Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTPHI6ST)

DOT Name	Proteasome subunit alpha type-7 (PSMA7)
Synonyms	Proteasome subunit RC6-1; Proteasome subunit XAPC7
Gene Name	PSMA7
Related Disease	Non-insulin dependent diabetes ( ) Acute monocytic leukemia ( ) Acute myelogenous leukaemia ( ) Advanced cancer ( ) Cervical cancer ( ) Cervical carcinoma ( ) Colon carcinoma ( ) Colorectal carcinoma ( ) Colorectal neoplasm ( ) Crohn disease ( ) Fanconi anemia complementation group A ( ) Fanconi's anemia ( ) Gastric cancer ( ) Haemophilia A ( ) Hematologic disease ( ) Hepatitis B virus infection ( ) Inflammatory bowel disease ( ) Leukemia ( ) Lung adenocarcinoma ( ) Major depressive disorder ( ) Mental disorder ( ) Myelodysplastic syndrome ( ) Prostate neoplasm ( ) Stomach cancer ( ) Ulcerative colitis ( ) Metachromatic leukodystrophy ( ) Neoplasm ( ) Wiskott-Aldrich syndrome ( ) Amyotrophic lateral sclerosis ( ) leukaemia ( ) Myeloproliferative neoplasm ( ) Sickle-cell anaemia ( )
UniProt ID	PSA7_HUMAN
3D Structure	Download 2D Sequence (FASTA) Download 3D Structure (PDB) Download
PDB ID	4R3O ; 4R67 ; 5A0Q ; 5GJQ ; 5GJR ; 5L4G ; 5LE5 ; 5LEX ; 5LEY ; 5LEZ ; 5LF0 ; 5LF1 ; 5LF3 ; 5LF4 ; 5LF6 ; 5LF7 ; 5LN3 ; 5M32 ; 5T0C ; 5T0G ; 5T0H ; 5T0I ; 5T0J ; 5VFO ; 5VFP ; 5VFQ ; 5VFR ; 5VFS ; 5VFT ; 5VFU ; 6AVO ; 6E5B ; 6KWY ; 6MSB ; 6MSD ; 6MSE ; 6MSG ; 6MSH ; 6MSJ ; 6MSK ; 6R70 ; 6REY ; 6RGQ ; 6WJD ; 6WJN ; 6XMJ ; 7AWE ; 7B12 ; 7LXV ; 7NAN ; 7NAO ; 7NAP ; 7NAQ ; 7NHT ; 7PG9 ; 7QXN ; 7QXP ; 7QXU ; 7QXW ; 7QXX ; 7QY7 ; 7QYA ; 7QYB ; 7V5G ; 7V5M ; 7W37 ; 7W38 ; 7W39 ; 7W3A ; 7W3B ; 7W3C ; 7W3F ; 7W3G ; 7W3H ; 7W3I ; 7W3J ; 7W3K ; 7W3M ; 8CVR ; 8CVS ; 8CVT ; 8CXB
Pfam ID	PF00227 ; PF10584
Sequence	MSYDRAITVFSPDGHLFQVEYAQEAVKKGSTAVGVRGRDIVVLGVEKKSVAKLQDERTVR KICALDDNVCMAFAGLTADARIVINRARVECQSHRLTVEDPVTVEYITRYIASLKQRYTQ SNGRRPFGISALIVGFDFDGTPRLYQTDPSGTYHAWKANAIGRGAKSVREFLEKNYTDEA IETDDLTIKLVIKALLEVVQSGGKNIELAVMRRDQSLKILNPEEIEKYVAEIEKEKEENE KKKQKKAS
Function	Component of the 20S core proteasome complex involved in the proteolytic degradation of most intracellular proteins. This complex plays numerous essential roles within the cell by associating with different regulatory particles. Associated with two 19S regulatory particles, forms the 26S proteasome and thus participates in the ATP-dependent degradation of ubiquitinated proteins. The 26S proteasome plays a key role in the maintenance of protein homeostasis by removing misfolded or damaged proteins that could impair cellular functions, and by removing proteins whose functions are no longer required. Associated with the PA200 or PA28, the 20S proteasome mediates ubiquitin-independent protein degradation. This type of proteolysis is required in several pathways including spermatogenesis (20S-PA200 complex) or generation of a subset of MHC class I-presented antigenic peptides (20S-PA28 complex). Inhibits the transactivation function of HIF-1A under both normoxic and hypoxia-mimicking conditions. The interaction with EMAP2 increases the proteasome-mediated HIF-1A degradation under the hypoxic conditions. Plays a role in hepatitis C virus internal ribosome entry site-mediated translation. Mediates nuclear translocation of the androgen receptor (AR) and thereby enhances androgen-mediated transactivation. Promotes MAVS degradation and thereby negatively regulates MAVS-mediated innate immune response.
KEGG Pathway	Proteasome (hsa03050 ) Alzheimer disease (hsa05010 ) Parkinson disease (hsa05012 ) Amyotrophic lateral sclerosis (hsa05014 ) Huntington disease (hsa05016 ) Spinocerebellar ataxia (hsa05017 ) Prion disease (hsa05020 ) Pathways of neurodegeneration - multiple diseases (hsa05022 )
Reactome Pathway	Oxygen-dependent proline hydroxylation of Hypoxia-inducible Factor Alpha (R-HSA-1234176 ) ER-Phagosome pathway (R-HSA-1236974 ) Cross-presentation of soluble exogenous antigens (endosomes) (R-HSA-1236978 ) Autodegradation of Cdh1 by Cdh1 (R-HSA-174084 ) SCF-beta-TrCP mediated degradation of Emi1 (R-HSA-174113 ) APC/C (R-HSA-174154 ) APC/C (R-HSA-174178 ) Cdc20 (R-HSA-174184 ) Vpu mediated degradation of CD4 (R-HSA-180534 ) Vif-mediated degradation of APOBEC3G (R-HSA-180585 ) SCF(Skp2)-mediated degradation of p27/p21 (R-HSA-187577 ) Degradation of beta-catenin by the destruction complex (R-HSA-195253 ) Downstream TCR signaling (R-HSA-202424 ) Regulation of activated PAK-2p34 by proteasome mediated degradation (R-HSA-211733 ) Separation of Sister Chromatids (R-HSA-2467813 ) FCERI mediated NF-kB activation (R-HSA-2871837 ) Autodegradation of the E3 ubiquitin ligase COP1 (R-HSA-349425 ) Regulation of ornithine decarboxylase (ODC) (R-HSA-350562 ) ABC-family proteins mediated transport (R-HSA-382556 ) AUF1 (hnRNP D0) binds and destabilizes mRNA (R-HSA-450408 ) Asymmetric localization of PCP proteins (R-HSA-4608870 ) Degradation of AXIN (R-HSA-4641257 ) Degradation of DVL (R-HSA-4641258 ) Hedgehog ligand biogenesis (R-HSA-5358346 ) Hh mutants are degraded by ERAD (R-HSA-5362768 ) Dectin-1 mediated noncanonical NF-kB signaling (R-HSA-5607761 ) CLEC7A (Dectin-1) signaling (R-HSA-5607764 ) Degradation of GLI1 by the proteasome (R-HSA-5610780 ) Degradation of GLI2 by the proteasome (R-HSA-5610783 ) GLI3 is processed to GLI3R by the proteasome (R-HSA-5610785 ) Hedgehog 'on' state (R-HSA-5632684 ) Regulation of RAS by GAPs (R-HSA-5658442 ) TNFR2 non-canonical NF-kB pathway (R-HSA-5668541 ) NIK-->noncanonical NF-kB signaling (R-HSA-5676590 ) Defective CFTR causes cystic fibrosis (R-HSA-5678895 ) MAPK6/MAPK4 signaling (R-HSA-5687128 ) UCH proteinases (R-HSA-5689603 ) Ub-specific processing proteases (R-HSA-5689880 ) Assembly of the pre-replicative complex (R-HSA-68867 ) Orc1 removal from chromatin (R-HSA-68949 ) CDK-mediated phosphorylation and removal of Cdc6 (R-HSA-69017 ) G2/M Checkpoints (R-HSA-69481 ) Ubiquitin Mediated Degradation of Phosphorylated Cdc25A (R-HSA-69601 ) Ubiquitin-dependent degradation of Cyclin D (R-HSA-75815 ) The role of GTSE1 in G2/M progression after G2 checkpoint (R-HSA-8852276 ) FBXL7 down-regulates AURKA during mitotic entry and in early mitosis (R-HSA-8854050 ) RUNX1 regulates transcription of genes involved in differentiation of HSCs (R-HSA-8939236 ) Regulation of RUNX2 expression and activity (R-HSA-8939902 ) Regulation of RUNX3 expression and activity (R-HSA-8941858 ) Regulation of PTEN stability and activity (R-HSA-8948751 ) Neddylation (R-HSA-8951664 ) Regulation of expression of SLITs and ROBOs (R-HSA-9010553 ) Interleukin-1 signaling (R-HSA-9020702 ) Negative regulation of NOTCH4 signaling (R-HSA-9604323 ) KEAP1-NFE2L2 pathway (R-HSA-9755511 ) GSK3B and BTRC (R-HSA-9762114 ) Somitogenesis (R-HSA-9824272 ) Antigen processing (R-HSA-983168 ) Activation of NF-kappaB in B cells (R-HSA-1169091 )

Molecular Interaction Atlas (MIA) of This DOT

32 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance
Non-insulin dependent diabetes	DISK1O5Z	Definitive	Biomarker	[1]
Acute monocytic leukemia	DIS28NEL	Strong	Biomarker	[2]
Acute myelogenous leukaemia	DISCSPTN	Strong	Biomarker	[2]
Advanced cancer	DISAT1Z9	Strong	Biomarker	[3]
Cervical cancer	DISFSHPF	Strong	Biomarker	[4]
Cervical carcinoma	DIST4S00	Strong	Biomarker	[4]
Colon carcinoma	DISJYKUO	Strong	Biomarker	[5]
Colorectal carcinoma	DIS5PYL0	Strong	Biomarker	[6]
Colorectal neoplasm	DISR1UCN	Strong	Biomarker	[7]
Crohn disease	DIS2C5Q8	Strong	Altered Expression	[8]
Fanconi anemia complementation group A	DIS8PZLI	Strong	Genetic Variation	[9]
Fanconi's anemia	DISGW6Q8	Strong	Genetic Variation	[9]
Gastric cancer	DISXGOUK	Strong	Biomarker	[3]
Haemophilia A	DIS0RQ2E	Strong	Biomarker	[10]
Hematologic disease	DIS9XD9A	Strong	Biomarker	[11]
Hepatitis B virus infection	DISLQ2XY	Strong	Biomarker	[12]
Inflammatory bowel disease	DISGN23E	Strong	Biomarker	[8]
Leukemia	DISNAKFL	Strong	Biomarker	[13]
Lung adenocarcinoma	DISD51WR	Strong	Biomarker	[14]
Major depressive disorder	DIS4CL3X	Strong	Altered Expression	[15]
Mental disorder	DIS3J5R8	Strong	Genetic Variation	[15]
Myelodysplastic syndrome	DISYHNUI	Strong	Biomarker	[16]
Prostate neoplasm	DISHDKGQ	Strong	Biomarker	[17]
Stomach cancer	DISKIJSX	Strong	Biomarker	[3]
Ulcerative colitis	DIS8K27O	Strong	Altered Expression	[8]
Metachromatic leukodystrophy	DIS3OMWS	moderate	Genetic Variation	[18]
Neoplasm	DISZKGEW	moderate	Biomarker	[19]
Wiskott-Aldrich syndrome	DISATMDB	moderate	Genetic Variation	[18]
Amyotrophic lateral sclerosis	DISF7HVM	Limited	Biomarker	[20]
leukaemia	DISS7D1V	Limited	Biomarker	[13]
Myeloproliferative neoplasm	DIS5KAPA	Limited	Genetic Variation	[21]
Sickle-cell anaemia	DIS5YNZB	Limited	Biomarker	[22]
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Molecular Interaction Atlas (MIA)

MIA Detail

Jump to Detail Molecular Interaction Atlas of This DOT

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Proteasome subunit alpha type-7 (PSMA7).	[23]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Proteasome subunit alpha type-7 (PSMA7).	[24]
Doxorubicin	DMVP5YE	Approved	Doxorubicin increases the expression of Proteasome subunit alpha type-7 (PSMA7).	[25]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Proteasome subunit alpha type-7 (PSMA7).	[26]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide increases the expression of Proteasome subunit alpha type-7 (PSMA7).	[27]
Isotretinoin	DM4QTBN	Approved	Isotretinoin decreases the expression of Proteasome subunit alpha type-7 (PSMA7).	[28]
Epigallocatechin gallate	DMCGWBJ	Phase 3	Epigallocatechin gallate increases the expression of Proteasome subunit alpha type-7 (PSMA7).	[29]
MG-132	DMKA2YS	Preclinical	MG-132 increases the expression of Proteasome subunit alpha type-7 (PSMA7).	[31]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Proteasome subunit alpha type-7 (PSMA7).	[32]
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⏷ Show the Full List of 9 Drug(s)

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

Drug Name	Drug ID	Highest Status	Interaction	REF
TAK-243	DM4GKV2	Phase 1	TAK-243 increases the sumoylation of Proteasome subunit alpha type-7 (PSMA7).	[30]
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References

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2	Single-Cell Gene Expression Analyses Reveal Distinct Self-Renewing and Proliferating Subsets in the Leukemia Stem Cell Compartment in Acute Myeloid Leukemia.Cancer Res. 2020 Feb 1;80(3):458-470. doi: 10.1158/0008-5472.CAN-18-2932. Epub 2019 Nov 29.
3	Overexpression of PSMA7 predicts poor prognosis in patients with gastric cancer.Oncol Lett. 2019 Nov;18(5):5341-5349. doi: 10.3892/ol.2019.10879. Epub 2019 Sep 19.
4	Effects of shRNA-mediated silencing of PSMA7 on cell proliferation and vascular endothelial growth factor expression via the ubiquitin-proteasome pathway in cervical cancer.J Cell Physiol. 2019 May;234(5):5851-5862. doi: 10.1002/jcp.26408. Epub 2018 Dec 11.
5	Cell cytotoxicity, immunostimulatory and antitumor effects of lipid content of liposomal delivery platforms in cancer immunotherapies. A comprehensive in-vivo and in-vitro study.Int J Pharm. 2019 Aug 15;567:118492. doi: 10.1016/j.ijpharm.2019.118492. Epub 2019 Jul 2.
6	EpCAM Aptamer-Functionalized Cationic Liposome-Based Nanoparticles Loaded with miR-139-5p for Targeted Therapy in Colorectal Cancer.Mol Pharm. 2019 Nov 4;16(11):4696-4710. doi: 10.1021/acs.molpharmaceut.9b00867. Epub 2019 Oct 21.
7	The proteasome subunit PSMA7 located on the 20q13 amplicon is overexpressed and associated with liver metastasis in colorectal cancer.Oncol Rep. 2008 Feb;19(2):441-6.
8	Salivary exosomal PSMA7: a promising biomarker of inflammatory bowel disease.Protein Cell. 2017 Sep;8(9):686-695. doi: 10.1007/s13238-017-0413-7. Epub 2017 May 18.
9	NHEJ-Mediated Repair of CRISPR-Cas9-Induced DNA Breaks Efficiently Corrects Mutations in HSPCs from Patients with Fanconi Anemia.Cell Stem Cell. 2019 Nov 7;25(5):607-621.e7. doi: 10.1016/j.stem.2019.08.016. Epub 2019 Sep 19.
10	Microfluidic Transduction Harnesses Mass Transport Principles to Enhance Gene Transfer Efficiency.Mol Ther. 2017 Oct 4;25(10):2372-2382. doi: 10.1016/j.ymthe.2017.07.002. Epub 2017 Jul 8.
11	Evaluation of committed and primitive cord blood progenitors after expansion on adipose stromal cells.Cell Tissue Res. 2018 Jun;372(3):523-533. doi: 10.1007/s00441-017-2766-x. Epub 2018 Jan 11.
12	Chromatin remodelling factor BAF155 protects hepatitis B virus X protein (HBx) from ubiquitin-independent proteasomal degradation.Emerg Microbes Infect. 2019;8(1):1393-1405. doi: 10.1080/22221751.2019.1666661.
13	Flow Cytometric Analysis of Mitochondrial Reactive Oxygen Species in Murine Hematopoietic Stem and Progenitor Cells and MLL-AF9 Driven Leukemia.J Vis Exp. 2019 Sep 5;(151):10.3791/59593. doi: 10.3791/59593.
14	PSMA7 inhibits the tumorigenicity of A549 human lung adenocarcinoma cells.Mol Cell Biochem. 2012 Jul;366(1-2):131-7. doi: 10.1007/s11010-012-1290-2. Epub 2012 May 15.
15	Proteasome system dysregulation and treatment resistance mechanisms in major depressive disorder.Transl Psychiatry. 2015 Dec 1;5(12):e687. doi: 10.1038/tp.2015.180.
16	Bone marrow MSCs in MDS: contribution towards dysfunctional hematopoiesis and potential targets for disease response to hypomethylating therapy.Leukemia. 2019 Jun;33(6):1487-1500. doi: 10.1038/s41375-018-0310-y. Epub 2018 Dec 21.
17	Identification of genes showing differential expression in antisense K-ras-transduced pancreatic cancer cells with suppressed tumorigenicity.Cancer Res. 1999 Nov 1;59(21):5565-71.
18	Bone marrow harvesting from paediatric patients undergoing haematopoietic stem cell gene therapy.Bone Marrow Transplant. 2019 Dec;54(12):1995-2003. doi: 10.1038/s41409-019-0573-6. Epub 2019 May 31.
19	An (18)F-Labeled PSMA Ligand for PET/CT of Prostate Cancer: First-in-Humans Observational Study and Clinical Experience with (18)F-JK-PSMA-7 During the First Year of Application.J Nucl Med. 2020 Feb;61(2):202-209. doi: 10.2967/jnumed.119.229542. Epub 2019 Jul 19.
20	Novel autoantibodies against the proteasome subunit PSMA7 in amyotrophic lateral sclerosis.J Neuroimmunol. 2018 Dec 15;325:54-60. doi: 10.1016/j.jneuroim.2018.09.013. Epub 2018 Oct 1.
21	Estrogen signaling selectively induces apoptosis of hematopoietic progenitors and myeloid neoplasms without harming steady-state hematopoiesis.Cell Stem Cell. 2014 Dec 4;15(6):791-804. doi: 10.1016/j.stem.2014.11.002.
22	Bone marrow characterization in sickle cell disease: inflammation and stress erythropoiesis lead to suboptimal CD34 recovery.Br J Haematol. 2019 Jul;186(2):286-299. doi: 10.1111/bjh.15902. Epub 2019 Apr 10.
23	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.
24	Pharmacogenomic analysis of acute promyelocytic leukemia cells highlights CYP26 cytochrome metabolism in differential all-trans retinoic acid sensitivity. Blood. 2007 May 15;109(10):4450-60.
25	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.
26	Quantitative proteomics reveals a broad-spectrum antiviral property of ivermectin, benefiting for COVID-19 treatment. J Cell Physiol. 2021 Apr;236(4):2959-2975. doi: 10.1002/jcp.30055. Epub 2020 Sep 22.
27	A comprehensive analysis of Wnt/beta-catenin signaling pathway-related genes and crosstalk pathways in the treatment of As2O3 in renal cancer. Ren Fail. 2018 Nov;40(1):331-339.
28	Temporal changes in gene expression in the skin of patients treated with isotretinoin provide insight into its mechanism of action. Dermatoendocrinol. 2009 May;1(3):177-87.
29	Comparative proteomics reveals concordant and discordant biochemical effects of caffeine versus epigallocatechin-3-gallate in human endothelial cells. Toxicol Appl Pharmacol. 2019 Sep 1;378:114621. doi: 10.1016/j.taap.2019.114621. Epub 2019 Jun 10.
30	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.
31	Proteasome inhibition creates a chromatin landscape favorable to RNA Pol II processivity. J Biol Chem. 2020 Jan 31;295(5):1271-1287. doi: 10.1074/jbc.RA119.011174. Epub 2019 Dec 5.
32	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.