Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT33HG7E)

• DOT Name: Gamma-secretase-activating protein (GSAP)
• Synonyms: GSAP; Protein pigeon homolog
• Gene Name: GSAP
• Related Disease:
  Alzheimer disease
  Glioblastoma multiforme
  Neoplasm
• UniProt ID: GSAP_HUMAN
• Pfam ID: PF14959
• Sequence:
  MALRLVADFDLGKDVLPWLRAQRAVSEASGAGSGGADVLENDYESLHVLNVERNGNIIYT
  YKDDKGNVVFGLYDCQTRQNELLYTFEKDLQVFSCSVNSERTLLAASLVQSTKEGKRNEL
  QPGSKCLTLLVEIHPVNNVKVLKAVDSYIWVQFLYPHIESHPLPENHLLLISEEKYIEQF
  RIHVAQEDGNRVVIKNSGHLPRDRIAEDFVWAQWDMSEQRLYYIDLKKSRSILKCIQFYA
  DESYNLMFEVPLDISLSNSGFKLVNFGCDYHQYRDKFSKHLTLCVFTNHTGSLCVCYSPK
  CASWGQITYSVFYIHKGHSKTFTTSLENVGSHMTKGITFLNLDYYVAVYLPGHFFHLLNV
  QHPDLICHNLFLTGNNEMIDMLPHCPLQSLSGSLVLDCCSGKLYRALLSQSSLLQLLQNT
  CLDCEKMAALHCALYCGQGAQFLEAQIIQWISENVSACHSFDLIQEFIIASSYWSVYSET
  SNMDKLLPHSSVLTWNTEIPGITLVTEDIALPLMKVLSFKGYWEKLNSNLEYVKYAKPHF
  HYNNSVVRREWHNLISEEKTGKRRSAAYVRNILDNAVKVISNLEARNLGPRLTPLLQEED
  SHQRLLMGLMVSELKDHFLRHLQGVEKKKIEQMVLDYISKLLDLICHIVETNWRKHNLHS
  WVLHFNSRGSAAEFAVFHIMTRILEATNSLFLPLPPGFHTLHTILGVQCLPLHNLLHCID
  SGVLLLTETAVIRLMKDLDNTEKNEKLKFSIIVRLPPLIGQKICRLWDHPMSSNIISRNH
  VTRLLQNYKKQPRNSMINKSSFSVEFLPLNYFIEILTDIESSNQALYPFEGHDNVDAEFV
  EEAALKHTAMLLGL
• Function: Regulator of gamma-secretase activity, which specifically activates the production of amyloid-beta protein (amyloid-beta protein 40 and amyloid-beta protein 42), without affecting the cleavage of other gamma-secretase targets such has Notch. The gamma-secretase complex is an endoprotease complex that catalyzes the intramembrane cleavage of integral membrane proteins such as Notch receptors and APP (amyloid-beta precursor protein). Specifically promotes the gamma-cleavage of APP CTF-alpha (also named APP-CTF) by the gamma-secretase complex to generate amyloid-beta, while it reduces the epsilon-cleavage of APP CTF-alpha, leading to a low production of AICD.
• Tissue Specificity: Widely expressed.

Molecular Interaction Atlas (MIA) of This DOT

3 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Alzheimer disease	DISF8S70	Strong	Biomarker	[1]
Glioblastoma multiforme	DISK8246	Strong	Biomarker	[2]
Neoplasm	DISZKGEW	Strong	Biomarker	[3]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the methylation of Gamma-secretase-activating protein (GSAP).	[4]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene affects the methylation of Gamma-secretase-activating protein (GSAP).	[14]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Gamma-secretase-activating protein (GSAP).	[5]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Gamma-secretase-activating protein (GSAP).	[6]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Gamma-secretase-activating protein (GSAP).	[7]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Gamma-secretase-activating protein (GSAP).	[8]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Gamma-secretase-activating protein (GSAP).	[9]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of Gamma-secretase-activating protein (GSAP).	[10]
Vorinostat	DMWMPD4	Approved	Vorinostat decreases the expression of Gamma-secretase-activating protein (GSAP).	[11]
Testosterone	DM7HUNW	Approved	Testosterone increases the expression of Gamma-secretase-activating protein (GSAP).	[12]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Gamma-secretase-activating protein (GSAP).	[13]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Gamma-secretase-activating protein (GSAP).	[15]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide decreases the expression of Gamma-secretase-activating protein (GSAP).	[16]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Gamma-secretase-activating protein (GSAP).	[17]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A affects the expression of Gamma-secretase-activating protein (GSAP).	[18]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of Gamma-secretase-activating protein (GSAP).	[19]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde increases the expression of Gamma-secretase-activating protein (GSAP).	[20]

References

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• [2] Inhibition of human glioblastoma cell invasion involves PION@E6 mediated autophagy process.Cancer Manag Res. 2019 Mar 29;11:2643-2652. doi: 10.2147/CMAR.S200151. eCollection 2019.
• [3] Iron oxide nanoparticles as nanocarriers to improve chlorin e6-based sonosensitivity in sonodynamic therapy.Drug Des Devel Ther. 2018 Dec 10;12:4207-4216. doi: 10.2147/DDDT.S184679. eCollection 2018.
• [4] Integrative omics data analyses of repeated dose toxicity of valproic acid in vitro reveal new mechanisms of steatosis induction. Toxicology. 2018 Jan 15;393:160-170.
• [5] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [6] Systems analysis of transcriptome and proteome in retinoic acid/arsenic trioxide-induced cell differentiation/apoptosis of promyelocytic leukemia. Proc Natl Acad Sci U S A. 2005 May 24;102(21):7653-8.
• [7] 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.
• [8] 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.
• [9] Low doses of cisplatin induce gene alterations, cell cycle arrest, and apoptosis in human promyelocytic leukemia cells. Biomark Insights. 2016 Aug 24;11:113-21.
• [10] Research resource: STR DNA profile and gene expression comparisons of human BG-1 cells and a BG-1/MCF-7 clonal variant. Mol Endocrinol. 2014 Dec;28(12):2072-81.
• [11] A transcriptome-based classifier to identify developmental toxicants by stem cell testing: design, validation and optimization for histone deacetylase inhibitors. Arch Toxicol. 2015 Sep;89(9):1599-618.
• [12] The exosome-like vesicles derived from androgen exposed-prostate stromal cells promote epithelial cells proliferation and epithelial-mesenchymal transition. Toxicol Appl Pharmacol. 2021 Jan 15;411:115384. doi: 10.1016/j.taap.2020.115384. Epub 2020 Dec 25.
• [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] Inhibition of BRD4 attenuates tumor cell self-renewal and suppresses stem cell signaling in MYC driven medulloblastoma. Oncotarget. 2014 May 15;5(9):2355-71.
• [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] The genomic response of Ishikawa cells to bisphenol A exposure is dose- and time-dependent. Toxicology. 2010 Apr 11;270(2-3):137-49. doi: 10.1016/j.tox.2010.02.008. Epub 2010 Feb 17.
• [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] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.