Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTD176ZS)

• DOT Name: Amyloid beta precursor like protein 1 (APLP1)
• Synonyms: Amyloid beta (A4) precursor-like protein 1; Amyloid-like protein 1; APLP; APLP-1
• Gene Name: APLP1
• Related Disease:
  Amyloidosis
  Carcinoid tumor
  Congenital nephrotic syndrome, Finnish type
  Epilepsy
  Familial Alzheimer disease
  Familial nephrotic syndrome
  Metastatic malignant neoplasm
  Neoplasm
  Neuroendocrine neoplasm
  Alzheimer disease
  Neuroblastoma
• UniProt ID: APLP1_HUMAN
• PDB ID: 3PMR; 3Q7G; 3Q7L; 3QMK; 4RD9; 4RDA
• Pfam ID: PF10515 ; PF12924 ; PF12925 ; PF02177
• Sequence:
  MGPASPAARGLSRRPGQPPLPLLLPLLLLLLRAQPAIGSLAGGSPGAAEAPGSAQVAGLC
  GRLTLHRDLRTGRWEPDPQRSRRCLRDPQRVLEYCRQMYPELQIARVEQATQAIPMERWC
  GGSRSGSCAHPHHQVVPFRCLPGEFVSEALLVPEGCRFLHQERMDQCESSTRRHQEAQEA
  CSSQGLILHGSGMLLPCGSDRFRGVEYVCCPPPGTPDPSGTAVGDPSTRSWPPGSRVEGA
  EDEEEEESFPQPVDDYFVEPPQAEEEEETVPPPSSHTLAVVGKVTPTPRPTDGVDIYFGM
  PGEISEHEGFLRAKMDLEERRMRQINEVMREWAMADNQSKNLPKADRQALNEHFQSILQT
  LEEQVSGERQRLVETHATRVIALINDQRRAALEGFLAALQADPPQAERVLLALRRYLRAE
  QKEQRHTLRHYQHVAAVDPEKAQQMRFQVHTHLQVIEERVNQSLGLLDQNPHLAQELRPQ
  IQELLHSEHLGPSELEAPAPGGSSEDKGGLQPPDSKDDTPMTLPKGSTEQDAASPEKEKM
  NPLEQYERKVNASVPRGFPFHSSEIQRDELAPAGTGVSREAVSGLLIMGAGGGSLIVLSM
  LLLRRKKPYGAISHGVVEVDPMLTLEEQQLRELQRHGYENPTYRFLEERP
• Function: May play a role in postsynaptic function. The C-terminal gamma-secretase processed fragment, ALID1, activates transcription activation through APBB1 (Fe65) binding. Couples to JIP signal transduction through C-terminal binding. May interact with cellular G-protein signaling pathways. Can regulate neurite outgrowth through binding to components of the extracellular matrix such as heparin and collagen I; The gamma-CTF peptide, C30, is a potent enhancer of neuronal apoptosis.
• Tissue Specificity: Expressed in the cerebral cortex where it is localized to the postsynaptic density (PSD).

Molecular Interaction Atlas (MIA) of This DOT

11 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Amyloidosis	DISHTAI2	Strong	Biomarker	[1]
Carcinoid tumor	DISMNRDC	Strong	Biomarker	[2]
Congenital nephrotic syndrome, Finnish type	DIS8P7EH	Strong	Biomarker	[1]
Epilepsy	DISBB28L	Strong	Altered Expression	[3]
Familial Alzheimer disease	DISE75U4	Strong	Biomarker	[4]
Familial nephrotic syndrome	DISADF8G	Strong	Genetic Variation	[1]
Metastatic malignant neoplasm	DIS86UK6	Strong	Altered Expression	[2]
Neoplasm	DISZKGEW	Strong	Biomarker	[2]
Neuroendocrine neoplasm	DISNPLOO	Strong	Altered Expression	[2]
Alzheimer disease	DISF8S70	Limited	Biomarker	[5]
Neuroblastoma	DISVZBI4	Limited	Altered Expression	[6]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the expression of Amyloid beta precursor like protein 1 (APLP1).	[7]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Amyloid beta precursor like protein 1 (APLP1).	[8]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Amyloid beta precursor like protein 1 (APLP1).	[9]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Amyloid beta precursor like protein 1 (APLP1).	[10]
Doxorubicin	DMVP5YE	Approved	Doxorubicin increases the expression of Amyloid beta precursor like protein 1 (APLP1).	[11]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Amyloid beta precursor like protein 1 (APLP1).	[12]
Quercetin	DM3NC4M	Approved	Quercetin increases the expression of Amyloid beta precursor like protein 1 (APLP1).	[14]
Temozolomide	DMKECZD	Approved	Temozolomide decreases the expression of Amyloid beta precursor like protein 1 (APLP1).	[15]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the expression of Amyloid beta precursor like protein 1 (APLP1).	[16]
Sulforaphane	DMQY3L0	Investigative	Sulforaphane decreases the expression of Amyloid beta precursor like protein 1 (APLP1).	[17]
Deguelin	DMXT7WG	Investigative	Deguelin decreases the expression of Amyloid beta precursor like protein 1 (APLP1).	[18]
Butanoic acid	DMTAJP7	Investigative	Butanoic acid increases the expression of Amyloid beta precursor like protein 1 (APLP1).	[19]

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 Amyloid beta precursor like protein 1 (APLP1).	[13]

References

• [1] Structure of the human amyloid-precursor-like protein gene APLP1 at 19q13.1.Hum Genet. 1998 Feb;102(2):192-6. doi: 10.1007/s004390050676.
• [2] Amyloid precursor-like protein 1 is differentially upregulated in neuroendocrine tumours of the gastrointestinal tract.Endocr Relat Cancer. 2008 Jun;15(2):569-81. doi: 10.1677/ERC-07-0145. Epub 2008 Apr 22.
• [3] Down-regulation of APLP1 mRNA expression in hippocampus of pilocarpine-induced epileptic rats.Neurosci Bull. 2009 Jun;25(3):109-14. doi: 10.1007/s12264-009-1229-0.
• [4] Search for the genes responsible for familial Alzheimer's disease.Ann N Y Acad Sci. 1993 Sep 24;695:203-8. doi: 10.1111/j.1749-6632.1993.tb23053.x.
• [5] Liquid biopsy of cerebrospinal fluid identifies neuronal pentraxin receptor (NPTXR) as a biomarker of progression of Alzheimer's disease.Clin Chem Lab Med. 2019 Nov 26;57(12):1875-1881. doi: 10.1515/cclm-2019-0428.
• [6] Amyloid-beta precursor-like protein APLP1 is a novel p53 transcriptional target gene that augments neuroblastoma cell death upon genotoxic stress.Oncogene. 2007 Nov 15;26(52):7302-12. doi: 10.1038/sj.onc.1210542. Epub 2007 May 28.
• [7] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [8] Integrative "-Omics" analysis in primary human hepatocytes unravels persistent mechanisms of cyclosporine A-induced cholestasis. Chem Res Toxicol. 2016 Dec 19;29(12):2164-2174.
• [9] Increased processing of APLP2 and APP with concomitant formation of APP intracellular domains in BDNF and retinoic acid-differentiated human neuroblastoma cells. J Neurochem. 2005 Nov;95(4):1059-68. doi: 10.1111/j.1471-4159.2005.03440.x. Epub 2005 Sep 7.
• [10] Predictive toxicology using systemic biology and liver microfluidic "on chip" approaches: application to acetaminophen injury. Toxicol Appl Pharmacol. 2012 Mar 15;259(3):270-80.
• [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] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [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] Comparison of phenotypic and transcriptomic effects of false-positive genotoxins, true genotoxins and non-genotoxins using HepG2 cells. Mutagenesis. 2011 Sep;26(5):593-604.
• [15] 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.
• [16] 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.
• [17] Transcriptome and DNA methylation changes modulated by sulforaphane induce cell cycle arrest, apoptosis, DNA damage, and suppression of proliferation in human liver cancer cells. Food Chem Toxicol. 2020 Feb;136:111047. doi: 10.1016/j.fct.2019.111047. Epub 2019 Dec 12.
• [18] Neurotoxicity and underlying cellular changes of 21 mitochondrial respiratory chain inhibitors. Arch Toxicol. 2021 Feb;95(2):591-615. doi: 10.1007/s00204-020-02970-5. Epub 2021 Jan 29.
• [19] MS4A3-HSP27 target pathway reveals potential for haematopoietic disorder treatment in alimentary toxic aleukia. Cell Biol Toxicol. 2023 Feb;39(1):201-216. doi: 10.1007/s10565-021-09639-4. Epub 2021 Sep 28.