Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTJWHMZ5)

• DOT Name: 26S proteasome non-ATPase regulatory subunit 14 (PSMD14)
• Synonyms: EC 3.4.19.-; 26S proteasome regulatory subunit RPN11; 26S proteasome-associated PAD1 homolog 1
• Gene Name: PSMD14
• Related Disease:
  Alcoholic liver diseases
  Advanced cancer
  Attention deficit hyperactivity disorder
  Breast cancer
  Breast carcinoma
  Carcinoma of esophagus
  Esophageal cancer
  Esophageal squamous cell carcinoma
  Hepatocellular carcinoma
  Neoplasm
  Neoplasm of esophagus
  Peripheral arterial disease
  Peripheral vascular disease
  Plasma cell myeloma
  Prostate cancer
  Prostate carcinoma
  Triple negative breast cancer
  Autoimmune disease
  Colorectal carcinoma
  Carcinoma of liver and intrahepatic biliary tract
  Liver cancer
  Metastatic malignant neoplasm
• UniProt ID: PSDE_HUMAN
• PDB ID: 5GJQ ; 5GJR ; 5L4K ; 5LN3 ; 5M32 ; 5T0C ; 5T0G ; 5T0H ; 5T0I ; 5T0J ; 5VFP ; 5VFQ ; 5VFR ; 5VFS ; 5VFT ; 5VFU ; 5VGZ ; 5VHF ; 5VHH ; 5VHI ; 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
• EC Number: 3.4.19.-
• Pfam ID: PF01398
• Sequence:
  MDRLLRLGGGMPGLGQGPPTDAPAVDTAEQVYISSLALLKMLKHGRAGVPMEVMGLMLGE
  FVDDYTVRVIDVFAMPQSGTGVSVEAVDPVFQAKMLDMLKQTGRPEMVVGWYHSHPGFGC
  WLSGVDINTQQSFEALSERAVAVVVDPIQSVKGKVVIDAFRLINANMMVLGHEPRQTTSN
  LGHLNKPSIQALIHGLNRHYYSITINYRKNELEQKMLLNLHKKSWMEGLTLQDYSEHCKH
  NESVVKEMLELAKNYNKAVEEEDKMTPEQLAIKNVGKQDPKRHLEEHVDVLMTSNIVQCL
  AAMLDTVVFK
• 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. The PSMD14 subunit is a metalloprotease that specifically cleaves 'Lys-63'-linked polyubiquitin chains within the complex. Plays a role in response to double-strand breaks (DSBs): acts as a regulator of non-homologous end joining (NHEJ) by cleaving 'Lys-63'-linked polyubiquitin, thereby promoting retention of JMJD2A/KDM4A on chromatin and restricting TP53BP1 accumulation. Also involved in homologous recombination repair by promoting RAD51 loading.
• Tissue Specificity: Widely expressed. Highest levels in heart and skeletal muscle.
• 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)
  Metalloprotease DUBs (R-HSA-5689901)
  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

22 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Alcoholic liver diseases	DISXEPHQ	Definitive	Biomarker	[1]
Advanced cancer	DISAT1Z9	Strong	Altered Expression	[2]
Attention deficit hyperactivity disorder	DISL8MX9	Strong	Biomarker	[3]
Breast cancer	DIS7DPX1	Strong	Altered Expression	[4]
Breast carcinoma	DIS2UE88	Strong	Altered Expression	[4]
Carcinoma of esophagus	DISS6G4D	Strong	Altered Expression	[5]
Esophageal cancer	DISGB2VN	Strong	Altered Expression	[5]
Esophageal squamous cell carcinoma	DIS5N2GV	Strong	Altered Expression	[6]
Hepatocellular carcinoma	DIS0J828	Strong	Altered Expression	[7]
Neoplasm	DISZKGEW	Strong	Altered Expression	[8]
Neoplasm of esophagus	DISOLKAQ	Strong	Altered Expression	[5]
Peripheral arterial disease	DIS78WFB	Strong	Biomarker	[9]
Peripheral vascular disease	DISXSU1Y	Strong	Biomarker	[9]
Plasma cell myeloma	DIS0DFZ0	Strong	Biomarker	[10]
Prostate cancer	DISF190Y	Strong	Altered Expression	[11]
Prostate carcinoma	DISMJPLE	Strong	Altered Expression	[11]
Triple negative breast cancer	DISAMG6N	Strong	Biomarker	[12]
Autoimmune disease	DISORMTM	moderate	Biomarker	[13]
Colorectal carcinoma	DIS5PYL0	moderate	Biomarker	[2]
Carcinoma of liver and intrahepatic biliary tract	DIS8WA0W	Limited	Biomarker	[14]
Liver cancer	DISDE4BI	Limited	Biomarker	[14]
Metastatic malignant neoplasm	DIS86UK6	Limited	Biomarker	[8]

16 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 non-ATPase regulatory subunit 14 (PSMD14).	[15]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of 26S proteasome non-ATPase regulatory subunit 14 (PSMD14).	[16]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of 26S proteasome non-ATPase regulatory subunit 14 (PSMD14).	[17]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of 26S proteasome non-ATPase regulatory subunit 14 (PSMD14).	[18]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of 26S proteasome non-ATPase regulatory subunit 14 (PSMD14).	[19]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of 26S proteasome non-ATPase regulatory subunit 14 (PSMD14).	[20]
Arsenic	DMTL2Y1	Approved	Arsenic affects the expression of 26S proteasome non-ATPase regulatory subunit 14 (PSMD14).	[21]
Phenobarbital	DMXZOCG	Approved	Phenobarbital affects the expression of 26S proteasome non-ATPase regulatory subunit 14 (PSMD14).	[22]
Fulvestrant	DM0YZC6	Approved	Fulvestrant decreases the expression of 26S proteasome non-ATPase regulatory subunit 14 (PSMD14).	[19]
Clozapine	DMFC71L	Approved	Clozapine increases the expression of 26S proteasome non-ATPase regulatory subunit 14 (PSMD14).	[23]
Afimoxifene	DMFORDT	Phase 2	Afimoxifene decreases the expression of 26S proteasome non-ATPase regulatory subunit 14 (PSMD14).	[19]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of 26S proteasome non-ATPase regulatory subunit 14 (PSMD14).	[25]
MG-132	DMKA2YS	Preclinical	MG-132 increases the expression of 26S proteasome non-ATPase regulatory subunit 14 (PSMD14).	[26]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of 26S proteasome non-ATPase regulatory subunit 14 (PSMD14).	[27]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of 26S proteasome non-ATPase regulatory subunit 14 (PSMD14).	[28]
chloropicrin	DMSGBQA	Investigative	chloropicrin increases the expression of 26S proteasome non-ATPase regulatory subunit 14 (PSMD14).	[29]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene affects the methylation of 26S proteasome non-ATPase regulatory subunit 14 (PSMD14).	[24]

References

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• [11] Targeting POH1 inhibits prostate cancer cell growth and enhances the suppressive efficacy of androgen deprivation and docetaxel.Prostate. 2019 Aug;79(11):1304-1315. doi: 10.1002/pros.23838. Epub 2019 Jun 18.
• [12] PAD1 promotes epithelial-mesenchymal transition and metastasis in triple-negative breast cancer cells by regulating MEK1-ERK1/2-MMP2 signaling.Cancer Lett. 2017 Nov 28;409:30-41. doi: 10.1016/j.canlet.2017.08.019. Epub 2017 Aug 24.
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• [16] 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.
• [17] Transcriptional and Metabolic Dissection of ATRA-Induced Granulocytic Differentiation in NB4 Acute Promyelocytic Leukemia Cells. Cells. 2020 Nov 5;9(11):2423. doi: 10.3390/cells9112423.
• [18] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [19] Comparative gene expression profiling reveals partially overlapping but distinct genomic actions of different antiestrogens in human breast cancer cells. J Cell Biochem. 2006 Aug 1;98(5):1163-84.
• [20] 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.
• [21] Drinking-water arsenic exposure modulates gene expression in human lymphocytes from a U.S. population. Environ Health Perspect. 2008 Apr;116(4):524-31. doi: 10.1289/ehp.10861.
• [22] Reproducible chemical-induced changes in gene expression profiles in human hepatoma HepaRG cells under various experimental conditions. Toxicol In Vitro. 2009 Apr;23(3):466-75. doi: 10.1016/j.tiv.2008.12.018. Epub 2008 Dec 30.
• [23] Cannabidiol Displays Proteomic Similarities to Antipsychotics in Cuprizone-Exposed Human Oligodendrocytic Cell Line MO3.13. Front Mol Neurosci. 2021 May 28;14:673144. doi: 10.3389/fnmol.2021.673144. eCollection 2021.
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• [28] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.
• [29] Transcriptomic analysis of human primary bronchial epithelial cells after chloropicrin treatment. Chem Res Toxicol. 2015 Oct 19;28(10):1926-35.