Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTI7WIYN)

• DOT Name: Dual specificity protein phosphatase 26 (DUSP26)
• Synonyms: EC 3.1.3.16; EC 3.1.3.48; Dual specificity phosphatase SKRP3; Low-molecular-mass dual-specificity phosphatase 4; DSP-4; LDP-4; Mitogen-activated protein kinase phosphatase 8; MAP kinase phosphatase 8; MKP-8; Novel amplified gene in thyroid anaplastic cancer
• Gene Name: DUSP26
• Related Disease:
  Adult glioblastoma
  Anxiety
  Anxiety disorder
  Glioblastoma multiforme
  Glioma
  Advanced cancer
  Diabetic kidney disease
  Fatty liver disease
  Hyperglycemia
  Non-alcoholic fatty liver disease
  Non-insulin dependent diabetes
  Parkinson disease
  Thyroid gland undifferentiated (anaplastic) carcinoma
  Thyroid tumor
  Castration-resistant prostate carcinoma
  Inflammation
  Neuroblastoma
  Tauopathy
  Temporal lobe epilepsy
• UniProt ID: DUS26_HUMAN
• PDB ID: 2E0T; 4B04; 4HRF; 5GTJ
• EC Number: 3.1.3.16; 3.1.3.48
• Pfam ID: PF00782
• Sequence:
  MCPGNWLWASMTFMARFSRSSSRSPVRTRGTLEEMPTVQHPFLNVFELERLLYTGKTACN
  HADEVWPGLYLGDQDMANNRRELRRLGITHVLNASHSRWRGTPEAYEGLGIRYLGVEAHD
  SPAFDMSIHFQTAADFIHRALSQPGGKILVHCAVGVSRSATLVLAYLMLYHHLTLVEAIK
  KVKDHRGIIPNRGFLRQLLALDRRLRQGLEA
• Function: Inactivates MAPK1 and MAPK3 which leads to dephosphorylation of heat shock factor protein 4 and a reduction in its DNA-binding activity. Inhibits MAP kinase p38 by dephosphorylating it and inhibits p38-mediated apoptosis in anaplastic thyroid cancer cells. Can also induce activation of MAP kinase p38 and c-Jun N-terminal kinase (JNK).
• Tissue Specificity: Brain. In the brain it is expressed ubiquitously except in the hippocampus. Expressed in embryonal cancers (retinoblastoma, neuroepithilioma and neuroblastoma) and in anaplatic thyroid cancer.

Molecular Interaction Atlas (MIA) of This DOT

19 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Adult glioblastoma	DISVP4LU	Definitive	Altered Expression	[1]
Anxiety	DISIJDBA	Definitive	Biomarker	[2]
Anxiety disorder	DISBI2BT	Definitive	Biomarker	[2]
Glioblastoma multiforme	DISK8246	Definitive	Altered Expression	[1]
Glioma	DIS5RPEH	Definitive	Altered Expression	[1]
Advanced cancer	DISAT1Z9	Strong	Biomarker	[3]
Diabetic kidney disease	DISJMWEY	Strong	Biomarker	[4]
Fatty liver disease	DIS485QZ	Strong	Posttranslational Modification	[5]
Hyperglycemia	DIS0BZB5	Strong	Biomarker	[6]
Non-alcoholic fatty liver disease	DISDG1NL	Strong	Biomarker	[5]
Non-insulin dependent diabetes	DISK1O5Z	Strong	Biomarker	[6]
Parkinson disease	DISQVHKL	Strong	Biomarker	[7]
Thyroid gland undifferentiated (anaplastic) carcinoma	DISYBB1W	Strong	Biomarker	[8]
Thyroid tumor	DISLVKMD	Strong	Biomarker	[8]
Castration-resistant prostate carcinoma	DISVGAE6	Limited	Biomarker	[9]
Inflammation	DISJUQ5T	Limited	Biomarker	[10]
Neuroblastoma	DISVZBI4	Limited	Biomarker	[11]
Tauopathy	DISY2IPA	Limited	Genetic Variation	[12]
Temporal lobe epilepsy	DISNOPXX	Limited	Biomarker	[13]

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 Dual specificity protein phosphatase 26 (DUSP26).	[14]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Dual specificity protein phosphatase 26 (DUSP26).	[15]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of Dual specificity protein phosphatase 26 (DUSP26).	[16]
Triclosan	DMZUR4N	Approved	Triclosan decreases the expression of Dual specificity protein phosphatase 26 (DUSP26).	[17]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Dual specificity protein phosphatase 26 (DUSP26).	[19]
THAPSIGARGIN	DMDMQIE	Preclinical	THAPSIGARGIN increases the expression of Dual specificity protein phosphatase 26 (DUSP26).	[20]
Acetaldehyde	DMJFKG4	Investigative	Acetaldehyde increases the expression of Dual specificity protein phosphatase 26 (DUSP26).	[22]

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 affects the methylation of Dual specificity protein phosphatase 26 (DUSP26).	[18]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Dual specificity protein phosphatase 26 (DUSP26).	[21]

References

• [1] Protein phosphatase Dusp26 associates with KIF3 motor and promotes N-cadherin-mediated cell-cell adhesion.Oncogene. 2009 Feb 5;28(5):752-61. doi: 10.1038/onc.2008.431. Epub 2008 Dec 1.
• [2] The alpha- and beta-noradrenergic receptors blockade in the dorsal raphe nucleus impairs the panic-like response elaborated by medial hypothalamus neurons.Brain Res. 2019 Dec 15;1725:146468. doi: 10.1016/j.brainres.2019.146468. Epub 2019 Sep 18.
• [3] Dual-specificity phosphatase 26 is a novel p53 phosphatase and inhibits p53 tumor suppressor functions in human neuroblastoma.Oncogene. 2010 Sep 2;29(35):4938-46. doi: 10.1038/onc.2010.244. Epub 2010 Jun 21.
• [4] DUSP26 regulates podocyte oxidative stress and fibrosis in a mouse model with diabetic nephropathy through the mediation of ROS.Biochem Biophys Res Commun. 2019 Jul 30;515(3):410-416. doi: 10.1016/j.bbrc.2019.05.032. Epub 2019 May 30.
• [5] Dual-Specificity Phosphatase 26 Protects Against Nonalcoholic Fatty Liver Disease in Mice Through Transforming Growth Factor Beta-Activated Kinase 1 Suppression.Hepatology. 2019 May;69(5):1946-1964. doi: 10.1002/hep.30485.
• [6] Adipsin preserves beta cells in diabetic mice and associates with protection from type 2 diabetes in humans.Nat Med. 2019 Nov;25(11):1739-1747. doi: 10.1038/s41591-019-0610-4. Epub 2019 Nov 7.
• [7] Lesion of the Locus Coeruleus Damages Learning and Memory Performance in Paraquat and Maneb-induced Mouse Parkinson's Disease Model.Neuroscience. 2019 Nov 1;419:129-140. doi: 10.1016/j.neuroscience.2019.09.006. Epub 2019 Oct 18.
• [8] A novel amplification target, DUSP26, promotes anaplastic thyroid cancer cell growth by inhibiting p38 MAPK activity.Oncogene. 2007 Feb 22;26(8):1178-87. doi: 10.1038/sj.onc.1209899. Epub 2006 Aug 21.
• [9] Prognostic value of blood mRNA expression signatures in castration-resistant prostate cancer: a prospective, two-stage study.Lancet Oncol. 2012 Nov;13(11):1114-24. doi: 10.1016/S1470-2045(12)70372-8. Epub 2012 Oct 9.
• [10] The Neurotoxin DSP-4 Induces Hyperalgesia in Rats that is Accompanied by Spinal Oxidative Stress and Cytokine Production.Neuroscience. 2018 Apr 15;376:13-23. doi: 10.1016/j.neuroscience.2018.01.058. Epub 2018 Feb 5.
• [11] NSC-87877 inhibits DUSP26 function in neuroblastoma resulting in p53-mediated apoptosis.Cell Death Dis. 2015 Aug 6;6(8):e1841. doi: 10.1038/cddis.2015.207.
• [12] Locus Coeruleus Ablation Exacerbates Cognitive Deficits, Neuropathology, and Lethality in P301S Tau Transgenic Mice.J Neurosci. 2018 Jan 3;38(1):74-92. doi: 10.1523/JNEUROSCI.1483-17.2017. Epub 2017 Nov 13.
• [13] DSP-4 induced depletion of brain noradrenaline and increased 6-hertz psychomotor seizure susceptibility in mice is prevented by sodium valproate.Brain Res Bull. 2018 Sep;142:263-269. doi: 10.1016/j.brainresbull.2018.08.002. Epub 2018 Aug 8.
• [14] Effects of lithium and valproic acid on gene expression and phenotypic markers in an NT2 neurosphere model of neural development. PLoS One. 2013;8(3):e58822.
• [15] Phenotypic characterization of retinoic acid differentiated SH-SY5Y cells by transcriptional profiling. PLoS One. 2013 May 28;8(5):e63862.
• [16] 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.
• [17] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [18] 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.
• [19] 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.
• [20] Endoplasmic reticulum stress impairs insulin signaling through mitochondrial damage in SH-SY5Y cells. Neurosignals. 2012;20(4):265-80.
• [21] 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.
• [22] Transcriptome profile analysis of saturated aliphatic aldehydes reveals carbon number-specific molecules involved in pulmonary toxicity. Chem Res Toxicol. 2014 Aug 18;27(8):1362-70.