Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTVF3LUG)

• DOT Name: Modulator of apoptosis 1 (MOAP1)
• Synonyms: MAP-1; MAP1; Paraneoplastic antigen Ma4
• Gene Name: MOAP1
• Related Disease:
  Neoplasm
  Alzheimer disease
  Epithelial ovarian cancer
  Esophageal squamous cell carcinoma
  Inclusion body myopathy with Paget disease of bone and frontotemporal dementia
  Osteoglophonic dwarfism
  Ovarian cancer
  Ovarian neoplasm
  Prostate cancer
  Prostate carcinoma
  Stroke
  Tenosynovial giant cell tumour
  Vascular dementia
  Colorectal carcinoma
  Lung cancer
  Lung carcinoma
  Lewy body dementia
• UniProt ID: MOAP1_HUMAN
• PDB ID: 7LGC
• Pfam ID: PF14893 ; PF20846
• Sequence:
  MTLRLLEDWCRGMDMNPRKALLIAGISQSCSVAEIEEALQAGLAPLGEYRLLGRMFRRDE
  NRKVALVGLTAETSHALVPKEIPGKGGIWRVIFKPPDPDNTFLSRLNEFLAGEGMTVGEL
  SRALGHENGSLDPEQGMIPEMWAPMLAQALEALQPALQCLKYKKLRVFSGRESPEPGEEE
  FGRWMFHTTQMIKAWQVPDVEKRRRLLESLRGPALDVIRVLKINNPLITVDECLQALEEV
  FGVTDNPRELQVKYLTTYQKDEEKLSAYVLRLEPLLQKLVQRGAIERDAVNQARLDQVIA
  GAVHKTIRRELNLPEDGPAPGFLQLLVLIKDYEAAEEEEALLQAILEGNFT
• Function: Retrotransposon-derived protein that forms virion-like capsids. Acts as an effector of BAX during apoptosis: enriched at outer mitochondria membrane and associates with BAX upon induction of apoptosis, facilitating BAX-dependent mitochondrial outer membrane permeabilization and apoptosis. Required for death receptor-dependent apoptosis. When associated with RASSF1, promotes BAX conformational change and translocation to mitochondrial membranes in response to TNF and TNFSF10 stimulation. Also promotes autophagy: promotes phagophore closure via association with ATG8 proteins. Acts as an inhibitor of the NFE2L2/NRF2 pathway via interaction with SQSTM1: interaction promotes dissociation of SQSTM1 inclusion bodies that sequester KEAP1, relieving inactivation of the BCR(KEAP1) complex.
• Tissue Specificity: Widely expressed, with high levels in heart and brain.

Molecular Interaction Atlas (MIA) of This DOT

17 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Neoplasm	DISZKGEW	Definitive	Biomarker	[1]
Alzheimer disease	DISF8S70	Strong	Biomarker	[2]
Epithelial ovarian cancer	DIS56MH2	Strong	Biomarker	[3]
Esophageal squamous cell carcinoma	DIS5N2GV	Strong	Altered Expression	[4]
Inclusion body myopathy with Paget disease of bone and frontotemporal dementia	DISK4S94	Strong	Biomarker	[5]
Osteoglophonic dwarfism	DISVSNPT	Strong	Biomarker	[6]
Ovarian cancer	DISZJHAP	Strong	Biomarker	[3]
Ovarian neoplasm	DISEAFTY	Strong	Biomarker	[3]
Prostate cancer	DISF190Y	Strong	Biomarker	[7]
Prostate carcinoma	DISMJPLE	Strong	Biomarker	[7]
Stroke	DISX6UHX	Strong	Biomarker	[6]
Tenosynovial giant cell tumour	DISYGQZI	Strong	Altered Expression	[8]
Vascular dementia	DISVO82H	Strong	Biomarker	[2]
Colorectal carcinoma	DIS5PYL0	moderate	Altered Expression	[9]
Lung cancer	DISCM4YA	moderate	Biomarker	[10]
Lung carcinoma	DISTR26C	moderate	Biomarker	[10]
Lewy body dementia	DISAE66J	Limited	Biomarker	[11]

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 Modulator of apoptosis 1 (MOAP1).	[12]
TAK-243	DM4GKV2	Phase 1	TAK-243 increases the sumoylation of Modulator of apoptosis 1 (MOAP1).	[21]

11 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 Modulator of apoptosis 1 (MOAP1).	[13]
Doxorubicin	DMVP5YE	Approved	Doxorubicin increases the expression of Modulator of apoptosis 1 (MOAP1).	[14]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of Modulator of apoptosis 1 (MOAP1).	[15]
Testosterone	DM7HUNW	Approved	Testosterone decreases the expression of Modulator of apoptosis 1 (MOAP1).	[16]
Menthol	DMG2KW7	Approved	Menthol decreases the expression of Modulator of apoptosis 1 (MOAP1).	[17]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Modulator of apoptosis 1 (MOAP1).	[18]
Epigallocatechin gallate	DMCGWBJ	Phase 3	Epigallocatechin gallate decreases the expression of Modulator of apoptosis 1 (MOAP1).	[19]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 increases the expression of Modulator of apoptosis 1 (MOAP1).	[20]
Coumestrol	DM40TBU	Investigative	Coumestrol decreases the expression of Modulator of apoptosis 1 (MOAP1).	[22]
Nickel chloride	DMI12Y8	Investigative	Nickel chloride decreases the expression of Modulator of apoptosis 1 (MOAP1).	[23]
Resorcinol	DMM37C0	Investigative	Resorcinol increases the expression of Modulator of apoptosis 1 (MOAP1).	[24]

References

• [1] RACK1/TRAF2 regulation of modulator of apoptosis-1 (MOAP-1).Biochim Biophys Acta Mol Cell Res. 2018 May;1865(5):684-694. doi: 10.1016/j.bbamcr.2018.02.006. Epub 2018 Feb 19.
• [2] N-homocysteinylation of tau and MAP1 is increased in autopsy specimens of Alzheimer's disease and vascular dementia.J Pathol. 2019 Jul;248(3):291-303. doi: 10.1002/path.5254. Epub 2019 Mar 19.
• [3] Downregulation of the proapoptotic protein MOAP-1 by the UBR5 ubiquitin ligase and its role in ovarian cancer resistance to cisplatin.Oncogene. 2017 Mar 23;36(12):1698-1706. doi: 10.1038/onc.2016.336. Epub 2016 Oct 10.
• [4] High p53 and MAP1 light chain 3A co-expression predicts poor prognosis in patients with esophageal squamous cell carcinoma.Mol Med Rep. 2013 Jul;8(1):41-6. doi: 10.3892/mmr.2013.1451. Epub 2013 Apr 30.
• [5] Valosin-containing protein (VCP) is required for autophagy and is disrupted in VCP disease.J Cell Biol. 2009 Dec 14;187(6):875-88. doi: 10.1083/jcb.200908115.
• [6] Modulator of apoptosis-1 is a potential therapeutic target in acute ischemic injury.J Cereb Blood Flow Metab. 2019 Dec;39(12):2406-2418. doi: 10.1177/0271678X18794839. Epub 2018 Aug 22.
• [7] A novel role for MAP1 LC3 in nonautophagic cytoplasmic vacuolation death of cancer cells.Oncogene. 2009 Jul 16;28(28):2556-68. doi: 10.1038/onc.2009.118. Epub 2009 May 18.
• [8] Analysis of pigmented villonodular synovitis with genome-wide complementary DNA microarray and tissue array technology reveals insight into potential novel therapeutic approaches.Arthritis Rheum. 2006 Mar;54(3):1009-19. doi: 10.1002/art.21641.
• [9] CAFs secreted exosomes promote metastasis and chemotherapy resistance by enhancing cell stemness and epithelial-mesenchymal transition in colorectal cancer.Mol Cancer. 2019 May 7;18(1):91. doi: 10.1186/s12943-019-1019-x.
• [10] miR-25 targets the modulator of apoptosis 1 gene in lung cancer.Carcinogenesis. 2015 Aug;36(8):925-35. doi: 10.1093/carcin/bgv068. Epub 2015 May 21.
• [11] Localization of MAP1-LC3 in vulnerable neurons and Lewy bodies in brains of patients with dementia with Lewy bodies.J Neuropathol Exp Neurol. 2011 Apr;70(4):264-80. doi: 10.1097/NEN.0b013e318211c86a.
• [12] 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.
• [13] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [14] 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.
• [15] Molecular mechanism of action of bisphenol and bisphenol A mediated by oestrogen receptor alpha in growth and apoptosis of breast cancer cells. Br J Pharmacol. 2013 May;169(1):167-78.
• [16] 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.
• [17] Repurposing L-menthol for systems medicine and cancer therapeutics? L-menthol induces apoptosis through caspase 10 and by suppressing HSP90. OMICS. 2016 Jan;20(1):53-64.
• [18] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [19] Molecular mechanisms of action of angiopreventive anti-oxidants on endothelial cells: microarray gene expression analyses. Mutat Res. 2005 Dec 11;591(1-2):198-211.
• [20] 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.
• [21] Inhibiting ubiquitination causes an accumulation of SUMOylated newly synthesized nuclear proteins at PML bodies. J Biol Chem. 2019 Oct 18;294(42):15218-15234. doi: 10.1074/jbc.RA119.009147. Epub 2019 Jul 8.
• [22] Pleiotropic combinatorial transcriptomes of human breast cancer cells exposed to mixtures of dietary phytoestrogens. Food Chem Toxicol. 2009 Apr;47(4):787-95.
• [23] The contact allergen nickel triggers a unique inflammatory and proangiogenic gene expression pattern via activation of NF-kappaB and hypoxia-inducible factor-1alpha. J Immunol. 2007 Mar 1;178(5):3198-207.
• [24] A transcriptomics-based in vitro assay for predicting chemical genotoxicity in vivo. Carcinogenesis. 2012 Jul;33(7):1421-9.