Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT7K7I8Q)

• DOT Name: NF-kappa-B-activating protein (NKAP)
• Gene Name: NKAP
• Related Disease:
  Breast cancer
  Breast carcinoma
  Ewing sarcoma
  Glioma
  Intellectual developmental disorder, X-linked, syndromic, Hackmann-Di Donato type
  Intellectual disability
  Neoplasm
  Colon cancer
  Colon carcinoma
  Hepatocellular carcinoma
  Rheumatoid arthritis
• UniProt ID: NKAP_HUMAN
• PDB ID: 6QDV; 7W5B; 8C6J
• Pfam ID: PF15692 ; PF06047
• Sequence:
  MAPVSGSRSPDREASGSGGRRRSSSKSPKPSKSARSPRGRRSRSHSCSRSGDRNGLTHQL
  GGLSQGSRNQSYRSRSRSRSRERPSAPRGIPFASASSSVYYGSYSRPYGSDKPWPSLLDK
  EREESLRQKRLSERERIGELGAPEVWGLSPKNPEPDSDEHTPVEDEEPKKSTTSASTSEE
  EKKKKSSRSKERSKKRRKKKSSKRKHKKYSEDSDSDSDSETDSSDEDNKRRAKKAKKKEK
  KKKHRSKKYKKKRSKKSRKESSDSSSKESQEEFLENPWKDRTKAEEPSDLIGPEAPKTLT
  SQDDKPLNYGHALLPGEGAAMAEYVKAGKRIPRRGEIGLTSEEIASFECSGYVMSGSRHR
  RMEAVRLRKENQIYSADEKRALASFNQEERRKRENKILASFREMVYRKTKGKDDK
• Function: Acts as a transcriptional repressor. Plays a role as a transcriptional corepressor of the Notch-mediated signaling required for T-cell development. Also involved in the TNF and IL-1 induced NF-kappa-B activation. Associates with chromatin at the Notch-regulated SKP2 promoter.
• Reactome Pathway: mRNA Splicing - Major Pathway (R-HSA-72163)

Molecular Interaction Atlas (MIA) of This DOT

11 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Breast cancer	DIS7DPX1	Strong	Altered Expression	[1]
Breast carcinoma	DIS2UE88	Strong	Altered Expression	[1]
Ewing sarcoma	DISQYLV3	Strong	Biomarker	[2]
Glioma	DIS5RPEH	Strong	Altered Expression	[3]
Intellectual developmental disorder, X-linked, syndromic, Hackmann-Di Donato type	DIS1DHP9	Strong	X-linked	[4]
Intellectual disability	DISMBNXP	Strong	Biomarker	[4]
Neoplasm	DISZKGEW	Strong	Biomarker	[3]
Colon cancer	DISVC52G	Limited	Biomarker	[5]
Colon carcinoma	DISJYKUO	Limited	Biomarker	[5]
Hepatocellular carcinoma	DIS0J828	Limited	Posttranslational Modification	[6]
Rheumatoid arthritis	DISTSB4J	Limited	Genetic Variation	[7]

3 Drug(s) Affected the Post-Translational Modifications of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the methylation of NF-kappa-B-activating protein (NKAP).	[8]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene affects the methylation of NF-kappa-B-activating protein (NKAP).	[12]
Coumarin	DM0N8ZM	Investigative	Coumarin affects the phosphorylation of NF-kappa-B-activating protein (NKAP).	[14]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of NF-kappa-B-activating protein (NKAP).	[9]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of NF-kappa-B-activating protein (NKAP).	[10]
Enzalutamide	DMGL19D	Approved	Enzalutamide affects the expression of NF-kappa-B-activating protein (NKAP).	[11]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A affects the expression of NF-kappa-B-activating protein (NKAP).	[13]

References

• [1] NKAP functions as an oncogene and its expression is induced by CoCl(2) treatment in breast cancer via AKT/mTOR signaling pathway.Cancer Manag Res. 2018 Oct 29;10:5091-5100. doi: 10.2147/CMAR.S178919. eCollection 2018.
• [2] NKAP functions as an oncogene in Ewing sarcoma cells partly through the AKT signaling pathway.Exp Ther Med. 2019 Oct;18(4):3037-3045. doi: 10.3892/etm.2019.7925. Epub 2019 Aug 20.
• [3] NKAP alters tumor immune microenvironment and promotes glioma growth via Notch1 signaling.J Exp Clin Cancer Res. 2019 Jul 6;38(1):291. doi: 10.1186/s13046-019-1281-1.
• [4] Missense Mutations in NKAP Cause a Disorder of Transcriptional Regulation Characterized by Marfanoid Habitus and Cognitive Impairment. Am J Hum Genet. 2019 Nov 7;105(5):987-995. doi: 10.1016/j.ajhg.2019.09.009. Epub 2019 Oct 3.
• [5] The oncogenic role of NKAP in the growth and invasion of colon cancer cells.Oncol Rep. 2019 Nov;42(5):2130-2138. doi: 10.3892/or.2019.7322. Epub 2019 Sep 18.
• [6] Hypermethylation of NF-B-Activating Protein-Like (NKAPL) Promoter in Hepatocellular Carcinoma Suppresses Its Expression and Predicts a Poor Prognosis.Dig Dis Sci. 2018 Mar;63(3):676-686. doi: 10.1007/s10620-018-4929-3. Epub 2018 Jan 20.
• [7] Identification of the NF-B activating protein-like locus as a risk locus for rheumatoid arthritis.Ann Rheum Dis. 2013 Jul;72(7):1249-54. doi: 10.1136/annrheumdis-2012-202076. Epub 2012 Dec 6.
• [8] 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.
• [9] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [10] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [11] NOTCH signaling is activated in and contributes to resistance in enzalutamide-resistant prostate cancer cells. J Biol Chem. 2019 May 24;294(21):8543-8554. doi: 10.1074/jbc.RA118.006983. Epub 2019 Apr 2.
• [12] 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.
• [13] Comprehensive analysis of transcriptomic changes induced by low and high doses of bisphenol A in HepG2 spheroids in vitro and rat liver in vivo. Environ Res. 2019 Jun;173:124-134. doi: 10.1016/j.envres.2019.03.035. Epub 2019 Mar 18.
• [14] 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.