Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTLNFV4J)

• DOT Name: Amyloid protein-binding protein 2 (APPBP2)
• Synonyms: Amyloid beta precursor protein-binding protein 2; APP-BP2; Protein interacting with APP tail 1
• Gene Name: APPBP2
• Related Disease:
  Breast cancer
  Breast carcinoma
  Inflammatory bowel disease
  Lung adenocarcinoma
  Lung cancer
  Lung carcinoma
  Non-small-cell lung cancer
  Primary hyperoxaluria type 1
  Prostate cancer
  Prostate carcinoma
  Prostate neoplasm
  Clear cell adenocarcinoma
  High blood pressure
  Neoplasm
• UniProt ID: APBP2_HUMAN
• PDB ID: 8JAL; 8JAQ; 8JAR; 8JAS; 8JAU; 8JAV
• Pfam ID: PF13374 ; PF13424
• Sequence:
  MAAVELEWIPETLYNTAISAVVDNYIRSRRDIRSLPENIQFDVYYKLYQQGRLCQLGSEF
  CELEVFAKVLRALDKRHLLHHCFQALMDHGVKVASVLAYSFSRRCSYIAESDAAVKEKAI
  QVGFVLGGFLSDAGWYSDAEKVFLSCLQLCTLHDEMLHWFRAVECCVRLLHVRNGNCKYH
  LGEETFKLAQTYMDKLSKHGQQANKAALYGELCALLFAKSHYDEAYKWCIEAMKEITAGL
  PVKVVVDVLRQASKACVVKREFKKAEQLIKHAVYLARDHFGSKHPKYSDTLLDYGFYLLN
  VDNICQSVAIYQAALDIRQSVFGGKNIHVATAHEDLAYSSYVHQYSSGKFDNALFHAERA
  IGIITHILPEDHLLLASSKRVKALILEEIAIDCHNKETEQRLLQEAHDLHLSSLQLAKKA
  FGEFNVQTAKHYGNLGRLYQSMRKFKEAEEMHIKAIQIKEQLLGQEDYEVALSVGHLASL
  YNYDMNQYENAEKLYLRSIAIGKKLFGEGYSGLEYDYRGLIKLYNSIGNYEKVFEYHNVL
  SNWNRLRDRQYSVTDALEDVSTSPQSTEEVVQSFLISQNVEGPSC
• Function: Substrate-recognition component of a Cul2-RING (CRL2) E3 ubiquitin-protein ligase complex of the DesCEND (destruction via C-end degrons) pathway, which recognizes a C-degron located at the extreme C terminus of target proteins, leading to their ubiquitination and degradation. The C-degron recognized by the DesCEND pathway is usually a motif of less than ten residues and can be present in full-length proteins, truncated proteins or proteolytically cleaved forms. The CRL2(APPBP2) complex specifically recognizes proteins with a -Arg-Xaa-Xaa-Gly degron at the C-terminus, leading to their ubiquitination and degradation. The CRL2(APPBP2) complex mediates ubiquitination and degradation of truncated SELENOV selenoproteins produced by failed UGA/Sec decoding, which end with a -Arg-Xaa-Xaa-Gly degron. May play a role in intracellular protein transport: may be involved in the translocation of APP along microtubules toward the cell surface.

Molecular Interaction Atlas (MIA) of This DOT

14 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Breast cancer	DIS7DPX1	Strong	Biomarker	[1]
Breast carcinoma	DIS2UE88	Strong	Biomarker	[1]
Inflammatory bowel disease	DISGN23E	Strong	Altered Expression	[2]
Lung adenocarcinoma	DISD51WR	Strong	Biomarker	[3]
Lung cancer	DISCM4YA	Strong	Biomarker	[3]
Lung carcinoma	DISTR26C	Strong	Biomarker	[3]
Non-small-cell lung cancer	DIS5Y6R9	Strong	Altered Expression	[3]
Primary hyperoxaluria type 1	DISS210K	Strong	Biomarker	[4]
Prostate cancer	DISF190Y	Strong	Genetic Variation	[5]
Prostate carcinoma	DISMJPLE	Strong	Genetic Variation	[5]
Prostate neoplasm	DISHDKGQ	Strong	Altered Expression	[6]
Clear cell adenocarcinoma	DISYUGHZ	Limited	Altered Expression	[7]
High blood pressure	DISY2OHH	Limited	Biomarker	[8]
Neoplasm	DISZKGEW	Limited	Biomarker	[7]

15 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 Amyloid protein-binding protein 2 (APPBP2).	[9]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Amyloid protein-binding protein 2 (APPBP2).	[10]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Amyloid protein-binding protein 2 (APPBP2).	[11]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Amyloid protein-binding protein 2 (APPBP2).	[12]
Calcitriol	DM8ZVJ7	Approved	Calcitriol increases the expression of Amyloid protein-binding protein 2 (APPBP2).	[13]
Testosterone	DM7HUNW	Approved	Testosterone increases the expression of Amyloid protein-binding protein 2 (APPBP2).	[13]
Dihydrotestosterone	DM3S8XC	Phase 4	Dihydrotestosterone increases the expression of Amyloid protein-binding protein 2 (APPBP2).	[14]
Tocopherol	DMBIJZ6	Phase 2	Tocopherol increases the expression of Amyloid protein-binding protein 2 (APPBP2).	[15]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Amyloid protein-binding protein 2 (APPBP2).	[16]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Amyloid protein-binding protein 2 (APPBP2).	[17]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of Amyloid protein-binding protein 2 (APPBP2).	[18]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of Amyloid protein-binding protein 2 (APPBP2).	[19]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of Amyloid protein-binding protein 2 (APPBP2).	[20]
[3H]methyltrienolone	DMTSGOW	Investigative	[3H]methyltrienolone increases the expression of Amyloid protein-binding protein 2 (APPBP2).	[21]
Forskolin	DM6ITNG	Investigative	Forskolin decreases the expression of Amyloid protein-binding protein 2 (APPBP2).	[21]

References

• [1] 17q23 amplifications in breast cancer involve the PAT1, RAD51C, PS6K, and SIGma1B genes.Cancer Res. 2000 Oct 1;60(19):5371-5.
• [2] Adenosinergic signaling inhibits oxalate transport by human intestinal Caco2-BBE cells through the A(2B) adenosine receptor.Am J Physiol Cell Physiol. 2018 Nov 1;315(5):C687-C698. doi: 10.1152/ajpcell.00024.2017. Epub 2018 Jul 18.
• [3] APPBP2 enhances non-small cell lung cancer proliferation and invasiveness through regulating PPM1D and SPOP.EBioMedicine. 2019 Jun;44:138-149. doi: 10.1016/j.ebiom.2019.05.028. Epub 2019 May 16.
• [4] Induction of enteric oxalate secretion by Oxalobacter formigenes in mice does not require the presence of either apical oxalate transport proteins Slc26A3 or Slc26A6.Urolithiasis. 2020 Feb;48(1):1-8. doi: 10.1007/s00240-019-01144-y. Epub 2019 Jun 14.
• [5] Polymorphisms in XPC gene and risk for prostate cancer.Mol Biol Rep. 2019 Feb;46(1):1117-1125. doi: 10.1007/s11033-018-4572-2. Epub 2018 Dec 14.
• [6] An infectious retrovirus susceptible to an IFN antiviral pathway from human prostate tumors.Proc Natl Acad Sci U S A. 2007 Jan 30;104(5):1655-60. doi: 10.1073/pnas.0610291104. Epub 2007 Jan 18.
• [7] Association of 17q21-q24 gain in ovarian clear cell adenocarcinomas with poor prognosis and identification of PPM1D and APPBP2 as likely amplification targets.Clin Cancer Res. 2003 Jun;9(6):1995-2004.
• [8] Dietary fructose, salt absorption and hypertension in metabolic syndrome: towards a new paradigm.Acta Physiol (Oxf). 2011 Jan;201(1):55-62. doi: 10.1111/j.1748-1716.2010.02167.x.
• [9] Stem cell transcriptome responses and corresponding biomarkers that indicate the transition from adaptive responses to cytotoxicity. Chem Res Toxicol. 2017 Apr 17;30(4):905-922.
• [10] 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.
• [11] 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.
• [12] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [13] Effects of 1alpha,25 dihydroxyvitamin D3 and testosterone on miRNA and mRNA expression in LNCaP cells. Mol Cancer. 2011 May 18;10:58.
• [14] LSD1 activates a lethal prostate cancer gene network independently of its demethylase function. Proc Natl Acad Sci U S A. 2018 May 1;115(18):E4179-E4188.
• [15] Selenium and vitamin E: cell type- and intervention-specific tissue effects in prostate cancer. J Natl Cancer Inst. 2009 Mar 4;101(5):306-20.
• [16] New insights into BaP-induced toxicity: role of major metabolites in transcriptomics and contribution to hepatocarcinogenesis. Arch Toxicol. 2016 Jun;90(6):1449-58.
• [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] Bisphenol A induces DSB-ATM-p53 signaling leading to cell cycle arrest, senescence, autophagy, stress response, and estrogen release in human fetal lung fibroblasts. Arch Toxicol. 2018 Apr;92(4):1453-1469.
• [19] From transient transcriptome responses to disturbed neurodevelopment: role of histone acetylation and methylation as epigenetic switch between reversible and irreversible drug effects. Arch Toxicol. 2014 Jul;88(7):1451-68.
• [20] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.
• [21] Identification of genes targeted by the androgen and PKA signaling pathways in prostate cancer cells. Oncogene. 2006 Nov 23;25(55):7311-23.