Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTOJ9OHA)

• DOT Name: Proteasome subunit beta type-4 (PSMB4)
• Synonyms: 26 kDa prosomal protein; HsBPROS26; PROS-26; Macropain beta chain; Multicatalytic endopeptidase complex beta chain; Proteasome beta chain; Proteasome chain 3; HsN3
• Gene Name: PSMB4
• Related Disease:
  Adult glioblastoma
  Breast cancer
  Breast carcinoma
  Cervical cancer
  Cervical carcinoma
  Epithelial ovarian cancer
  Glioblastoma multiforme
  Glioma
  HIV infectious disease
  Major depressive disorder
  Myocardial infarction
  Neoplasm
  Ovarian cancer
  Plasma cell myeloma
  Advanced cancer
  Proteasome-associated autoinflammatory syndrome 3
• UniProt ID: PSB4_HUMAN
• 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
• Sequence:
  MEAFLGSRSGLWAGGPAPGQFYRIPSTPDSFMDPASALYRGPITRTQNPMVTGTSVLGVK
  FEGGVVIAADMLGSYGSLARFRNISRIMRVNNSTMLGASGDYADFQYLKQVLGQMVIDEE
  LLGDGHSYSPRAIHSWLTRAMYSRRSKMNPLWNTMVIGGYADGESFLGYVDMLGVAYEAP
  SLATGYGAYLAQPLLREVLEKQPVLSQTEARDLVERCMRVLYYRDARSYNRFQIATVTEK
  GVEIEGPLSTETNWDIAHMISGFE
• Function: Non-catalytic 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). SMAD1/OAZ1/PSMB4 complex mediates the degradation of the CREBBP/EP300 repressor SNIP1.
• 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

16 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Adult glioblastoma	DISVP4LU	Strong	Biomarker	[1]
Breast cancer	DIS7DPX1	Strong	Biomarker	[2]
Breast carcinoma	DIS2UE88	Strong	Biomarker	[2]
Cervical cancer	DISFSHPF	Strong	Biomarker	[3]
Cervical carcinoma	DIST4S00	Strong	Biomarker	[3]
Epithelial ovarian cancer	DIS56MH2	Strong	Altered Expression	[4]
Glioblastoma multiforme	DISK8246	Strong	Biomarker	[1]
Glioma	DIS5RPEH	Strong	Biomarker	[1]
HIV infectious disease	DISO97HC	Strong	Biomarker	[5]
Major depressive disorder	DIS4CL3X	Strong	Biomarker	[6]
Myocardial infarction	DIS655KI	Strong	Genetic Variation	[7]
Neoplasm	DISZKGEW	Strong	Biomarker	[1]
Ovarian cancer	DISZJHAP	Strong	Altered Expression	[4]
Plasma cell myeloma	DIS0DFZ0	Strong	Biomarker	[8]
Advanced cancer	DISAT1Z9	Limited	Biomarker	[2]
Proteasome-associated autoinflammatory syndrome 3	DIST9D7E	Limited	Autosomal recessive	[9]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of Proteasome subunit beta type-4 (PSMB4).	[10]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Proteasome subunit beta type-4 (PSMB4).	[11]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide increases the expression of Proteasome subunit beta type-4 (PSMB4).	[12]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide decreases the expression of Proteasome subunit beta type-4 (PSMB4).	[13]
Vorinostat	DMWMPD4	Approved	Vorinostat decreases the expression of Proteasome subunit beta type-4 (PSMB4).	[14]
Decitabine	DMQL8XJ	Approved	Decitabine decreases the expression of Proteasome subunit beta type-4 (PSMB4).	[15]
Marinol	DM70IK5	Approved	Marinol decreases the expression of Proteasome subunit beta type-4 (PSMB4).	[16]
Selenium	DM25CGV	Approved	Selenium increases the expression of Proteasome subunit beta type-4 (PSMB4).	[17]
Diethylstilbestrol	DMN3UXQ	Approved	Diethylstilbestrol increases the expression of Proteasome subunit beta type-4 (PSMB4).	[18]
Aminoglutethimide	DMWFHMZ	Approved	Aminoglutethimide decreases the expression of Proteasome subunit beta type-4 (PSMB4).	[19]
Tocopherol	DMBIJZ6	Phase 2	Tocopherol increases the expression of Proteasome subunit beta type-4 (PSMB4).	[17]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the expression of Proteasome subunit beta type-4 (PSMB4).	[20]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Proteasome subunit beta type-4 (PSMB4).	[21]
MG-132	DMKA2YS	Preclinical	MG-132 increases the expression of Proteasome subunit beta type-4 (PSMB4).	[22]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of Proteasome subunit beta type-4 (PSMB4).	[23]
chloropicrin	DMSGBQA	Investigative	chloropicrin decreases the expression of Proteasome subunit beta type-4 (PSMB4).	[24]

References

• [1] Interference with PSMB4 Expression Exerts an Anti-Tumor Effect by Decreasing the Invasion and Proliferation of Human Glioblastoma Cells.Cell Physiol Biochem. 2018;45(2):819-831. doi: 10.1159/000487174. Epub 2018 Jan 31.
• [2] PSMB4 overexpression enhances the cell growth and viability of breast cancer cells leading to a poor prognosis.Oncol Rep. 2018 Oct;40(4):2343-2352. doi: 10.3892/or.2018.6588. Epub 2018 Jul 20.
• [3] A novel FoxM1-PSMB4 axis contributes to proliferation and progression of cervical cancer.Biochem Biophys Res Commun. 2020 Jan 15;521(3):746-752. doi: 10.1016/j.bbrc.2019.10.183. Epub 2019 Nov 5.
• [4] PSMB4 expression associates with epithelial ovarian cancer growth and poor prognosis.Arch Gynecol Obstet. 2016 Jun;293(6):1297-307. doi: 10.1007/s00404-015-3904-x. Epub 2015 Oct 6.
• [5] Host cell gene expression during human immunodeficiency virus type 1 latency and reactivation and effects of targeting genes that are differentially expressed in viral latency.J Virol. 2004 Sep;78(17):9458-73. doi: 10.1128/JVI.78.17.9458-9473.2004.
• [6] Polymorphisms in inflammation-related genes are associated with susceptibility to major depression and antidepressant response.Mol Psychiatry. 2008 Aug;13(8):800-12. doi: 10.1038/mp.2008.59. Epub 2008 May 27.
• [7] Association of a polymorphism of BTN2A1 with myocardial infarction in East Asian populations.Atherosclerosis. 2011 Mar;215(1):145-52. doi: 10.1016/j.atherosclerosis.2010.12.005. Epub 2010 Dec 15.
• [8] PSMB4 promotes multiple myeloma cell growth by activating NF-B-miR-21 signaling.Biochem Biophys Res Commun. 2015 Mar 6;458(2):328-33. doi: 10.1016/j.bbrc.2015.01.110. Epub 2015 Feb 3.
• [9] Classification of Genes: Standardized Clinical Validity Assessment of Gene-Disease Associations Aids Diagnostic Exome Analysis and Reclassifications. Hum Mutat. 2017 May;38(5):600-608. doi: 10.1002/humu.23183. Epub 2017 Feb 13.
• [10] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [11] 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.
• [12] Essential role of cell cycle regulatory genes p21 and p27 expression in inhibition of breast cancer cells by arsenic trioxide. Med Oncol. 2011 Dec;28(4):1225-54.
• [13] 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.
• [14] Proteomic analysis of liver cancer cells treated with suberonylanilide hydroxamic acid. Cancer Chemother Pharmacol. 2008 Apr;61(5):791-802.
• [15] Synergistic effect of trichostatin A and 5-aza-2'-deoxycytidine on growth inhibition of pancreatic endocrine tumour cell lines: a proteomic study. Proteomics. 2009 Apr;9(7):1952-66. doi: 10.1002/pmic.200701089.
• [16] THC exposure of human iPSC neurons impacts genes associated with neuropsychiatric disorders. Transl Psychiatry. 2018 Apr 25;8(1):89. doi: 10.1038/s41398-018-0137-3.
• [17] 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.
• [18] Identification of biomarkers and outcomes of endocrine disruption in human ovarian cortex using In Vitro Models. Toxicology. 2023 Feb;485:153425. doi: 10.1016/j.tox.2023.153425. Epub 2023 Jan 5.
• [19] Proteomic profile of aminoglutethimide-induced apoptosis in HL-60 cells: role of myeloperoxidase and arylamine free radicals. Chem Biol Interact. 2015 Sep 5;239:129-38.
• [20] Benzo[a]pyrene treatment leads to changes in nuclear protein expression and alternative splicing. Mutat Res. 2010 Apr 1;686(1-2):47-56. doi: 10.1016/j.mrfmmm.2010.01.015. Epub 2010 Jan 25.
• [21] 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.
• [22] 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.
• [23] Low-dose Bisphenol A exposure alters the functionality and cellular environment in a human cardiomyocyte model. Environ Pollut. 2023 Oct 15;335:122359. doi: 10.1016/j.envpol.2023.122359. Epub 2023 Aug 9.
• [24] Transcriptomic analysis of human primary bronchial epithelial cells after chloropicrin treatment. Chem Res Toxicol. 2015 Oct 19;28(10):1926-35.