Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTG8997V)

DOT Name 26S proteasome regulatory subunit 10B (PSMC6)
Synonyms 26S proteasome AAA-ATPase subunit RPT4; Proteasome 26S subunit ATPase 6; Proteasome subunit p42
Gene Name PSMC6
Related Disease
Adult glioblastoma ( )
Glioblastoma multiforme ( )
Hepatocellular carcinoma ( )
Acute myelogenous leukaemia ( )
Carcinoma ( )
Juvenile idiopathic arthritis ( )
Plasma cell myeloma ( )
Promyelocytic leukaemia ( )
Prostate cancer ( )
Prostate carcinoma ( )
Asthma ( )
Brain infarction ( )
Type-1 diabetes ( )
UniProt ID
PRS10_HUMAN
3D Structure
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2D Sequence (FASTA)
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3D Structure (PDB)
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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 ; 6WJN ; 7QY7 ; 8CVT
Pfam ID
PF00004 ; PF17862 ; PF16450
Sequence
MADPRDKALQDYRKKLLEHKEIDGRLKELREQLKELTKQYEKSENDLKALQSVGQIVGEV
LKQLTEEKFIVKATNGPRYVVGCRRQLDKSKLKPGTRVALDMTTLTIMRYLPREVDPLVY
NMSHEDPGNVSYSEIGGLSEQIRELREVIELPLTNPELFQRVGIIPPKGCLLYGPPGTGK
TLLARAVASQLDCNFLKVVSSSIVDKYIGESARLIREMFNYARDHQPCIIFMDEIDAIGG
RRFSEGTSADREIQRTLMELLNQMDGFDTLHRVKMIMATNRPDTLDPALLRPGRLDRKIH
IDLPNEQARLDILKIHAGPITKHGEIDYEAIVKLSDGFNGADLRNVCTEAGMFAIRADHD
FVVQEDFMKAVRKVADSKKLESKLDYKPV
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. PSMC6 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 )
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 )
SARS-CoV-1 targets host intracellular signalling and regulatory pathways (R-HSA-9735871 )
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

13 Disease(s) Related to This DOT
Disease Name Disease ID Evidence Level Mode of Inheritance REF
Adult glioblastoma DISVP4LU Definitive Altered Expression [1]
Glioblastoma multiforme DISK8246 Definitive Altered Expression [1]
Hepatocellular carcinoma DIS0J828 Definitive Biomarker [2]
Acute myelogenous leukaemia DISCSPTN Strong Biomarker [3]
Carcinoma DISH9F1N Strong Altered Expression [4]
Juvenile idiopathic arthritis DISQZGBV Strong Genetic Variation [5]
Plasma cell myeloma DIS0DFZ0 Strong Biomarker [6]
Promyelocytic leukaemia DISYGG13 Strong Biomarker [7]
Prostate cancer DISF190Y moderate Biomarker [8]
Prostate carcinoma DISMJPLE moderate Biomarker [8]
Asthma DISW9QNS Limited Genetic Variation [9]
Brain infarction DISPPGYK Limited Genetic Variation [10]
Type-1 diabetes DIS7HLUB Limited Genetic Variation [11]
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⏷ Show the Full List of 13 Disease(s)
Molecular Interaction Atlas (MIA) Jump to Detail Molecular Interaction Atlas of This DOT
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 26S proteasome regulatory subunit 10B (PSMC6). [12]
Arsenic DMTL2Y1 Approved Arsenic increases the methylation of 26S proteasome regulatory subunit 10B (PSMC6). [16]
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11 Drug(s) Affected the Gene/Protein Processing of This DOT
Drug Name Drug ID Highest Status Interaction REF
Doxorubicin DMVP5YE Approved Doxorubicin affects the expression of 26S proteasome regulatory subunit 10B (PSMC6). [13]
Cupric Sulfate DMP0NFQ Approved Cupric Sulfate decreases the expression of 26S proteasome regulatory subunit 10B (PSMC6). [14]
Ivermectin DMDBX5F Approved Ivermectin decreases the expression of 26S proteasome regulatory subunit 10B (PSMC6). [15]
Temozolomide DMKECZD Approved Temozolomide increases the expression of 26S proteasome regulatory subunit 10B (PSMC6). [17]
Hydrogen peroxide DM1NG5W Approved Hydrogen peroxide affects the expression of 26S proteasome regulatory subunit 10B (PSMC6). [18]
Marinol DM70IK5 Approved Marinol decreases the expression of 26S proteasome regulatory subunit 10B (PSMC6). [19]
Aspirin DM672AH Approved Aspirin decreases the expression of 26S proteasome regulatory subunit 10B (PSMC6). [20]
Mifepristone DMGZQEF Approved Mifepristone increases the expression of 26S proteasome regulatory subunit 10B (PSMC6). [21]
MG-132 DMKA2YS Preclinical MG-132 increases the expression of 26S proteasome regulatory subunit 10B (PSMC6). [22]
Bisphenol A DM2ZLD7 Investigative Bisphenol A decreases the expression of 26S proteasome regulatory subunit 10B (PSMC6). [23]
KOJIC ACID DMP84CS Investigative KOJIC ACID decreases the expression of 26S proteasome regulatory subunit 10B (PSMC6). [24]
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⏷ Show the Full List of 11 Drug(s)

References

1 EBP1 protein modulates the expression of human MHC class II molecules in non-hematopoietic cancer cells.Int J Oncol. 2015 Aug;47(2):481-9. doi: 10.3892/ijo.2015.3051. Epub 2015 Jun 16.
2 YC-1 Antagonizes Wnt/-Catenin Signaling Through the EBP1 p42 Isoform in Hepatocellular Carcinoma.Cancers (Basel). 2019 May 13;11(5):661. doi: 10.3390/cancers11050661.
3 The presence of C/EBP and its degradation are both required for TRIB2-mediated leukaemia.Oncogene. 2016 Oct 6;35(40):5272-5281. doi: 10.1038/onc.2016.66. Epub 2016 Mar 21.
4 Overexpression of the Ets-1 transcription factor in human breast cancer.Br J Cancer. 2004 Oct 4;91(7):1308-15. doi: 10.1038/sj.bjc.6602128.
5 Juvenile idiopathic arthritis subtype- and sex-specific associations with genetic variants in the PSMA6/PSMC6/PSMA3 gene cluster.Pediatr Neonatol. 2014 Oct;55(5):393-403. doi: 10.1016/j.pedneo.2014.01.007. Epub 2014 May 27.
6 CRISPR Genome-Wide Screening Identifies Dependence on the Proteasome Subunit PSMC6 for Bortezomib Sensitivity in Multiple Myeloma.Mol Cancer Ther. 2017 Dec;16(12):2862-2870. doi: 10.1158/1535-7163.MCT-17-0130. Epub 2017 Sep 27.
7 Restoration of CCAAT enhancer binding protein P42 induces myeloid differentiation and overcomes all-trans retinoic acid resistance in human acute promyelocytic leukemia NB4-R1 cells.Int J Oncol. 2015 Nov;47(5):1685-95. doi: 10.3892/ijo.2015.3163. Epub 2015 Sep 14.
8 Novel identification of the ETS-1 splice variants p42 and p27 in prostate cancer cell lines.Oncol Rep. 2012 May;27(5):1321-4. doi: 10.3892/or.2012.1667. Epub 2012 Feb 1.
9 Evaluation of proteasomal gene polymorphisms in Lithuanian patients with asthma.J Asthma. 2015 Jun;52(5):447-52. doi: 10.3109/02770903.2014.982761. Epub 2014 Nov 21.
10 Thrombin Preconditioning Enhances Therapeutic Efficacy of Human Wharton's Jelly-Derived Mesenchymal Stem Cells in Severe Neonatal Hypoxic Ischemic Encephalopathy.Int J Mol Sci. 2019 May 20;20(10):2477. doi: 10.3390/ijms20102477.
11 Genetic variations in the PSMA3, PSMA6 and PSMC6 genes are associated with type 1 diabetes in Latvians and with expression level of number of UPS-related and T1DM-susceptible genes in HapMap individuals.Mol Genet Genomics. 2016 Apr;291(2):891-903. doi: 10.1007/s00438-015-1153-0. Epub 2015 Dec 12.
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 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.
14 Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
15 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.
16 Epigenetic changes in individuals with arsenicosis. Chem Res Toxicol. 2011 Feb 18;24(2):165-7. doi: 10.1021/tx1004419. Epub 2011 Feb 4.
17 Temozolomide induces activation of Wnt/-catenin signaling in glioma cells via PI3K/Akt pathway: implications in glioma therapy. Cell Biol Toxicol. 2020 Jun;36(3):273-278. doi: 10.1007/s10565-019-09502-7. Epub 2019 Nov 22.
18 Global gene expression analysis reveals differences in cellular responses to hydroxyl- and superoxide anion radical-induced oxidative stress in caco-2 cells. Toxicol Sci. 2010 Apr;114(2):193-203. doi: 10.1093/toxsci/kfp309. Epub 2009 Dec 31.
19 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.
20 Expression profile analysis of colon cancer cells in response to sulindac or aspirin. Biochem Biophys Res Commun. 2002 Mar 29;292(2):498-512.
21 Mifepristone induced progesterone withdrawal reveals novel regulatory pathways in human endometrium. Mol Hum Reprod. 2007 Sep;13(9):641-54.
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 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.
24 Toxicogenomics of kojic acid on gene expression profiling of a375 human malignant melanoma cells. Biol Pharm Bull. 2006 Apr;29(4):655-69.