Details of Drug Off-Target (DOT)

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

• DOT Name: Amyloid beta precursor protein binding family B member 1 (APBB1)
• Synonyms: Amyloid-beta A4 precursor protein-binding family B member 1; Protein Fe65
• Gene Name: APBB1
• Related Disease:
  High blood pressure
  Metabolic disorder
  Advanced cancer
  Familial Alzheimer disease
  Growth delay due to insulin-like growth factor I resistance
  Immunodeficiency
  Myositis disease
  Progressive multifocal leukoencephalopathy
  Breast cancer
  Breast carcinoma
  Neuroblastoma
  Nicotine dependence
  Parkinson disease
• UniProt ID: APBB1_HUMAN
• PDB ID: 2E45; 2HO2; 2IDH; 2OEI; 3D8D; 3D8E; 3D8F; 3DXC; 3DXD; 3DXE; 5NQH
• Pfam ID: PF00640 ; PF00397
• Sequence:
  MSVPSSLSQSAINANSHGGPALSLPLPLHAAHNQLLNAKLQATAVGPKDLRSAMGEGGGP
  EPGPANAKWLKEGQNQLRRAATAHRDQNRNVTLTLAEEASQEPEMAPLGPKGLIHLYSEL
  ELSAHNAANRGLRGPGLIISTQEQGPDEGEEKAAGEAEEEEEDDDDEEEEEDLSSPPGLP
  EPLESVEAPPRPQALTDGPREHSKSASLLFGMRNSAASDEDSSWATLSQGSPSYGSPEDT
  DSFWNPNAFETDSDLPAGWMRVQDTSGTYYWHIPTGTTQWEPPGRASPSQGSSPQEESQL
  TWTGFAHGEGFEDGEFWKDEPSDEAPMELGLKEPEEGTLTFPAQSLSPEPLPQEEEKLPP
  RNTNPGIKCFAVRSLGWVEMTEEELAPGRSSVAVNNCIRQLSYHKNNLHDPMSGGWGEGK
  DLLLQLEDETLKLVEPQSQALLHAQPIISIRVWGVGRDSGRERDFAYVARDKLTQMLKCH
  VFRCEAPAKNIATSLHEICSKIMAERRNARCLVNGLSLDHSKLVDVPFQVEFPAPKNELV
  QKFQVYYLGNVPVAKPVGVDVINGALESVLSSSSREQWTPSHVSVAPATLTILHQQTEAV
  LGECRVRFLSFLAVGRDVHTFAFIMAAGPASFCCHMFWCEPNAASLSEAVQAACMLRYQK
  CLDARSQASTSCLPAPPAESVARRVGWTVRRGVQSLWGSLKPKRLGAHTP
• Function: Transcription coregulator that can have both coactivator and corepressor functions. Adapter protein that forms a transcriptionally active complex with the gamma-secretase-derived amyloid precursor protein (APP) intracellular domain. Plays a central role in the response to DNA damage by translocating to the nucleus and inducing apoptosis. May act by specifically recognizing and binding histone H2AX phosphorylated on 'Tyr-142' (H2AXY142ph) at double-strand breaks (DSBs), recruiting other pro-apoptosis factors such as MAPK8/JNK1. Required for histone H4 acetylation at double-strand breaks (DSBs). Its ability to specifically bind modified histones and chromatin modifying enzymes such as KAT5/TIP60, probably explains its transcription activation activity. Functions in association with TSHZ3, SET and HDAC factors as a transcriptional repressor, that inhibits the expression of CASP4. Associates with chromatin in a region surrounding the CASP4 transcriptional start site(s). Involved in hippocampal neurite branching and neuromuscular junction formation, as a result plays a role in spatial memory functioning. Plays a role in the maintenance of lens transparency. May play a role in muscle cell strength. Acts as a molecular adapter that functions in neurite outgrowth by activating the RAC1-ARF6 axis upon insulin treatment.
• Tissue Specificity: Highly expressed in brain; strongly reduced in post-mortem elderly subjects with Alzheimer disease.; [Isoform 4]: Expressed preferentially in the brain.
• KEGG Pathway: Alzheimer disease (hsa05010)
• Reactome Pathway: Recruitment and ATM-mediated phosphorylation of repair and signaling proteins at DNA double strand breaks (R-HSA-5693565)

Molecular Interaction Atlas (MIA) of This DOT

13 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
High blood pressure	DISY2OHH	Definitive	Biomarker	[1]
Metabolic disorder	DIS71G5H	Definitive	Biomarker	[1]
Advanced cancer	DISAT1Z9	Strong	Biomarker	[2]
Familial Alzheimer disease	DISE75U4	Strong	Biomarker	[3]
Growth delay due to insulin-like growth factor I resistance	DISWL710	Strong	Biomarker	[2]
Immunodeficiency	DIS093I0	Strong	Biomarker	[4]
Myositis disease	DISCIXF0	Strong	Biomarker	[5]
Progressive multifocal leukoencephalopathy	DISX02WS	Strong	Biomarker	[6]
Breast cancer	DIS7DPX1	moderate	Biomarker	[7]
Breast carcinoma	DIS2UE88	moderate	Biomarker	[7]
Neuroblastoma	DISVZBI4	Limited	Altered Expression	[8]
Nicotine dependence	DISZD9W7	Limited	Biomarker	[9]
Parkinson disease	DISQVHKL	Limited	Biomarker	[9]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Doxorubicin	DMVP5YE	Approved	Doxorubicin increases the expression of Amyloid beta precursor protein binding family B member 1 (APBB1).	[10]
Arsenic	DMTL2Y1	Approved	Arsenic affects the expression of Amyloid beta precursor protein binding family B member 1 (APBB1).	[11]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide decreases the expression of Amyloid beta precursor protein binding family B member 1 (APBB1).	[12]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of Amyloid beta precursor protein binding family B member 1 (APBB1).	[13]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide decreases the expression of Amyloid beta precursor protein binding family B member 1 (APBB1).	[15]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Amyloid beta precursor protein binding family B member 1 (APBB1).	[16]

2 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 increases the methylation of Amyloid beta precursor protein binding family B member 1 (APBB1).	[14]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the methylation of Amyloid beta precursor protein binding family B member 1 (APBB1).	[17]

References

• [1] A W-test collapsing method for rare-variant association testing in exome sequencing data.Genet Epidemiol. 2016 Nov;40(7):591-596. doi: 10.1002/gepi.22000. Epub 2016 Aug 16.
• [2] APBB1 reinforces cancer stem cell and epithelial-to-mesenchymal transition by regulating the IGF1R signaling pathway in non-small-cell lung cancer cells.Biochem Biophys Res Commun. 2017 Jan 1;482(1):35-42. doi: 10.1016/j.bbrc.2016.11.030. Epub 2016 Nov 9.
• [3] Interaction of the phosphotyrosine interaction/phosphotyrosine binding-related domains of Fe65 with wild-type and mutant Alzheimer's beta-amyloid precursor proteins.J Biol Chem. 1997 Mar 7;272(10):6399-405. doi: 10.1074/jbc.272.10.6399.
• [4] A rat brain mRNA encoding a transcriptional activator homologous to the DNA binding domain of retroviral integrases.Nucleic Acids Res. 1991 Oct 11;19(19):5269-74. doi: 10.1093/nar/19.19.5269.
• [5] Proposed pathogenetic cascade of inclusion-body myositis: importance of amyloid-beta, misfolded proteins, predisposing genes, and aging.Curr Opin Rheumatol. 2003 Nov;15(6):737-44. doi: 10.1097/00002281-200311000-00009.
• [6] Critical role of presenilin-dependent -secretase activity in DNA damage-induced promyelocytic leukemia protein expression and apoptosis.Cell Death Differ. 2013 Apr;20(4):639-48. doi: 10.1038/cdd.2012.162. Epub 2013 Jan 11.
• [7] Fe65 Suppresses Breast Cancer Cell Migration and Invasion through Tip60 Mediated Cortactin Acetylation.Sci Rep. 2015 Jul 13;5:11529. doi: 10.1038/srep11529.
• [8] Nuclear localization of amyloid- precursor protein-binding protein Fe65 is dependent on regulated intramembrane proteolysis.PLoS One. 2017 Mar 21;12(3):e0173888. doi: 10.1371/journal.pone.0173888. eCollection 2017.
• [9] Association of amyloid precursor protein-binding protein, family B, member 1 with nicotine dependence in African and European American smokers.Hum Genet. 2008 Nov;124(4):393-8. doi: 10.1007/s00439-008-0558-9. Epub 2008 Sep 7.
• [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] Drinking-water arsenic exposure modulates gene expression in human lymphocytes from a U.S. population. Environ Health Perspect. 2008 Apr;116(4):524-31. doi: 10.1289/ehp.10861.
• [12] Global effects of inorganic arsenic on gene expression profile in human macrophages. Mol Immunol. 2009 Feb;46(4):649-56.
• [13] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [14] 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.
• [15] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [16] 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.
• [17] 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.