Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTJ4V337)

• DOT Name: 26S proteasome regulatory subunit 7 (PSMC2)
• Synonyms: 26S proteasome AAA-ATPase subunit RPT1; Proteasome 26S subunit ATPase 2
• Gene Name: PSMC2
• Related Disease:
  Advanced cancer
  Alveolar soft part sarcoma
  Bone osteosarcoma
  Colorectal carcinoma
  Osteosarcoma
• UniProt ID: PRS7_HUMAN
• PDB ID: 5GJQ ; 5GJR ; 5L4G ; 5LN3 ; 5M32 ; 5T0C ; 5T0G ; 5T0H ; 5T0I ; 5T0J ; 5VFP ; 5VFQ ; 5VFR ; 5VFS ; 5VFT ; 5VFU ; 5VGZ ; 5VHF ; 5VHH ; 5VHI ; 5VHJ ; 5VHM ; 5VHN ; 5VHO ; 5VHP ; 5VHQ ; 5VHR ; 5VHS ; 6MSB ; 6MSD ; 6MSE ; 6MSG ; 6MSH ; 6MSJ ; 6MSK ; 6WJD ; 6WJN ; 7QXN ; 7QXP ; 7QXU ; 7QXW ; 7QXX ; 7QY7 ; 7QYA ; 7QYB ; 7W37 ; 7W38 ; 7W39 ; 7W3A ; 7W3B ; 7W3C ; 7W3F ; 7W3G ; 7W3H ; 7W3I ; 7W3J ; 7W3K ; 7W3M ; 8CVT
• Pfam ID: PF00004 ; PF17862 ; PF21236
• Sequence:
  MPDYLGADQRKTKEDEKDDKPIRALDEGDIALLKTYGQSTYSRQIKQVEDDIQQLLKKIN
  ELTGIKESDTGLAPPALWDLAADKQTLQSEQPLQVARCTKIINADSEDPKYIINVKQFAK
  FVVDLSDQVAPTDIEEGMRVGVDRNKYQIHIPLPPKIDPTVTMMQVEEKPDVTYSDVGGC
  KEQIEKLREVVETPLLHPERFVNLGIEPPKGVLLFGPPGTGKTLCARAVANRTDACFIRV
  IGSELVQKYVGEGARMVRELFEMARTKKACLIFFDEIDAIGGARFDDGAGGDNEVQRTML
  ELINQLDGFDPRGNIKVLMATNRPDTLDPALMRPGRLDRKIEFSLPDLEGRTHIFKIHAR
  SMSVERDIRFELLARLCPNSTGAEIRSVCTEAGMFAIRARRKIATEKDFLEAVNKVIKSY
  AKFSATPRYMTYN
• Function: Component of the 26S proteasome, a multiprotein complex involved in the ATP-dependent degradation of ubiquitinated proteins. This complex plays a key role in the maintenance of protein homeostasis by removing misfolded or damaged proteins, which could impair cellular functions, and by removing proteins whose functions are no longer required. Therefore, the proteasome participates in numerous cellular processes, including cell cycle progression, apoptosis, or DNA damage repair. PSMC2 belongs to the heterohexameric ring of AAA (ATPases associated with diverse cellular activities) proteins that unfolds ubiquitinated target proteins that are concurrently translocated into a proteolytic chamber and degraded into peptides.
• 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)
  Epstein-Barr virus infection (hsa05169)
• 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)
  Neutrophil degranulation (R-HSA-6798695)
  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

5 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Advanced cancer	DISAT1Z9	Strong	Altered Expression	[1]
Alveolar soft part sarcoma	DISLKJKZ	Strong	Biomarker	[2]
Bone osteosarcoma	DIST1004	Strong	Biomarker	[3]
Colorectal carcinoma	DIS5PYL0	Strong	Altered Expression	[1]
Osteosarcoma	DISLQ7E2	Strong	Biomarker	[3]

19 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 26S proteasome regulatory subunit 7 (PSMC2).	[4]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of 26S proteasome regulatory subunit 7 (PSMC2).	[5]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of 26S proteasome regulatory subunit 7 (PSMC2).	[6]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of 26S proteasome regulatory subunit 7 (PSMC2).	[7]
Doxorubicin	DMVP5YE	Approved	Doxorubicin increases the expression of 26S proteasome regulatory subunit 7 (PSMC2).	[8]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of 26S proteasome regulatory subunit 7 (PSMC2).	[9]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of 26S proteasome regulatory subunit 7 (PSMC2).	[10]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide decreases the expression of 26S proteasome regulatory subunit 7 (PSMC2).	[12]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide increases the expression of 26S proteasome regulatory subunit 7 (PSMC2).	[13]
Piroxicam	DMTK234	Approved	Piroxicam decreases the expression of 26S proteasome regulatory subunit 7 (PSMC2).	[14]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the expression of 26S proteasome regulatory subunit 7 (PSMC2).	[15]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of 26S proteasome regulatory subunit 7 (PSMC2).	[17]
MG-132	DMKA2YS	Preclinical	MG-132 increases the expression of 26S proteasome regulatory subunit 7 (PSMC2).	[18]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of 26S proteasome regulatory subunit 7 (PSMC2).	[19]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of 26S proteasome regulatory subunit 7 (PSMC2).	[20]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of 26S proteasome regulatory subunit 7 (PSMC2).	[21]
chloropicrin	DMSGBQA	Investigative	chloropicrin increases the expression of 26S proteasome regulatory subunit 7 (PSMC2).	[22]
Butanoic acid	DMTAJP7	Investigative	Butanoic acid decreases the expression of 26S proteasome regulatory subunit 7 (PSMC2).	[13]
Aminohippuric acid	DMUN54G	Investigative	Aminohippuric acid affects the expression of 26S proteasome regulatory subunit 7 (PSMC2).	[23]

2 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 26S proteasome regulatory subunit 7 (PSMC2).	[11]
TAK-243	DM4GKV2	Phase 1	TAK-243 decreases the sumoylation of 26S proteasome regulatory subunit 7 (PSMC2).	[16]

References

• [1] Silencing of Proteasome 26S Subunit ATPase 2 Regulates Colorectal Cancer Cell Proliferation, Apoptosis, and Migration.Chemotherapy. 2019;64(3):146-154. doi: 10.1159/000502224. Epub 2019 Nov 12.
• [2] A comparative genomic approach for identifying synthetic lethal interactions in human cancer.Cancer Res. 2013 Oct 15;73(20):6128-36. doi: 10.1158/0008-5472.CAN-12-3956. Epub 2013 Aug 26.
• [3] Lower miR-630 expression predicts poor prognosis of osteosarcoma and promotes cell proliferation, migration and invasion by targeting PSMC2.Eur Rev Med Pharmacol Sci. 2019 Mar;23(5):1915-1925. doi: 10.26355/eurrev_201903_17229.
• [4] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [5] 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.
• [6] 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.
• [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] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [10] 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.
• [11] 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.
• [12] Proteomic and functional analyses reveal a dual molecular mechanism underlying arsenic-induced apoptosis in human multiple myeloma cells. J Proteome Res. 2009 Jun;8(6):3006-19.
• [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] Apoptosis induced by piroxicam plus cisplatin combined treatment is triggered by p21 in mesothelioma. PLoS One. 2011;6(8):e23569.
• [15] 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.
• [16] 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.
• [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] 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.
• [19] Characterization of the Molecular Alterations Induced by the Prolonged Exposure of Normal Colon Mucosa and Colon Cancer Cells to Low-Dose Bisphenol A. Int J Mol Sci. 2022 Oct 1;23(19):11620. doi: 10.3390/ijms231911620.
• [20] 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.
• [21] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.
• [22] Transcriptomic analysis of human primary bronchial epithelial cells after chloropicrin treatment. Chem Res Toxicol. 2015 Oct 19;28(10):1926-35.
• [23] Identification of molecular signatures predicting the carcinogenicity of polycyclic aromatic hydrocarbons (PAHs). Toxicol Lett. 2012 Jul 7;212(1):18-28. doi: 10.1016/j.toxlet.2012.04.013. Epub 2012 May 1.