Details of Drug Off-Target (DOT)

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

• DOT Name: Dual specificity protein phosphatase CDC14B (CDC14B)
• Synonyms: EC 3.1.3.16; EC 3.1.3.48; CDC14 cell division cycle 14 homolog B
• Gene Name: CDC14B
• Related Disease:
  Adult glioblastoma
  Astrocytoma
  Clear cell renal carcinoma
  Glioblastoma multiforme
  Multiple self-healing squamous epithelioma
  Neoplasm
  Thyroid gland papillary carcinoma
• UniProt ID: CC14B_HUMAN
• PDB ID: 1OHC; 1OHD; 1OHE
• EC Number: 3.1.3.16; 3.1.3.48
• Pfam ID: PF00782 ; PF14671
• Sequence:
  MKRKSERRSSWAAAPPCSRRCSSTSPGVKKIRSSTQQDPRRRDPQDDVYLDITDRLCFAI
  LYSRPKSASNVHYFSIDNELEYENFYADFGPLNLAMVYRYCCKINKKLKSITMLRKKIVH
  FTGSDQRKQANAAFLVGCYMVIYLGRTPEEAYRILIFGETSYIPFRDAAYGSCNFYITLL
  DCFHAVKKAMQYGFLNFNSFNLDEYEHYEKAENGDLNWIIPDRFIAFCGPHSRARLESGY
  HQHSPETYIQYFKNHNVTTIIRLNKRMYDAKRFTDAGFDHHDLFFADGSTPTDAIVKEFL
  DICENAEGAIAVHCKAGLGRTGTLIACYIMKHYRMTAAETIAWVRICRPGSVIGPQQQFL
  VMKQTNLWLEGDYFRQKLKGQENGQHRAAFSKLLSGVDDISINGVENQDQQEPEPYSDDD
  EINGVTQGDRLRALKSRRQSKTNAIPLTVILQSSVQSCKTSEPNISGSAGITKRTTRSAS
  RKSSVKSLSISRTKTVLR
• Function: Dual-specificity phosphatase involved in DNA damage response. Essential regulator of the G2 DNA damage checkpoint: following DNA damage, translocates to the nucleus and dephosphorylates FZR1/CDH1, a key activator of the anaphase promoting complex/cyclosome (APC/C). Dephosphorylates SIRT2 around early anaphase. Dephosphorylation of FZR1/CDH1 activates the APC/C, leading to the ubiquitination of PLK1, preventing entry into mitosis. Preferentially dephosphorylates proteins modified by proline-directed kinases.
• KEGG Pathway: Cell cycle (hsa04110)
• Reactome Pathway: MAPK6/MAPK4 signaling (R-HSA-5687128)

Molecular Interaction Atlas (MIA) of This DOT

7 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Adult glioblastoma	DISVP4LU	Strong	Biomarker	[1]
Astrocytoma	DISL3V18	Strong	Altered Expression	[1]
Clear cell renal carcinoma	DISBXRFJ	Strong	Altered Expression	[2]
Glioblastoma multiforme	DISK8246	Strong	Biomarker	[1]
Multiple self-healing squamous epithelioma	DISPYT7K	Strong	Genetic Variation	[3]
Neoplasm	DISZKGEW	Disputed	Biomarker	[4]
Thyroid gland papillary carcinoma	DIS48YMM	Disputed	Biomarker	[4]

21 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 Dual specificity protein phosphatase CDC14B (CDC14B).	[5]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Dual specificity protein phosphatase CDC14B (CDC14B).	[6]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Dual specificity protein phosphatase CDC14B (CDC14B).	[7]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Dual specificity protein phosphatase CDC14B (CDC14B).	[8]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Dual specificity protein phosphatase CDC14B (CDC14B).	[9]
Methotrexate	DM2TEOL	Approved	Methotrexate increases the expression of Dual specificity protein phosphatase CDC14B (CDC14B).	[11]
Marinol	DM70IK5	Approved	Marinol increases the expression of Dual specificity protein phosphatase CDC14B (CDC14B).	[12]
Selenium	DM25CGV	Approved	Selenium decreases the expression of Dual specificity protein phosphatase CDC14B (CDC14B).	[13]
Progesterone	DMUY35B	Approved	Progesterone increases the expression of Dual specificity protein phosphatase CDC14B (CDC14B).	[14]
Menadione	DMSJDTY	Approved	Menadione affects the expression of Dual specificity protein phosphatase CDC14B (CDC14B).	[15]
Isotretinoin	DM4QTBN	Approved	Isotretinoin increases the expression of Dual specificity protein phosphatase CDC14B (CDC14B).	[16]
Paclitaxel	DMLB81S	Approved	Paclitaxel decreases the expression of Dual specificity protein phosphatase CDC14B (CDC14B).	[17]
Melphalan	DMOLNHF	Approved	Melphalan decreases the expression of Dual specificity protein phosphatase CDC14B (CDC14B).	[18]
Dihydrotestosterone	DM3S8XC	Phase 4	Dihydrotestosterone increases the expression of Dual specificity protein phosphatase CDC14B (CDC14B).	[19]
Curcumin	DMQPH29	Phase 3	Curcumin increases the expression of Dual specificity protein phosphatase CDC14B (CDC14B).	[20]
Tocopherol	DMBIJZ6	Phase 2	Tocopherol decreases the expression of Dual specificity protein phosphatase CDC14B (CDC14B).	[13]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Dual specificity protein phosphatase CDC14B (CDC14B).	[21]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide increases the expression of Dual specificity protein phosphatase CDC14B (CDC14B).	[22]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Dual specificity protein phosphatase CDC14B (CDC14B).	[23]
Coumestrol	DM40TBU	Investigative	Coumestrol decreases the expression of Dual specificity protein phosphatase CDC14B (CDC14B).	[24]
GW-3965	DMG60ET	Investigative	GW-3965 decreases the expression of Dual specificity protein phosphatase CDC14B (CDC14B).	[25]

1 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 Dual specificity protein phosphatase CDC14B (CDC14B).	[10]

References

• [1] ADAR2-editing activity inhibits glioblastoma growth through the modulation of the CDC14B/Skp2/p21/p27 axis.Oncogene. 2013 Feb 21;32(8):998-1009. doi: 10.1038/onc.2012.125. Epub 2012 Apr 23.
• [2] Loss of CDC14B expression in clear cell renal cell carcinoma: meta-analysis of microarray data sets.Am J Clin Pathol. 2014 Apr;141(4):551-8. doi: 10.1309/AJCP4PE4JPSRGBQS.
• [3] The elusive multiple self-healing squamous epithelioma (MSSE) gene: further mapping, analysis of candidates, and loss of heterozygosity.Oncogene. 2006 Feb 2;25(5):806-12. doi: 10.1038/sj.onc.1209092.
• [4] Differences in the transcriptome of medullary thyroid cancer regarding the status and type of RET gene mutations.Sci Rep. 2017 Feb 9;7:42074. doi: 10.1038/srep42074.
• [5] 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.
• [6] Comparison of phenotypic and transcriptomic effects of false-positive genotoxins, true genotoxins and non-genotoxins using HepG2 cells. Mutagenesis. 2011 Sep;26(5):593-604.
• [7] Transcriptional and Metabolic Dissection of ATRA-Induced Granulocytic Differentiation in NB4 Acute Promyelocytic Leukemia Cells. Cells. 2020 Nov 5;9(11):2423. doi: 10.3390/cells9112423.
• [8] Multiple microRNAs function as self-protective modules in acetaminophen-induced hepatotoxicity in humans. Arch Toxicol. 2018 Feb;92(2):845-858.
• [9] 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.
• [10] 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.
• [11] Global molecular effects of tocilizumab therapy in rheumatoid arthritis synovium. Arthritis Rheumatol. 2014 Jan;66(1):15-23.
• [12] Delta9-tetrahydrocannabinol inhibits cytotrophoblast cell proliferation and modulates gene transcription. Mol Hum Reprod. 2006 May;12(5):321-33. doi: 10.1093/molehr/gal036. Epub 2006 Apr 5.
• [13] 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.
• [14] Progesterone regulation of implantation-related genes: new insights into the role of oestrogen. Cell Mol Life Sci. 2007 Apr;64(7-8):1009-32.
• [15] 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.
• [16] Temporal changes in gene expression in the skin of patients treated with isotretinoin provide insight into its mechanism of action. Dermatoendocrinol. 2009 May;1(3):177-87.
• [17] Marked regression of liver metastasis by combined therapy of ultrasound-mediated NF kappaB-decoy transfer and transportal injection of paclitaxel, in mouse. Int J Cancer. 2008 Apr 1;122(7):1645-56. doi: 10.1002/ijc.23280.
• [18] Bone marrow osteoblast damage by chemotherapeutic agents. PLoS One. 2012;7(2):e30758. doi: 10.1371/journal.pone.0030758. Epub 2012 Feb 17.
• [19] LSD1 activates a lethal prostate cancer gene network independently of its demethylase function. Proc Natl Acad Sci U S A. 2018 May 1;115(18):E4179-E4188.
• [20] Gene-expression profiling during curcumin-induced apoptosis reveals downregulation of CXCR4. Exp Hematol. 2007 Jan;35(1):84-95.
• [21] Identification of a transcriptomic signature of food-relevant genotoxins in human HepaRG hepatocarcinoma cells. Food Chem Toxicol. 2020 Jun;140:111297. doi: 10.1016/j.fct.2020.111297. Epub 2020 Mar 28.
• [22] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [23] 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.
• [24] Pleiotropic combinatorial transcriptomes of human breast cancer cells exposed to mixtures of dietary phytoestrogens. Food Chem Toxicol. 2009 Apr;47(4):787-95.
• [25] System analysis of cross-talk between nuclear receptors reveals an opposite regulation of the cell cycle by LXR and FXR in human HepaRG liver cells. PLoS One. 2019 Aug 22;14(8):e0220894. doi: 10.1371/journal.pone.0220894. eCollection 2019.