Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT73KJ5P)

• DOT Name: DNA-binding protein RFX5 (RFX5)
• Synonyms: Regulatory factor X 5
• Gene Name: RFX5
• Related Disease:
  Advanced cancer
  MHC class II deficiency
  Arteriosclerosis
  Atherosclerosis
  Chromosomal disorder
  Non-small-cell lung cancer
  Hepatocellular carcinoma
  Neoplasm
  Colorectal carcinoma
• UniProt ID: RFX5_HUMAN
• PDB ID: 2KW3; 3V30
• Pfam ID: PF14621 ; PF18326 ; PF02257
• Sequence:
  MAEDEPDAKSPKTGGRAPPGGAEAGEPTTLLQRLRGTISKAVQNKVEGILQDVQKFSDND
  KLYLYLQLPSGPTTGDKSSEPSTLSNEEYMYAYRWIRNHLEEHTDTCLPKQSVYDAYRKY
  CESLACCRPLSTANFGKIIREIFPDIKARRLGGRGQSKYCYSGIRRKTLVSMPPLPGLDL
  KGSESPEMGPEVTPAPRDELVEAACALTCDWAERILKRSFSSIVEVARFLLQQHLISARS
  AHAHVLKAMGLAEEDEHAPRERSSKPKNGLENPEGGAHKKPERLAQPPKDLEARTGAGPL
  ARGERKKSVVESSAPGANNLQVNALVARLPLLLPRAPRSLIPPIPVSPPILAPRLSSGAL
  KVATLPLSSRAGAPPAAVPIINMILPTVPALPGPGPGPGRAPPGGLTQPRGTENREVGIG
  GDQGPHDKGVKRTAEVPVSEASGQAPPAKAAKQDIEDTASDAKRKRGRPRKKSGGSGERN
  STPLKSAAAMESAQSSRLPWETWGSGGEGNSAGGAERPGPMGEAEKGAVLAQGQGDGTVS
  KGGRGPGSQHTKEAEDKIPLVPSKVSVIKGSRSQKEAFPLAKGEVDTAPQGNKDLKEHVL
  QSSLSQEHKDPKATPP
• Function: Activates transcription from class II MHC promoters. Recognizes X-boxes. Mediates cooperative binding between RFX and NF-Y. RFX binds the X1 box of MHC-II promoters.
• Tissue Specificity: Ubiquitous.
• KEGG Pathway:
  Antigen processing and presentation (hsa04612)
  Tuberculosis (hsa05152)
  Primary immunodeficiency (hsa05340)

Molecular Interaction Atlas (MIA) of This DOT

9 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Advanced cancer	DISAT1Z9	Definitive	Altered Expression	[1]
MHC class II deficiency	DISWMI0G	Definitive	Autosomal recessive	[2]
Arteriosclerosis	DISK5QGC	Strong	Altered Expression	[3]
Atherosclerosis	DISMN9J3	Strong	Altered Expression	[3]
Chromosomal disorder	DISM5BB5	Strong	Genetic Variation	[4]
Non-small-cell lung cancer	DIS5Y6R9	Strong	Altered Expression	[5]
Hepatocellular carcinoma	DIS0J828	moderate	Biomarker	[1]
Neoplasm	DISZKGEW	moderate	Biomarker	[1]
Colorectal carcinoma	DIS5PYL0	Limited	Biomarker	[6]

This DOT Affected the Drug Response of 1 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Paclitaxel	DMLB81S	Approved	DNA-binding protein RFX5 (RFX5) decreases the response to substance of Paclitaxel.	[21]

13 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 DNA-binding protein RFX5 (RFX5).	[7]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of DNA-binding protein RFX5 (RFX5).	[8]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of DNA-binding protein RFX5 (RFX5).	[9]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of DNA-binding protein RFX5 (RFX5).	[10]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of DNA-binding protein RFX5 (RFX5).	[11]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of DNA-binding protein RFX5 (RFX5).	[12]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of DNA-binding protein RFX5 (RFX5).	[14]
Hydroquinone	DM6AVR4	Approved	Hydroquinone decreases the expression of DNA-binding protein RFX5 (RFX5).	[15]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide decreases the expression of DNA-binding protein RFX5 (RFX5).	[16]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of DNA-binding protein RFX5 (RFX5).	[17]
THAPSIGARGIN	DMDMQIE	Preclinical	THAPSIGARGIN decreases the expression of DNA-binding protein RFX5 (RFX5).	[18]
methyl p-hydroxybenzoate	DMO58UW	Investigative	methyl p-hydroxybenzoate decreases the expression of DNA-binding protein RFX5 (RFX5).	[19]
geraniol	DMS3CBD	Investigative	geraniol increases the expression of DNA-binding protein RFX5 (RFX5).	[20]

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 DNA-binding protein RFX5 (RFX5).	[13]

References

• [1] Regulatory factor X5 promotes hepatocellular carcinoma progression by transactivating tyrosine 3-monooxygenase/tryptophan 5-monooxygenase activation protein theta and suppressing apoptosis.Chin Med J (Engl). 2019 Jul 5;132(13):1572-1581. doi: 10.1097/CM9.0000000000000296.
• [2] Technical standards for the interpretation and reporting of constitutional copy-number variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics (ACMG) and the Clinical Genome Resource (ClinGen). Genet Med. 2020 Feb;22(2):245-257. doi: 10.1038/s41436-019-0686-8. Epub 2019 Nov 6.
• [3] Interferon-gamma induces major histocompatibility class II transactivator (CIITA), which mediates collagen repression and major histocompatibility class II activation by human aortic smooth muscle cells.Circ Res. 2006 Mar 3;98(4):472-9. doi: 10.1161/01.RES.0000204725.46332.97. Epub 2006 Jan 26.
• [4] Analysis of mutations and chromosomal localisation of the gene encoding RFX5, a novel transcription factor affected in major histocompatibility complex class II deficiency.Hum Mutat. 1997;10(6):430-5. doi: 10.1002/(SICI)1098-1004(1997)10:6<430::AID-HUMU3>3.0.CO;2-H.
• [5] MiR-4319 hinders YAP expression to restrain non-small cell lung cancer growth through regulation of LIN28-mediated RFX5 stability.Biomed Pharmacother. 2019 Jul;115:108956. doi: 10.1016/j.biopha.2019.108956. Epub 2019 May 14.
• [6] Lack of HLA class II antigen expression in microsatellite unstable colorectal carcinomas is caused by mutations in HLA class II regulatory genes.Int J Cancer. 2010 Aug 15;127(4):889-98. doi: 10.1002/ijc.25106.
• [7] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [8] Comparison of HepG2 and HepaRG by whole-genome gene expression analysis for the purpose of chemical hazard identification. Toxicol Sci. 2010 May;115(1):66-79.
• [9] Gene expression analysis of precision-cut human liver slices indicates stable expression of ADME-Tox related genes. Toxicol Appl Pharmacol. 2011 May 15;253(1):57-69.
• [10] 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.
• [11] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [12] 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.
• [13] 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.
• [14] 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.
• [15] Keratinocyte-derived IL-36gama plays a role in hydroquinone-induced chemical leukoderma through inhibition of melanogenesis in human epidermal melanocytes. Arch Toxicol. 2019 Aug;93(8):2307-2320.
• [16] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [17] 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.
• [18] Endoplasmic reticulum stress impairs insulin signaling through mitochondrial damage in SH-SY5Y cells. Neurosignals. 2012;20(4):265-80.
• [19] Transcriptome dynamics of alternative splicing events revealed early phase of apoptosis induced by methylparaben in H1299 human lung carcinoma cells. Arch Toxicol. 2020 Jan;94(1):127-140. doi: 10.1007/s00204-019-02629-w. Epub 2019 Nov 20.
• [20] Geraniol suppresses prostate cancer growth through down-regulation of E2F8. Cancer Med. 2016 Oct;5(10):2899-2908.
• [21] cDNA microarray analysis of isogenic paclitaxel- and doxorubicin-resistant breast tumor cell lines reveals distinct drug-specific genetic signatures of resistance. Breast Cancer Res Treat. 2006 Mar;96(1):17-39. doi: 10.1007/s10549-005-9026-6. Epub 2005 Dec 2.