Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTQGG0JM)

DOT Name Clusterin (CLU)
Synonyms
Aging-associated gene 4 protein; Apolipoprotein J; Apo-J; Complement cytolysis inhibitor; CLI; Complement-associated protein SP-40,40; Ku70-binding protein 1; NA1/NA2; Sulfated glycoprotein 2; SGP-2; Testosterone-repressed prostate message 2; TRPM-2
Gene Name CLU
UniProt ID
CLUS_HUMAN
3D Structure
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2D Sequence (FASTA)
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3D Structure (PDB)
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PDB ID
7ZET; 7ZEU
Pfam ID
PF01093
Sequence
MMKTLLLFVGLLLTWESGQVLGDQTVSDNELQEMSNQGSKYVNKEIQNAVNGVKQIKTLI
EKTNEERKTLLSNLEEAKKKKEDALNETRESETKLKELPGVCNETMMALWEECKPCLKQT
CMKFYARVCRSGSGLVGRQLEEFLNQSSPFYFWMNGDRIDSLLENDRQQTHMLDVMQDHF
SRASSIIDELFQDRFFTREPQDTYHYLPFSLPHRRPHFFFPKSRIVRSLMPFSPYEPLNF
HAMFQPFLEMIHEAQQAMDIHFHSPAFQHPPTEFIREGDDDRTVCREIRHNSTGCLRMKD
QCDKCREILSVDCSTNNPSQAKLRRELDESLQVAERLTRKYNELLKSYQWKMLNTSSLLE
QLNEQFNWVSRLANLTQGEDQYYLRVTTVASHTSDSDVPSGVTEVVVKLFDSDPITVTVP
VEVSRKNPKFMETVAEKALQEYRKKHREE
Function
[Isoform 1]: Functions as extracellular chaperone that prevents aggregation of non native proteins. Prevents stress-induced aggregation of blood plasma proteins. Inhibits formation of amyloid fibrils by APP, APOC2, B2M, CALCA, CSN3, SNCA and aggregation-prone LYZ variants (in vitro). Does not require ATP. Maintains partially unfolded proteins in a state appropriate for subsequent refolding by other chaperones, such as HSPA8/HSC70. Does not refold proteins by itself. Binding to cell surface receptors triggers internalization of the chaperone-client complex and subsequent lysosomal or proteasomal degradation. Protects cells against apoptosis and against cytolysis by complement. Intracellular forms interact with ubiquitin and SCF (SKP1-CUL1-F-box protein) E3 ubiquitin-protein ligase complexes and promote the ubiquitination and subsequent proteasomal degradation of target proteins. Promotes proteasomal degradation of COMMD1 and IKBKB. Modulates NF-kappa-B transcriptional activity. A mitochondrial form suppresses BAX-dependent release of cytochrome c into the cytoplasm and inhibit apoptosis. Plays a role in the regulation of cell proliferation. An intracellular form suppresses stress-induced apoptosis by stabilizing mitochondrial membrane integrity through interaction with HSPA5. Secreted form does not affect caspase or BAX-mediated intrinsic apoptosis and TNF-induced NF-kappa-B-activity. Secreted form act as an important modulator during neuronal differentiation through interaction with STMN3. Plays a role in the clearance of immune complexes that arise during cell injury; [Isoform 6]: Does not affect caspase or BAX-mediated intrinsic apoptosis and TNF-induced NF-kappa-B-activity; [Isoform 4]: Does not affect caspase or BAX-mediated intrinsic apoptosis and TNF-induced NF-kappa-B-activity. Promotes cell death through interaction with BCL2L1 that releases and activates BAX.
Tissue Specificity
Detected in blood plasma, cerebrospinal fluid, milk, seminal plasma and colon mucosa. Detected in the germinal center of colon lymphoid nodules and in colon parasympathetic ganglia of the Auerbach plexus (at protein level). Ubiquitous. Detected in brain, testis, ovary, liver and pancreas, and at lower levels in kidney, heart, spleen and lung.
KEGG Pathway
Complement and coagulation cascades (hsa04610 )
Reactome Pathway
Terminal pathway of complement (R-HSA-166665 )
Antimicrobial peptides (R-HSA-6803157 )
Regulation of Complement cascade (R-HSA-977606 )
Platelet degranulation (R-HSA-114608 )

Molecular Interaction Atlas (MIA) of This DOT

Molecular Interaction Atlas (MIA) Jump to Detail Molecular Interaction Atlas of This DOT
This DOT Affected the Drug Response of 6 Drug(s)
Drug Name Drug ID Highest Status Interaction REF
Doxorubicin DMVP5YE Approved Clusterin (CLU) decreases the response to substance of Doxorubicin. [41]
Cisplatin DMRHGI9 Approved Clusterin (CLU) decreases the response to substance of Cisplatin. [42]
Paclitaxel DMLB81S Approved Clusterin (CLU) decreases the response to substance of Paclitaxel. [42]
Mitoxantrone DMM39BF Approved Clusterin (CLU) affects the response to substance of Mitoxantrone. [43]
Ropivacaine DMSPJG2 Approved Clusterin (CLU) decreases the response to substance of Ropivacaine. [44]
Dacarbazine DMNPZL4 Approved Clusterin (CLU) affects the response to substance of Dacarbazine. [42]
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⏷ Show the Full List of 6 Drug(s)
45 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 Clusterin (CLU). [1]
Ciclosporin DMAZJFX Approved Ciclosporin decreases the expression of Clusterin (CLU). [2]
Tretinoin DM49DUI Approved Tretinoin decreases the expression of Clusterin (CLU). [3]
Acetaminophen DMUIE76 Approved Acetaminophen increases the expression of Clusterin (CLU). [4]
Cupric Sulfate DMP0NFQ Approved Cupric Sulfate affects the expression of Clusterin (CLU). [5]
Estradiol DMUNTE3 Approved Estradiol decreases the expression of Clusterin (CLU). [6]
Arsenic trioxide DM61TA4 Approved Arsenic trioxide increases the expression of Clusterin (CLU). [7]
Calcitriol DM8ZVJ7 Approved Calcitriol increases the expression of Clusterin (CLU). [8]
Testosterone DM7HUNW Approved Testosterone decreases the expression of Clusterin (CLU). [9]
Decitabine DMQL8XJ Approved Decitabine increases the expression of Clusterin (CLU). [10]
Selenium DM25CGV Approved Selenium increases the expression of Clusterin (CLU). [11]
Panobinostat DM58WKG Approved Panobinostat increases the expression of Clusterin (CLU). [12]
Dexamethasone DMMWZET Approved Dexamethasone decreases the expression of Clusterin (CLU). [13]
Bortezomib DMNO38U Approved Bortezomib increases the expression of Clusterin (CLU). [14]
Diethylstilbestrol DMN3UXQ Approved Diethylstilbestrol increases the expression of Clusterin (CLU). [15]
Ethanol DMDRQZU Approved Ethanol increases the expression of Clusterin (CLU). [16]
Dasatinib DMJV2EK Approved Dasatinib increases the expression of Clusterin (CLU). [17]
Menthol DMG2KW7 Approved Menthol decreases the expression of Clusterin (CLU). [18]
Amphotericin B DMTAJQE Approved Amphotericin B decreases the expression of Clusterin (CLU). [19]
Gemcitabine DMSE3I7 Approved Gemcitabine increases the expression of Clusterin (CLU). [20]
Sulindac DM2QHZU Approved Sulindac affects the expression of Clusterin (CLU). [21]
Ibuprofen DM8VCBE Approved Ibuprofen affects the expression of Clusterin (CLU). [22]
Rofecoxib DM3P5DA Approved Rofecoxib increases the expression of Clusterin (CLU). [22]
Romidepsin DMT5GNL Approved Romidepsin increases the expression of Clusterin (CLU). [24]
Levamisole DM5EN79 Approved Levamisole decreases the expression of Clusterin (CLU). [25]
Meclizine DMS7T13 Approved Meclizine affects the expression of Clusterin (CLU). [21]
Methazolamide DM7J2TA Approved Methazolamide affects the expression of Clusterin (CLU). [21]
Megestrol DMDH9KX Approved Megestrol affects the expression of Clusterin (CLU). [21]
Dihydrotestosterone DM3S8XC Phase 4 Dihydrotestosterone decreases the expression of Clusterin (CLU). [26]
SNDX-275 DMH7W9X Phase 3 SNDX-275 increases the expression of Clusterin (CLU). [12]
Resveratrol DM3RWXL Phase 3 Resveratrol increases the expression of Clusterin (CLU). [27]
Seocalcitol DMKL9QO Phase 3 Seocalcitol increases the expression of Clusterin (CLU). [8]
Verapamil DMA7PEW Phase 2/3 Trial Verapamil affects the expression of Clusterin (CLU). [21]
Tocopherol DMBIJZ6 Phase 2 Tocopherol increases the expression of Clusterin (CLU). [11]
Belinostat DM6OC53 Phase 2 Belinostat increases the expression of Clusterin (CLU). [28]
PEITC DMOMN31 Phase 2 PEITC increases the expression of Clusterin (CLU). [29]
(+)-JQ1 DM1CZSJ Phase 1 (+)-JQ1 increases the expression of Clusterin (CLU). [31]
PMID28460551-Compound-2 DM4DOUB Patented PMID28460551-Compound-2 decreases the expression of Clusterin (CLU). [33]
Bisphenol A DM2ZLD7 Investigative Bisphenol A increases the expression of Clusterin (CLU). [34]
Trichostatin A DM9C8NX Investigative Trichostatin A increases the expression of Clusterin (CLU). [35]
Formaldehyde DM7Q6M0 Investigative Formaldehyde increases the expression of Clusterin (CLU). [36]
Milchsaure DM462BT Investigative Milchsaure increases the expression of Clusterin (CLU). [37]
Phencyclidine DMQBEYX Investigative Phencyclidine increases the expression of Clusterin (CLU). [38]
[3H]methyltrienolone DMTSGOW Investigative [3H]methyltrienolone decreases the expression of Clusterin (CLU). [39]
Okadaic acid DM47CO1 Investigative Okadaic acid increases the expression of Clusterin (CLU). [40]
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⏷ Show the Full List of 45 Drug(s)
3 Drug(s) Affected the Post-Translational Modifications of This DOT
Drug Name Drug ID Highest Status Interaction REF
Olanzapine DMPFN6Y Approved Olanzapine affects the phosphorylation of Clusterin (CLU). [23]
Benzo(a)pyrene DMN7J43 Phase 1 Benzo(a)pyrene affects the methylation of Clusterin (CLU). [30]
TAK-243 DM4GKV2 Phase 1 TAK-243 increases the sumoylation of Clusterin (CLU). [32]
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References

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11 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.
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13 Identification of mechanisms of action of bisphenol a-induced human preadipocyte differentiation by transcriptional profiling. Obesity (Silver Spring). 2014 Nov;22(11):2333-43.
14 The proapoptotic effect of zoledronic acid is independent of either the bone microenvironment or the intrinsic resistance to bortezomib of myeloma cells and is enhanced by the combination with arsenic trioxide. Exp Hematol. 2011 Jan;39(1):55-65.
15 Analysis of gene expression induced by diethylstilbestrol (DES) in human primitive Mullerian duct cells using microarray. Cancer Lett. 2005 Apr 8;220(2):197-210.
16 Comparison of replicative senescence and stress-induced premature senescence combining differential display and low-density DNA arrays. FEBS Lett. 2005 Jul 4;579(17):3651-9. doi: 10.1016/j.febslet.2005.05.056.
17 Dasatinib reverses cancer-associated fibroblasts (CAFs) from primary lung carcinomas to a phenotype comparable to that of normal fibroblasts. Mol Cancer. 2010 Jun 27;9:168.
18 Repurposing L-menthol for systems medicine and cancer therapeutics? L-menthol induces apoptosis through caspase 10 and by suppressing HSP90. OMICS. 2016 Jan;20(1):53-64.
19 Differential expression of microRNAs and their predicted targets in renal cells exposed to amphotericin B and its complex with copper (II) ions. Toxicol Mech Methods. 2017 Sep;27(7):537-543. doi: 10.1080/15376516.2017.1333554. Epub 2017 Jun 8.
20 Chemosensitization of gemcitabine-resistant human bladder cancer cell line both in vitro and in vivo using antisense oligonucleotide targeting the anti-apoptotic gene, clusterin. BJU Int. 2009 Feb;103(3):384-90. doi: 10.1111/j.1464-410X.2008.08098.x. Epub 2008 Oct 24.
21 Discovery of molecular mechanisms of neuroprotection using cell-based bioassays and oligonucleotide arrays. Physiol Genomics. 2002 Oct 29;11(2):45-52. doi: 10.1152/physiolgenomics.00064.2002.
22 Rofecoxib modulates multiple gene expression pathways in a clinical model of acute inflammatory pain. Pain. 2007 Mar;128(1-2):136-47.
23 Effects of olanzapine on serum protein phosphorylation patterns in patients with schizophrenia. Proteomics Clin Appl. 2015 Oct;9(9-10):907-16. doi: 10.1002/prca.201400148. Epub 2015 May 15.
24 5-Aza-2'-deoxycytidine and depsipeptide synergistically induce expression of BIK (BCL2-interacting killer). Biochem Biophys Res Commun. 2006 Dec 15;351(2):455-61. doi: 10.1016/j.bbrc.2006.10.055. Epub 2006 Oct 18.
25 Levamisole induced apoptosis in cultured vascular endothelial cells. Br J Pharmacol. 2000 Dec;131(8):1577-83.
26 Dicofol degradation to p,p'-dichlorobenzophenone - a potential antiandrogen. Toxicology. 2011 Apr 11;282(3):88-93. doi: 10.1016/j.tox.2011.01.016. Epub 2011 Feb 1.
27 Quantitative nuclear proteomics identifies that miR-137-mediated EZH2 reduction regulates resveratrol-induced apoptosis of neuroblastoma cells. Mol Cell Proteomics. 2015 Feb;14(2):316-28. doi: 10.1074/mcp.M114.041905. Epub 2014 Dec 11.
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29 Phenethyl isothiocyanate alters the gene expression and the levels of protein associated with cell cycle regulation in human glioblastoma GBM 8401 cells. Environ Toxicol. 2017 Jan;32(1):176-187.
30 Effect of aflatoxin B(1), benzo[a]pyrene, and methapyrilene on transcriptomic and epigenetic alterations in human liver HepaRG cells. Food Chem Toxicol. 2018 Nov;121:214-223. doi: 10.1016/j.fct.2018.08.034. Epub 2018 Aug 26.
31 Inhibition of BRD4 attenuates tumor cell self-renewal and suppresses stem cell signaling in MYC driven medulloblastoma. Oncotarget. 2014 May 15;5(9):2355-71.
32 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.
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