Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTUVY0P6)

• DOT Name: NF-kappa-B-repressing factor (NKRF)
• Synonyms: NFkB-repressing factor; NRF; Protein ITBA4
• Gene Name: NKRF
• Related Disease:
  Tuberculosis
  Acute myocardial infarction
  Colonic neoplasm
  Hepatocellular carcinoma
  Neoplasm
  Osteoporosis
  Pancreatic cancer
  Relapsing-remitting multiple sclerosis
  Squamous cell carcinoma
  Stroke
• UniProt ID: NKRF_HUMAN
• PDB ID: 6SH6; 6SH7
• Pfam ID: PF01585 ; PF01424
• Sequence:
  MEKILQMAEGIDIGEMPSYDLVLSKPSKGQKRHLSTCDGQNPPKKQAGSKFHARPRFEPV
  HFVASSSKDERQEDPYGPQTKEVNEQTHFASMPRDIYQDYTQDSFSIQDGNSQYCDSSGF
  ILTKDQPVTANMYFDSGNPAPSTTSQQANSQSTPEPSPSQTFPESVVAEKQYFIEKLTAT
  IWKNLSNPEMTSGSDKINYTYMLTRCIQACKTNPEYIYAPLKEIPPADIPKNKKLLTDGY
  ACEVRCQNIYLTTGYAGSKNGSRDRATELAVKLLQKRIEVRVVRRKFKHTFGEDLVVCQI
  GMSSYEFPPALKPPEDLVVLGKDASGQPIFNASAKHWTNFVITENANDAIGILNNSASFN
  KMSIEYKYEMMPNRTWRCRVFLQDHCLAEGYGTKKTSKHAAADEALKILQKTQPTYPSVK
  SSQCHTGSSPRGSGKKKDIKDLVVYENSSNPVCTLNDTAQFNRMTVEYVYERMTGLRWKC
  KVILESEVIAEAVGVKKTVKYEAAGEAVKTLKKTQPTVINNLKKGAVEDVISRNEIQGRS
  AEEAYKQQIKEDNIGNQLLRKMGWTGGGLGKSGEGIREPISVKEQHKREGLGLDVERVNK
  IAKRDIEQIIRNYARSESHTDLTFSRELTNDERKQIHQIAQKYGLKSKSHGVGHDRYLVV
  GRKRRKEDLLDQLKQEGQVGHYELVMPQAN
• Function: Enhances the ATPase activity of DHX15 by acting like a brace that tethers mobile sections of DHX15 together, stabilizing a functional conformation with high RNA affinity of DHX15. Involved in the constitutive silencing of the interferon beta promoter, independently of the virus-induced signals, and in the inhibition of the basal and cytokine-induced iNOS promoter activity. Also involved in the regulation of IL-8 transcription. May also act as a DNA-binding transcription regulator: interacts with a specific negative regulatory element (NRE) 5'-AATTCCTCTGA-3' to mediate transcriptional repression of certain NK-kappa-B responsive genes.
• Tissue Specificity: Widely and constitutively expressed . Expressed at lower level in colon, peripheral blood lymphocytes, lung and kidney .

Molecular Interaction Atlas (MIA) of This DOT

10 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Tuberculosis	DIS2YIMD	Definitive	Altered Expression	[1]
Acute myocardial infarction	DISE3HTG	Strong	Biomarker	[2]
Colonic neoplasm	DISSZ04P	Strong	Altered Expression	[3]
Hepatocellular carcinoma	DIS0J828	Strong	Altered Expression	[4]
Neoplasm	DISZKGEW	Strong	Altered Expression	[5]
Osteoporosis	DISF2JE0	Strong	Biomarker	[6]
Pancreatic cancer	DISJC981	Strong	Altered Expression	[7]
Relapsing-remitting multiple sclerosis	DISSXFCF	Strong	Altered Expression	[8]
Squamous cell carcinoma	DISQVIFL	moderate	Altered Expression	[5]
Stroke	DISX6UHX	Limited	Biomarker	[9]

5 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-repressing factor (NKRF).	[10]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of NF-kappa-B-repressing factor (NKRF).	[15]
TAK-243	DM4GKV2	Phase 1	TAK-243 increases the sumoylation of NF-kappa-B-repressing factor (NKRF).	[16]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 affects the phosphorylation of NF-kappa-B-repressing factor (NKRF).	[17]
Coumarin	DM0N8ZM	Investigative	Coumarin decreases the phosphorylation of NF-kappa-B-repressing factor (NKRF).	[17]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of NF-kappa-B-repressing factor (NKRF).	[11]
Temozolomide	DMKECZD	Approved	Temozolomide increases the expression of NF-kappa-B-repressing factor (NKRF).	[12]
Zoledronate	DMIXC7G	Approved	Zoledronate decreases the expression of NF-kappa-B-repressing factor (NKRF).	[13]
Melphalan	DMOLNHF	Approved	Melphalan increases the expression of NF-kappa-B-repressing factor (NKRF).	[14]

References

• [1] NF-B repressing factor downregulates basal expression and mycobacterium tuberculosis induced IP-10 and IL-8 synthesis via interference with NF-B in monocytes.J Biomed Sci. 2014 Aug 19;21(1):71. doi: 10.1186/s12929-014-0071-5.
• [2] Inhibition of microRNA?24?p protects against acute myocardial infarction by suppressing the apoptosis of cardiomyocytes.Mol Med Rep. 2019 Oct;20(4):3379-3387. doi: 10.3892/mmr.2019.10565. Epub 2019 Aug 6.
• [3] Role of IKK and oscillatory NFkappaB kinetics in MMP-9 gene expression and chemoresistance to 5-fluorouracil in RKO colorectal cancer cells.Mol Carcinog. 2007 May;46(5):402-13. doi: 10.1002/mc.20288.
• [4] Abnormal expression of NRF-2 in hepatocellular carcinoma identified with a newly prepared monoclonal antibody against human NRF-2 protein.Mol Biol Rep. 2011 Jun;38(5):3083-8. doi: 10.1007/s11033-010-9976-6. Epub 2010 Feb 3.
• [5] NRF2 Pathway Activation and Adjuvant Chemotherapy Benefit in Lung Squamous Cell Carcinoma.Clin Cancer Res. 2015 Jun 1;21(11):2499-505. doi: 10.1158/1078-0432.CCR-14-2206. Epub 2015 Mar 4.
• [6] Plastin 3 influences bone homeostasis through regulation of osteoclast activity.Hum Mol Genet. 2018 Dec 15;27(24):4249-4262. doi: 10.1093/hmg/ddy318.
• [7] miR-301a as an NF-B activator in pancreatic cancer cells.EMBO J. 2011 Jan 5;30(1):57-67. doi: 10.1038/emboj.2010.296. Epub 2010 Nov 26.
• [8] Increased expression of mir-301a in PBMCs of patients with relapsing-remitting multiple sclerosis is associated with reduced NKRF and PIAS3 expression levels and disease activity.J Neuroimmunol. 2018 Dec 15;325:79-86. doi: 10.1016/j.jneuroim.2018.10.002. Epub 2018 Oct 4.
• [9] Clinical outcomes of stroke in hemodialysis patients: a retrospective single-center study.Int Urol Nephrol. 2019 Aug;51(8):1435-1441. doi: 10.1007/s11255-019-02218-x. Epub 2019 Jul 1.
• [10] 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.
• [11] 17-Estradiol Activates HSF1 via MAPK Signaling in ER-Positive Breast Cancer Cells. Cancers (Basel). 2019 Oct 11;11(10):1533. doi: 10.3390/cancers11101533.
• [12] Temozolomide induces activation of Wnt/-catenin signaling in glioma cells via PI3K/Akt pathway: implications in glioma therapy. Cell Biol Toxicol. 2020 Jun;36(3):273-278. doi: 10.1007/s10565-019-09502-7. Epub 2019 Nov 22.
• [13] The proapoptotic effect of zoledronic acid is independent of either the bone microenvironment or the intrinsic resistance to bortezomib of myeloma cells and is enhanced by the combination with arsenic trioxide. Exp Hematol. 2011 Jan;39(1):55-65.
• [14] Bone marrow osteoblast damage by chemotherapeutic agents. PLoS One. 2012;7(2):e30758. doi: 10.1371/journal.pone.0030758. Epub 2012 Feb 17.
• [15] 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.
• [16] 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.
• [17] 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.