Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTD7CUG0)

• DOT Name: Recombining binding protein suppressor of hairless (RBPJ)
• Synonyms: CBF-1; J kappa-recombination signal-binding protein; RBP-J kappa; RBP-J; RBP-JK; Renal carcinoma antigen NY-REN-30
• Gene Name: RBPJ
• Related Disease:
  Adams-Oliver syndrome 3
  Adams-Oliver syndrome
• UniProt ID: SUH_HUMAN
• PDB ID: 2F8X; 3NBN; 3V79; 6PY8
• Pfam ID: PF09270 ; PF09271 ; PF20144
• Sequence:
  MDHTEGSPAEEPPAHAPSPGKFGERPPPKRLTREAMRNYLKERGDQTVLILHAKVAQKSY
  GNEKRFFCPPPCVYLMGSGWKKKKEQMERDGCSEQESQPCAFIGIGNSDQEMQQLNLEGK
  NYCTAKTLYISDSDKRKHFMLSVKMFYGNSDDIGVFLSKRIKVISKPSKKKQSLKNADLC
  IASGTKVALFNRLRSQTVSTRYLHVEGGNFHASSQQWGAFFIHLLDDDESEGEEFTVRDG
  YIHYGQTVKLVCSVTGMALPRLIIRKVDKQTALLDADDPVSQLHKCAFYLKDTERMYLCL
  SQERIIQFQATPCPKEPNKEMINDGASWTIISTDKAEYTFYEGMGPVLAPVTPVPVVESL
  QLNGGGDVAMLELTGQNFTPNLRVWFGDVEAETMYRCGESMLCVVPDISAFREGWRWVRQ
  PVQVPVTLVRNDGIIYSTSLTFTYTPEPGPRPHCSAAGAILRANSSQVPPNESNTNSEGS
  YTNASTNSTSVTSSTATVVS
• Function: Transcriptional regulator that plays a central role in Notch signaling, a signaling pathway involved in cell-cell communication that regulates a broad spectrum of cell-fate determinations. Acts as a transcriptional repressor when it is not associated with Notch proteins. When associated with some NICD product of Notch proteins (Notch intracellular domain), it acts as a transcriptional activator that activates transcription of Notch target genes. Probably represses or activates transcription via the recruitment of chromatin remodeling complexes containing histone deacetylase or histone acetylase proteins, respectively. Specifically binds to the immunoglobulin kappa-type J segment recombination signal sequence. Binds specifically to methylated DNA. Binds to the oxygen responsive element of COX4I2 and activates its transcription under hypoxia conditions (4% oxygen). Negatively regulates the phagocyte oxidative burst in response to bacterial infection by repressing transcription of NADPH oxidase subunits.
• KEGG Pathway:
  Notch sig.ling pathway (hsa04330)
  Th1 and Th2 cell differentiation (hsa04658)
  Spinocerebellar ataxia (hsa05017)
  Human papillomavirus infection (hsa05165)
  Epstein-Barr virus infection (hsa05169)
  Viral carcinogenesis (hsa05203)
• Reactome Pathway:
  Regulation of gene expression in late stage (branching morphogenesis) pancreatic bud precursor cells (R-HSA-210744)
  NOTCH1 Intracellular Domain Regulates Transcription (R-HSA-2122947)
  NOTCH2 intracellular domain regulates transcription (R-HSA-2197563)
  Constitutive Signaling by NOTCH1 PEST Domain Mutants (R-HSA-2644606)
  Constitutive Signaling by NOTCH1 HD+PEST Domain Mutants (R-HSA-2894862)
  Notch-HLH transcription pathway (R-HSA-350054)
  RUNX3 regulates NOTCH signaling (R-HSA-8941856)
  NOTCH3 Intracellular Domain Regulates Transcription (R-HSA-9013508)
  NOTCH4 Intracellular Domain Regulates Transcription (R-HSA-9013695)
  Formation of paraxial mesoderm (R-HSA-9793380)
  Somitogenesis (R-HSA-9824272)
  Pre-NOTCH Transcription and Translation (R-HSA-1912408)

Molecular Interaction Atlas (MIA) of This DOT

2 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Adams-Oliver syndrome 3	DIS0AM6V	Strong	Autosomal dominant	[1]
Adams-Oliver syndrome	DISQO525	Supportive	Autosomal dominant	[1]

14 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 Recombining binding protein suppressor of hairless (RBPJ).	[2]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Recombining binding protein suppressor of hairless (RBPJ).	[3]
Cisplatin	DMRHGI9	Approved	Cisplatin affects the expression of Recombining binding protein suppressor of hairless (RBPJ).	[4]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of Recombining binding protein suppressor of hairless (RBPJ).	[6]
Decitabine	DMQL8XJ	Approved	Decitabine affects the expression of Recombining binding protein suppressor of hairless (RBPJ).	[4]
Irinotecan	DMP6SC2	Approved	Irinotecan decreases the expression of Recombining binding protein suppressor of hairless (RBPJ).	[8]
Enzalutamide	DMGL19D	Approved	Enzalutamide affects the expression of Recombining binding protein suppressor of hairless (RBPJ).	[9]
Chloroquine	DMSI5CB	Phase 3 Trial	Chloroquine increases the expression of Recombining binding protein suppressor of hairless (RBPJ).	[10]
DNCB	DMDTVYC	Phase 2	DNCB decreases the expression of Recombining binding protein suppressor of hairless (RBPJ).	[11]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Recombining binding protein suppressor of hairless (RBPJ).	[13]
MG-132	DMKA2YS	Preclinical	MG-132 increases the expression of Recombining binding protein suppressor of hairless (RBPJ).	[10]
Glyphosate	DM0AFY7	Investigative	Glyphosate decreases the expression of Recombining binding protein suppressor of hairless (RBPJ).	[14]
Cycloheximide	DMGDA3C	Investigative	Cycloheximide decreases the expression of Recombining binding protein suppressor of hairless (RBPJ).	[10]
MG-101	DM3RUT8	Investigative	MG-101 increases the expression of Recombining binding protein suppressor of hairless (RBPJ).	[10]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Arsenic	DMTL2Y1	Approved	Arsenic increases the methylation of Recombining binding protein suppressor of hairless (RBPJ).	[5]
Fulvestrant	DM0YZC6	Approved	Fulvestrant increases the methylation of Recombining binding protein suppressor of hairless (RBPJ).	[7]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Recombining binding protein suppressor of hairless (RBPJ).	[12]

References

• [1] RBPJ mutations identified in two families affected by Adams-Oliver syndrome. Am J Hum Genet. 2012 Aug 10;91(2):391-5. doi: 10.1016/j.ajhg.2012.07.005.
• [2] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [3] 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.
• [4] Acute hypersensitivity of pluripotent testicular cancer-derived embryonal carcinoma to low-dose 5-aza deoxycytidine is associated with global DNA Damage-associated p53 activation, anti-pluripotency and DNA demethylation. PLoS One. 2012;7(12):e53003. doi: 10.1371/journal.pone.0053003. Epub 2012 Dec 27.
• [5] Epigenetic changes in individuals with arsenicosis. Chem Res Toxicol. 2011 Feb 18;24(2):165-7. doi: 10.1021/tx1004419. Epub 2011 Feb 4.
• [6] 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.
• [7] DNA methylome-wide alterations associated with estrogen receptor-dependent effects of bisphenols in breast cancer. Clin Epigenetics. 2019 Oct 10;11(1):138. doi: 10.1186/s13148-019-0725-y.
• [8] Clinical determinants of response to irinotecan-based therapy derived from cell line models. Clin Cancer Res. 2008 Oct 15;14(20):6647-55.
• [9] 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.
• [10] Presenilin-2 regulates the degradation of RBP-Jk protein through p38 mitogen-activated protein kinase. J Cell Sci. 2012 Mar 1;125(Pt 5):1296-308. doi: 10.1242/jcs.095984. Epub 2012 Feb 2.
• [11] Microarray analyses in dendritic cells reveal potential biomarkers for chemical-induced skin sensitization. Mol Immunol. 2007 May;44(12):3222-33.
• [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] 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.
• [14] Glyphosate-based herbicides at low doses affect canonical pathways in estrogen positive and negative breast cancer cell lines. PLoS One. 2019 Jul 11;14(7):e0219610. doi: 10.1371/journal.pone.0219610. eCollection 2019.