Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTJL128N)

• DOT Name: Transcriptional repressor p66-beta (GATAD2B)
• Synonyms: GATA zinc finger domain-containing protein 2B; p66/p68
• Gene Name: GATAD2B
• Related Disease:
  Severe intellectual disability-poor language-strabismus-grimacing face-long fingers syndrome
  Adrenal cortex neoplasm
  Advanced cancer
  Autoimmune disease
  Cervical cancer
  Cervical carcinoma
  Craniosynostosis
  Head-neck squamous cell carcinoma
  Influenza
  Lung cancer
  Lung carcinoma
  Myopathy
  Neurodevelopmental disorder
  Prostate cancer
  Prostate carcinoma
  Intellectual disability
  Movement disorder
  Breast cancer
  Breast carcinoma
  Breast neoplasm
  Castration-resistant prostate carcinoma
  Colon cancer
  Colon carcinoma
  Invasive ductal breast carcinoma
  Kleefstra syndrome
  Kleefstra syndrome 1
  Megalencephaly
• UniProt ID: P66B_HUMAN
• Pfam ID: PF00320 ; PF16563
• Sequence:
  MDRMTEDALRLNLLKRSLDPADERDDVLAKRLKMEGHEAMERLKMLALLKRKDLANLEVP
  HELPTKQDGSGVKGYEEKLNGNLRPHGDNRTAGRPGKENINDEPVDMSARRSEPERGRLT
  PSPDIIVLSDNEASSPRSSSRMEERLKAANLEMFKGKGIEERQQLIKQLRDELRLEEARL
  VLLKKLRQSQLQKENVVQKTPVVQNAASIVQPSPAHVGQQGLSKLPSRPGAQGVEPQNLR
  TLQGHSVIRSATNTTLPHMLMSQRVIAPNPAQLQGQRGPPKPGLVRTTTPNMNPAINYQP
  QSSSSVPCQRTTSSAIYMNLASHIQPGTVNRVSSPLPSPSAMTDAANSQAAAKLALRKQL
  EKTLLEIPPPKPPAPLLHFLPSAANSEFIYMVGLEEVVQSVIDSQGKSCASLLRVEPFVC
  AQCRTDFTPHWKQEKNGKILCEQCMTSNQKKALKAEHTNRLKNAFVKALQQEQEIEQRLQ
  QQAALSPTTAPAVSSVSKQETIMRHHTLRQAPQPQSSLQRGIPTSARSMLSNFAQAPQLS
  VPGGLLGMPGVNIAYLNTGIGGHKGPSLADRQREYLLDMIPPRSISQSISGQK
• Function: Transcriptional repressor. Acts as a component of the histone deacetylase NuRD complex which participates in the remodeling of chromatin. Enhances MBD2-mediated repression. Efficient repression requires the presence of GATAD2A. Targets MBD3 to discrete loci in the nucleus. May play a role in synapse development.
• Tissue Specificity: Widely expressed.
• KEGG Pathway: ATP-dependent chromatin remodeling (hsa03082)
• Reactome Pathway:
  ERCC6 (CSB) and EHMT2 (G9a) positively regulate rRNA expression (R-HSA-427389)
  Regulation of TP53 Activity through Acetylation (R-HSA-6804758)
  RNA Polymerase I Transcription Initiation (R-HSA-73762)
  Regulation of PTEN gene transcription (R-HSA-8943724)
  Potential therapeutics for SARS (R-HSA-9679191)
  HDACs deacetylate histones (R-HSA-3214815)

Molecular Interaction Atlas (MIA) of This DOT

27 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Severe intellectual disability-poor language-strabismus-grimacing face-long fingers syndrome	DISLB21H	Definitive	Autosomal dominant	[1]
Adrenal cortex neoplasm	DISO17X1	Strong	Altered Expression	[2]
Advanced cancer	DISAT1Z9	Strong	Altered Expression	[3]
Autoimmune disease	DISORMTM	Strong	Altered Expression	[4]
Cervical cancer	DISFSHPF	Strong	Biomarker	[5]
Cervical carcinoma	DIST4S00	Strong	Biomarker	[5]
Craniosynostosis	DIS6J405	Strong	Biomarker	[6]
Head-neck squamous cell carcinoma	DISF7P24	Strong	Altered Expression	[7]
Influenza	DIS3PNU3	Strong	Biomarker	[8]
Lung cancer	DISCM4YA	Strong	Altered Expression	[9]
Lung carcinoma	DISTR26C	Strong	Altered Expression	[9]
Myopathy	DISOWG27	Strong	Biomarker	[10]
Neurodevelopmental disorder	DIS372XH	Strong	Biomarker	[11]
Prostate cancer	DISF190Y	Strong	Biomarker	[12]
Prostate carcinoma	DISMJPLE	Strong	Biomarker	[12]
Intellectual disability	DISMBNXP	moderate	Biomarker	[11]
Movement disorder	DISOJJ2D	moderate	CausalMutation	[13]
Breast cancer	DIS7DPX1	Limited	Biomarker	[3]
Breast carcinoma	DIS2UE88	Limited	Biomarker	[3]
Breast neoplasm	DISNGJLM	Limited	Biomarker	[14]
Castration-resistant prostate carcinoma	DISVGAE6	Limited	Altered Expression	[12]
Colon cancer	DISVC52G	Limited	Altered Expression	[15]
Colon carcinoma	DISJYKUO	Limited	Biomarker	[15]
Invasive ductal breast carcinoma	DIS43J58	Limited	Altered Expression	[16]
Kleefstra syndrome	DISHH9SN	Limited	Biomarker	[17]
Kleefstra syndrome 1	DISNODDM	Limited	Biomarker	[17]
Megalencephaly	DISYW5SV	Limited	Biomarker	[11]

8 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 Transcriptional repressor p66-beta (GATAD2B).	[18]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Transcriptional repressor p66-beta (GATAD2B).	[19]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Transcriptional repressor p66-beta (GATAD2B).	[20]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Transcriptional repressor p66-beta (GATAD2B).	[21]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Transcriptional repressor p66-beta (GATAD2B).	[22]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of Transcriptional repressor p66-beta (GATAD2B).	[23]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of Transcriptional repressor p66-beta (GATAD2B).	[24]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of Transcriptional repressor p66-beta (GATAD2B).	[28]

3 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 decreases the methylation of Transcriptional repressor p66-beta (GATAD2B).	[25]
TAK-243	DM4GKV2	Phase 1	TAK-243 affects the sumoylation of Transcriptional repressor p66-beta (GATAD2B).	[26]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 affects the phosphorylation of Transcriptional repressor p66-beta (GATAD2B).	[27]

References

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• [2] Amplification of the transketolase gene in desensitization-resistant mutant Y1 mouse adrenocortical tumor cells.J Biol Chem. 1996 Mar 1;271(9):4993-8. doi: 10.1074/jbc.271.9.4993.
• [3] The role of DEAD-box RNA helicase p68 (DDX5) in the development and treatment of breast cancer.J Cell Physiol. 2019 May;234(5):5478-5487. doi: 10.1002/jcp.26912. Epub 2018 Nov 11.
• [4] Major autoantigenic sites of the (U1) small nuclear ribonucleoprotein-specific 68-kDa protein.Scand J Immunol. 1990 Aug;32(2):163-76. doi: 10.1111/j.1365-3083.1990.tb02906.x.
• [5] p68 prompts the epithelial-mesenchymal transition in cervical cancer cells by transcriptionally activating the TGF-1 signaling pathway.Oncol Lett. 2018 Feb;15(2):2111-2116. doi: 10.3892/ol.2017.7552. Epub 2017 Dec 8.
• [6] Long-Term Safety of Topical Bacteriophage Application to the Frontal Sinus Region.Front Cell Infect Microbiol. 2017 Feb 24;7:49. doi: 10.3389/fcimb.2017.00049. eCollection 2017.
• [7] Overexpression of p68 mRNA in head and neck squamous cell carcinoma cells.Anticancer Res. 2006 May-Jun;26(3A):1941-6.
• [8] Purification and partial characterization of a cellular inhibitor of the interferon-induced protein kinase of Mr 68,000 from influenza virus-infected cells.Proc Natl Acad Sci U S A. 1990 Aug;87(16):6208-12. doi: 10.1073/pnas.87.16.6208.
• [9] In vivo screening identifies GATAD2B as a metastasis driver in KRAS-driven lung cancer.Nat Commun. 2018 Jul 16;9(1):2732. doi: 10.1038/s41467-018-04572-3.
• [10] Reduction of toxic RNAs in myotonic dystrophies type 1 and type 2 by the RNA helicase p68/DDX5.Proc Natl Acad Sci U S A. 2015 Jun 30;112(26):8041-5. doi: 10.1073/pnas.1422273112. Epub 2015 Jun 15.
• [11] The NuRD complex and macrocephaly associated neurodevelopmental disorders.Am J Med Genet C Semin Med Genet. 2019 Dec;181(4):548-556. doi: 10.1002/ajmg.c.31752. Epub 2019 Nov 18.
• [12] p68/DdX5 supports -catenin & RNAP II during androgen receptor mediated transcription in prostate cancer.PLoS One. 2013;8(1):e54150. doi: 10.1371/journal.pone.0054150. Epub 2013 Jan 17.
• [13] Outcome of Whole Exome Sequencing for Diagnostic Odyssey Cases of an Individualized Medicine Clinic: The Mayo Clinic Experience.Mayo Clin Proc. 2016 Mar;91(3):297-307. doi: 10.1016/j.mayocp.2015.12.018.
• [14] DEAD-box protein p68 is regulated by -catenin/transcription factor 4 to maintain a positive feedback loop in control of breast cancer progression.Breast Cancer Res. 2014 Dec 12;16(6):496. doi: 10.1186/s13058-014-0496-5.
• [15] The DEAD box protein p68: a novel coactivator of Stat3 in mediating oncogenesis.Oncogene. 2017 Jun 1;36(22):3080-3093. doi: 10.1038/onc.2016.449. Epub 2016 Dec 12.
• [16] Expression of the double-stranded RNA-dependent protein kinase (p68) in human breast tissues.Tumour Biol. 1996;17(1):5-12. doi: 10.1159/000217961.
• [17] Adaptive and maladaptive functioning in Kleefstra syndrome compared to other rare genetic disorders with intellectual disabilities.Am J Med Genet A. 2017 Jul;173(7):1821-1830. doi: 10.1002/ajmg.a.38280. Epub 2017 May 12.
• [18] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [19] Predictive toxicology using systemic biology and liver microfluidic "on chip" approaches: application to acetaminophen injury. Toxicol Appl Pharmacol. 2012 Mar 15;259(3):270-80.
• [20] 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.
• [21] Low doses of cisplatin induce gene alterations, cell cycle arrest, and apoptosis in human promyelocytic leukemia cells. Biomark Insights. 2016 Aug 24;11:113-21.
• [22] 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.
• [23] Gene Expression Regulation and Pathway Analysis After Valproic Acid and Carbamazepine Exposure in a Human Embryonic Stem Cell-Based Neurodevelopmental Toxicity Assay. Toxicol Sci. 2015 Aug;146(2):311-20. doi: 10.1093/toxsci/kfv094. Epub 2015 May 15.
• [24] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [25] 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.
• [26] 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.
• [27] 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.
• [28] 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.