSPPEGKLETKAGHPPAVKAGGMRIVQKHPHTGDTKEEKDKDDQEWESPSPPKPTVFIS
  GVIARGDKDFPPAAAQVAHQKPHASMDKHPSPRTQHIQQPRK
• Function: Ribosome-binding protein involved in ribosome hibernation, a process during which ribosomes are stabilized in an inactive state and preserved from proteasomal degradation. Acts via its association with eiF5a (EIF5A and EIF5A2) at the polypeptide exit tunnel of the ribosome, preventing mRNA translation. Involved in ribosome hibernation in the mature oocyte by preventing mRNA translation, leading to ribosome inactivation. Ribosomes, which are produced in large quantities during oogenesis, are stored and translationally repressed in the oocyte and early embryo. Also acts as a negative regulator of autophagy. Involved in mediating interferon-gamma-induced cell death.

Molecular Interaction Atlas (MIA) of This DOT

48 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
B-cell neoplasm	DISVY326	Definitive	Posttranslational Modification	[1]
Acute lymphocytic leukaemia	DISPX75S	Strong	Posttranslational Modification	[2]
Acute myelogenous leukaemia	DISCSPTN	Strong	Biomarker	[3]
B-cell lymphoma	DISIH1YQ	Strong	Genetic Variation	[4]
Bladder cancer	DISUHNM0	Strong	Genetic Variation	[5]
Breast cancer	DIS7DPX1	Strong	Biomarker	[6]
Breast carcinoma	DIS2UE88	Strong	Biomarker	[6]
Breast neoplasm	DISNGJLM	Strong	Posttranslational Modification	[7]
Carcinoma of esophagus	DISS6G4D	Strong	Posttranslational Modification	[8]
Colorectal carcinoma	DIS5PYL0	Strong	Biomarker	[9]
Endometrium adenocarcinoma	DISY6744	Strong	Biomarker	[10]
Epilepsy	DISBB28L	Strong	Biomarker	[11]
Esophageal cancer	DISGB2VN	Strong	Posttranslational Modification	[8]
Esophageal squamous cell carcinoma	DIS5N2GV	Strong	Biomarker	[12]
Follicular lymphoma	DISVEUR6	Strong	Biomarker	[13]
Gastric cancer	DISXGOUK	Strong	Genetic Variation	[14]
Hepatocellular carcinoma	DIS0J828	Strong	Genetic Variation	[15]
LambertEaton myasthenic syndrome	DISN0Q7Q	Strong	Biomarker	[16]
Lung adenocarcinoma	DISD51WR	Strong	Posttranslational Modification	[17]
Lung cancer	DISCM4YA	Strong	Biomarker	[18]
Lymphoma	DISN6V4S	Strong	Posttranslational Modification	[19]
Metastatic malignant neoplasm	DIS86UK6	Strong	Genetic Variation	[20]
Myelodysplastic syndrome	DISYHNUI	Strong	Altered Expression	[21]
Nasopharyngeal carcinoma	DISAOTQ0	Strong	Biomarker	[22]
Neoplasm of esophagus	DISOLKAQ	Strong	Posttranslational Modification	[8]
Non-small-cell lung cancer	DIS5Y6R9	Strong	Genetic Variation	[23]
Pancreatic cancer	DISJC981	Strong	Biomarker	[24]
Plasma cell myeloma	DIS0DFZ0	Strong	Posttranslational Modification	[25]
Small lymphocytic lymphoma	DIS30POX	Strong	Biomarker	[26]
Squamous cell carcinoma	DISQVIFL	Strong	Altered Expression	[20]
Stomach cancer	DISKIJSX	Strong	Genetic Variation	[14]
Triple negative breast cancer	DISAMG6N	Strong	Biomarker	[6]
Ulcerative colitis	DIS8K27O	Strong	Genetic Variation	[27]
Urinary bladder cancer	DISDV4T7	Strong	Genetic Variation	[5]
Urinary bladder neoplasm	DIS7HACE	Strong	Genetic Variation	[5]
Congenital myasthenic syndrome	DISJLG2T	moderate	Biomarker	[28]
Inflammatory bowel disease	DISGN23E	moderate	Genetic Variation	[29]
Lung carcinoma	DISTR26C	moderate	Biomarker	[18]
Methicillin-resistant staphylococci infection	DIS6DRDZ	moderate	Genetic Variation	[30]
Neuroblastoma	DISVZBI4	moderate	Biomarker	[31]
Cervical cancer	DISFSHPF	Disputed	Posttranslational Modification	[32]
Cervical carcinoma	DIST4S00	Disputed	Posttranslational Modification	[32]
Ankylosing spondylitis	DISRC6IR	Limited	Genetic Variation	[27]
Carcinoma	DISH9F1N	Limited	Posttranslational Modification	[33]
Crohn disease	DIS2C5Q8	Limited	Genetic Variation	[34]
Psoriasis	DIS59VMN	Limited	Genetic Variation	[27]
Sclerosing cholangitis	DIS7GZNB	Limited	Genetic Variation	[27]
Tuberculosis	DIS2YIMD	Limited	Biomarker	[35]

This DOT Affected the Drug Response of 1 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Acetaminophen	DMUIE76	Approved	Death-associated protein 1 (DAP) affects the response to substance of Acetaminophen.	[49]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the expression of Death-associated protein 1 (DAP).	[36]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Death-associated protein 1 (DAP).	[37]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of Death-associated protein 1 (DAP).	[38]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Death-associated protein 1 (DAP).	[39]
Phenobarbital	DMXZOCG	Approved	Phenobarbital affects the expression of Death-associated protein 1 (DAP).	[40]
Hydroquinone	DM6AVR4	Approved	Hydroquinone decreases the expression of Death-associated protein 1 (DAP).	[41]
Rosiglitazone	DMILWZR	Approved	Rosiglitazone increases the expression of Death-associated protein 1 (DAP).	[42]
Aspirin	DM672AH	Approved	Aspirin decreases the expression of Death-associated protein 1 (DAP).	[43]
Menthol	DMG2KW7	Approved	Menthol decreases the expression of Death-associated protein 1 (DAP).	[44]
Capsaicin	DMGMF6V	Approved	Capsaicin increases the expression of Death-associated protein 1 (DAP).	[45]
THAPSIGARGIN	DMDMQIE	Preclinical	THAPSIGARGIN increases the expression of Death-associated protein 1 (DAP).	[47]

2 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 Death-associated protein 1 (DAP).	[46]
Coumarin	DM0N8ZM	Investigative	Coumarin decreases the phosphorylation of Death-associated protein 1 (DAP).	[48]

References

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• [2] Epigenetic dysregulation of the DAP kinase/p14/HDM2/p53/Apaf-1 apoptosis pathway in acute leukaemias.J Clin Pathol. 2008 Jul;61(7):844-7. doi: 10.1136/jcp.2007.047324.
• [3] CD33, CD96 and Death Associated Protein Kinase (DAPK) Expression Are Associated with the Survival Rate and/or Response to the Chemotherapy in the Patients with Acute Myeloid Leukemia (AML).Med Sci Monit. 2017 Apr 9;23:1725-1732. doi: 10.12659/msm.900305.
• [4] Hypermethylation of DAPK1 is an independent prognostic factor predicting survival in diffuse large B-cell lymphoma.Oncotarget. 2014 Oct 30;5(20):9798-810. doi: 10.18632/oncotarget.2394.
• [5] DAPK Promoter Methylation and Bladder Cancer Risk: A Systematic Review and Meta-Analysis.PLoS One. 2016 Dec 1;11(12):e0167228. doi: 10.1371/journal.pone.0167228. eCollection 2016.
• [6] Increased hypermethylation of glutathione S-transferase P1, DNA-binding protein inhibitor, death associated protein kinase and paired box protein-5... Asian Pac J Cancer Prev. 2015;16(2):541-9.
• [7] Dual promoter regulation of death-associated protein kinase gene leads to differentially silenced transcripts by methylation in cancer.Carcinogenesis. 2009 Dec;30(12):2023-30. doi: 10.1093/carcin/bgp276.
• [8] Death-associated protein kinase (DAPK) promoter methylation and response to neoadjuvant radiochemotherapy in esophageal cancer.Ann Surg Oncol. 2009 May;16(5):1378-83. doi: 10.1245/s10434-009-0356-1. Epub 2009 Feb 18.
• [9] Death associated protein 1 is correlated with the clinical outcome of patients with colorectal cancer and has a role in the regulation of cell death.Oncol Rep. 2014 Jan;31(1):175-82. doi: 10.3892/or.2013.2866. Epub 2013 Nov 20.
• [10] Impaired death-associated protein kinase-mediated survival signals in 5-fluorouracil-resistant human endometrial adenocarcinoma cells.Oncol Rep. 2012 Jul;28(1):330-6. doi: 10.3892/or.2012.1774. Epub 2012 Apr 23.
• [11] Death-associated protein kinase expression in human temporal lobe epilepsy.Ann Neurol. 2004 Apr;55(4):485-94. doi: 10.1002/ana.20001.
• [12] CpG island hypermethylation of E-cadherin (CDH1) and integrin alpha4 is associated with recurrence of early stage esophageal squamous cell carcinoma.Int J Cancer. 2008 Nov 1;123(9):2073-9. doi: 10.1002/ijc.23598.
• [13] DAP-kinase hypermethylation in the bone marrow of patients with follicular lymphoma.Haematologica. 2006 Sep;91(9):1252-6.
• [14] Increased number of CpG island hypermethylation in tumor suppressor genes of non-neoplastic gastric mucosa correlates with higher risk of gastric cancer.Digestion. 2010;82(1):27-36. doi: 10.1159/000252766. Epub 2010 Feb 11.
• [15] Quantitative promoter methylation analysis of hepatocellular carcinoma, cirrhotic and normal liver.Int J Cancer. 2008 Jun 15;122(12):2800-4. doi: 10.1002/ijc.23433.
• [16] Amifampridine for the Management of Lambert-Eaton Myasthenic Syndrome: A New Take on an Old Drug.Ann Pharmacother. 2020 Jan;54(1):56-63. doi: 10.1177/1060028019864574. Epub 2019 Jul 18.
• [17] 5-Aza-CdR can reverse gefitinib resistance caused by DAPK gene promoter methylation in lung adenocarcinoma cells.Int J Clin Exp Pathol. 2015 Oct 1;8(10):12961-6. eCollection 2015.
• [18] Frequent death-associated protein-kinase promoter hypermethylation in brain metastases of solid tumors.Oncol Rep. 2003 Jul-Aug;10(4):1031-3.
• [19] Frequent aberrant promoter hypermethylation of O6-methylguanine-DNA methyltransferase and death-associated protein kinase genes in immunodeficiency-related lymphomas.Br J Haematol. 2003 Nov;123(3):475-8. doi: 10.1046/j.1365-2141.2003.04644.x.
• [20] DAP1 high expression increases risk of lymph node metastases in squamous cell carcinoma of the oral cavity.Genet Mol Res. 2015 Sep 8;14(3):10515-23. doi: 10.4238/2015.September.8.13.
• [21] Aberrant methylation of DAP-kinase in therapy-related acute myeloid leukemia and myelodysplastic syndromes.Blood. 2004 Jan 15;103(2):698-700. doi: 10.1182/blood-2003-07-2249. Epub 2003 Sep 22.
• [22] Inactivation of RASSF1A, RARbeta2 and DAP-kinase by promoter methylation correlates with lymph node metastasis in nasopharyngeal carcinoma.Cancer Biol Ther. 2009 Mar;8(5):444-51. doi: 10.4161/cbt.8.5.7686. Epub 2009 Mar 21.
• [23] Prognostic significance of DAPK and RASSF1A promoter hypermethylation in non-small cell lung cancer (NSCLC).Folia Histochem Cytobiol. 2009;47(2):275-80. doi: 10.2478/v10042-009-0091-2.
• [24] Enhancing apoptosis and overcoming resistance of gemcitabine in pancreatic cancer with bortezomib: a role of death-associated protein kinase-related apoptosis-inducing protein kinase 1.Tumori. 2009 Nov-Dec;95(6):796-803. doi: 10.1177/030089160909500624.
• [25] Epigenetic dysregulation of the death-associated protein kinase/p14/HDM2/p53/Apaf-1 apoptosis pathway in multiple myeloma. J Clin Pathol. 2007 Jun;60(6):664-9. doi: 10.1136/jcp.2006.038331.
• [26] Frequent DAP kinase but not p14 or Apaf-1 hypermethylation in B-cell chronic lymphocytic leukemia.J Hum Genet. 2006;51(9):832-838. doi: 10.1007/s10038-006-0029-x. Epub 2006 Aug 3.
• [27] Analysis of five chronic inflammatory diseases identifies 27 new associations and highlights disease-specific patterns at shared loci.Nat Genet. 2016 May;48(5):510-8. doi: 10.1038/ng.3528. Epub 2016 Mar 14.
• [28] Inherited disorders of the neuromuscular junction: an update.J Neurol. 2014 Nov;261(11):2234-43. doi: 10.1007/s00415-014-7520-7. Epub 2014 Oct 11.
• [29] Association analyses identify 38 susceptibility loci for inflammatory bowel disease and highlight shared genetic risk across populations.Nat Genet. 2015 Sep;47(9):979-986. doi: 10.1038/ng.3359. Epub 2015 Jul 20.
• [30] Gain-of-Function Mutations in the Phospholipid Flippase MprF Confer Specific Daptomycin Resistance.mBio. 2018 Dec 18;9(6):e01659-18. doi: 10.1128/mBio.01659-18.
• [31] Antisense palmitoyl protein thioesterase 1 (PPT1) treatment inhibits PPT1 activity and increases cell death in LA-N-5 neuroblastoma cells.J Neurosci Res. 2000 Oct 15;62(2):234-40. doi: 10.1002/1097-4547(20001015)62:2<234::AID-JNR8>3.0.CO;2-8.
• [32] Promoter methylation of death-associated protein kinase and its role in irradiation response in cervical cancer.Oncol Rep. 2008 May;19(5):1339-45.
• [33] E-cadherin and DAP kinase in pancreatic adenocarcinoma and corresponding lymph node metastases.Oncol Rep. 2006 May;15(5):1125-31.
• [34] Genome-wide association study implicates immune activation of multiple integrin genes in inflammatory bowel disease.Nat Genet. 2017 Feb;49(2):256-261. doi: 10.1038/ng.3760. Epub 2017 Jan 9.
• [35] ATP-dependent MurE ligase in Mycobacterium tuberculosis: biochemical and structural characterisation.Tuberculosis (Edinb). 2010 Jan;90(1):16-24. doi: 10.1016/j.tube.2009.10.007. Epub 2009 Nov 27.
• [36] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [37] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [38] Molecular mechanism of action of bisphenol and bisphenol A mediated by oestrogen receptor alpha in growth and apoptosis of breast cancer cells. Br J Pharmacol. 2013 May;169(1):167-78.
• [39] 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.
• [40] 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.
• [41] Survival of retinal pigment epithelium after exposure to prolonged oxidative injury: a detailed gene expression and cellular analysis. Invest Ophthalmol Vis Sci. 2004 Oct;45(10):3767-77.
• [42] Rosiglitazone sensitizes MDA-MB-231 breast cancer cells to anti-tumour effects of tumour necrosis factor-alpha, CH11 and CYC202. Endocr Relat Cancer. 2007 Jun;14(2):305-15. doi: 10.1677/ERC-06-0003.
• [43] Expression profile analysis of human peripheral blood mononuclear cells in response to aspirin. Arch Immunol Ther Exp (Warsz). 2005 Mar-Apr;53(2):151-8.
• [44] Repurposing L-menthol for systems medicine and cancer therapeutics? L-menthol induces apoptosis through caspase 10 and by suppressing HSP90. OMICS. 2016 Jan;20(1):53-64.
• [45] Capsaicin inhibits the migration, invasion and EMT of renal cancer cells by inducing AMPK/mTOR-mediated autophagy. Chem Biol Interact. 2022 Oct 1;366:110043. doi: 10.1016/j.cbi.2022.110043. Epub 2022 Aug 28.
• [46] 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.
• [47] Endoplasmic reticulum stress impairs insulin signaling through mitochondrial damage in SH-SY5Y cells. Neurosignals. 2012;20(4):265-80.
• [48] 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.
• [49] Interindividual variation in gene expression responses and metabolite formation in acetaminophen-exposed primary human hepatocytes. Arch Toxicol. 2016 May;90(5):1103-15. doi: 10.1007/s00204-015-1545-2. Epub 2015 Jun 24.