Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTD5B41X)

DOT Name S-phase kinase-associated protein 2 (SKP2)
Synonyms Cyclin-A/CDK2-associated protein p45; F-box protein Skp2; F-box/LRR-repeat protein 1; p45skp2
Gene Name SKP2
UniProt ID
SKP2_HUMAN
3D Structure
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2D Sequence (FASTA)
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3D Structure (PDB)
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PDB ID
1FQV; 1FS1; 1FS2; 1LDK; 2ASS; 2AST; 7B5L; 7B5M; 7B5R; 7LUO; 7Z8T; 7Z8V; 7ZBW; 7ZBZ; 8BYA; 8BYL; 8CDJ; 8CDK; 8OR0; 8OR3; 8OR4
Pfam ID
PF12937
Sequence
MHRKHLQEIPDLSSNVATSFTWGWDSSKTSELLSGMGVSALEKEEPDSENIPQELLSNLG
HPESPPRKRLKSKGSDKDFVIVRRPKLNRENFPGVSWDSLPDELLLGIFSCLCLPELLKV
SGVCKRWYRLASDESLWQTLDLTGKNLHPDVTGRLLSQGVIAFRCPRSFMDQPLAEHFSP
FRVQHMDLSNSVIEVSTLHGILSQCSKLQNLSLEGLRLSDPIVNTLAKNSNLVRLNLSGC
SGFSEFALQTLLSSCSRLDELNLSWCFDFTEKHVQVAVAHVSETITQLNLSGYRKNLQKS
DLSTLVRRCPNLVHLDLSDSVMLKNDCFQEFFQLNYLQHLSLSRCYDIIPETLLELGEIP
TLKTLQVFGIVPDGTLQLLKEALPHLQINCSHFTTIARPTIGNKKNQEIWGIKCRLTLQK
PSCL
Function
Substrate recognition component of a SCF (SKP1-CUL1-F-box protein) E3 ubiquitin-protein ligase complex which mediates the ubiquitination and subsequent proteasomal degradation of target proteins involved in cell cycle progression, signal transduction and transcription. Specifically recognizes phosphorylated CDKN1B/p27kip and is involved in regulation of G1/S transition. Degradation of CDKN1B/p27kip also requires CKS1. Recognizes target proteins ORC1, CDT1, RBL2, KMT2A/MLL1, CDK9, RAG2, FOXO1, UBP43, YTHDF2, and probably MYC, TOB1 and TAL1. Degradation of TAL1 also requires STUB1. Recognizes CDKN1A in association with CCNE1 or CCNE2 and CDK2. Promotes ubiquitination and destruction of CDH1 in a CK1-dependent manner, thereby regulating cell migration ; Through the ubiquitin-mediated proteasomal degradation of hepatitis C virus non-structural protein 5A, has an antiviral activity towards that virus.
KEGG Pathway
FoxO sig.ling pathway (hsa04068 )
Cell cycle (hsa04110 )
Ubiquitin mediated proteolysis (hsa04120 )
mTOR sig.ling pathway (hsa04150 )
Epstein-Barr virus infection (hsa05169 )
Pathways in cancer (hsa05200 )
Viral carcinogenesis (hsa05203 )
Small cell lung cancer (hsa05222 )
Reactome Pathway
SCF(Skp2)-mediated degradation of p27/p21 (R-HSA-187577 )
Ub-specific processing proteases (R-HSA-5689880 )
Orc1 removal from chromatin (R-HSA-68949 )
Cyclin D associated events in G1 (R-HSA-69231 )
Regulation of RUNX2 expression and activity (R-HSA-8939902 )
Neddylation (R-HSA-8951664 )
Aberrant regulation of mitotic exit in cancer due to RB1 defects (R-HSA-9687136 )
Regulation of BACH1 activity (R-HSA-9708530 )
Antigen processing (R-HSA-983168 )
APC/C (R-HSA-174178 )
BioCyc Pathway
MetaCyc:ENSG00000145604-MONOMER

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 4 Drug(s)
Drug Name Drug ID Highest Status Interaction REF
Irinotecan DMP6SC2 Approved S-phase kinase-associated protein 2 (SKP2) increases the response to substance of Irinotecan. [40]
Paclitaxel DMLB81S Approved S-phase kinase-associated protein 2 (SKP2) affects the response to substance of Paclitaxel. [41]
Topotecan DMP6G8T Approved S-phase kinase-associated protein 2 (SKP2) affects the response to substance of Topotecan. [41]
Vinblastine DM5TVS3 Approved S-phase kinase-associated protein 2 (SKP2) affects the response to substance of Vinblastine. [41]
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4 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 S-phase kinase-associated protein 2 (SKP2). [1]
TAK-243 DM4GKV2 Phase 1 TAK-243 increases the sumoylation of S-phase kinase-associated protein 2 (SKP2). [28]
PMID28870136-Compound-52 DMFDERP Patented PMID28870136-Compound-52 decreases the phosphorylation of S-phase kinase-associated protein 2 (SKP2). [30]
Coumarin DM0N8ZM Investigative Coumarin affects the phosphorylation of S-phase kinase-associated protein 2 (SKP2). [30]
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39 Drug(s) Affected the Gene/Protein Processing of This DOT
Drug Name Drug ID Highest Status Interaction REF
Ciclosporin DMAZJFX Approved Ciclosporin decreases the expression of S-phase kinase-associated protein 2 (SKP2). [2]
Tretinoin DM49DUI Approved Tretinoin decreases the expression of S-phase kinase-associated protein 2 (SKP2). [3]
Acetaminophen DMUIE76 Approved Acetaminophen decreases the expression of S-phase kinase-associated protein 2 (SKP2). [4]
Doxorubicin DMVP5YE Approved Doxorubicin affects the expression of S-phase kinase-associated protein 2 (SKP2). [5]
Cupric Sulfate DMP0NFQ Approved Cupric Sulfate decreases the expression of S-phase kinase-associated protein 2 (SKP2). [6]
Estradiol DMUNTE3 Approved Estradiol increases the expression of S-phase kinase-associated protein 2 (SKP2). [7]
Arsenic DMTL2Y1 Approved Arsenic decreases the expression of S-phase kinase-associated protein 2 (SKP2). [8]
Quercetin DM3NC4M Approved Quercetin decreases the expression of S-phase kinase-associated protein 2 (SKP2). [9]
Arsenic trioxide DM61TA4 Approved Arsenic trioxide decreases the expression of S-phase kinase-associated protein 2 (SKP2). [10]
Calcitriol DM8ZVJ7 Approved Calcitriol decreases the expression of S-phase kinase-associated protein 2 (SKP2). [11]
Testosterone DM7HUNW Approved Testosterone decreases the expression of S-phase kinase-associated protein 2 (SKP2). [11]
Methotrexate DM2TEOL Approved Methotrexate decreases the expression of S-phase kinase-associated protein 2 (SKP2). [12]
Demecolcine DMCZQGK Approved Demecolcine decreases the expression of S-phase kinase-associated protein 2 (SKP2). [13]
Cannabidiol DM0659E Approved Cannabidiol decreases the expression of S-phase kinase-associated protein 2 (SKP2). [14]
Bortezomib DMNO38U Approved Bortezomib decreases the expression of S-phase kinase-associated protein 2 (SKP2). [15]
Troglitazone DM3VFPD Approved Troglitazone decreases the expression of S-phase kinase-associated protein 2 (SKP2). [16]
Diethylstilbestrol DMN3UXQ Approved Diethylstilbestrol decreases the expression of S-phase kinase-associated protein 2 (SKP2). [17]
Azathioprine DMMZSXQ Approved Azathioprine decreases the expression of S-phase kinase-associated protein 2 (SKP2). [18]
Piroxicam DMTK234 Approved Piroxicam decreases the expression of S-phase kinase-associated protein 2 (SKP2). [19]
Orlistat DMRJSP8 Approved Orlistat decreases the expression of S-phase kinase-associated protein 2 (SKP2). [20]
Gamolenic acid DMQN30Z Approved Gamolenic acid decreases the expression of S-phase kinase-associated protein 2 (SKP2). [21]
Urethane DM7NSI0 Phase 4 Urethane decreases the expression of S-phase kinase-associated protein 2 (SKP2). [22]
Silymarin DMXBYQR Phase 4 Silymarin decreases the expression of S-phase kinase-associated protein 2 (SKP2). [23]
Tamibarotene DM3G74J Phase 3 Tamibarotene decreases the expression of S-phase kinase-associated protein 2 (SKP2). [3]
GSK2110183 DMZHB37 Phase 2 GSK2110183 decreases the expression of S-phase kinase-associated protein 2 (SKP2). [24]
PEITC DMOMN31 Phase 2 PEITC decreases the expression of S-phase kinase-associated protein 2 (SKP2). [25]
Benzo(a)pyrene DMN7J43 Phase 1 Benzo(a)pyrene decreases the expression of S-phase kinase-associated protein 2 (SKP2). [2]
(+)-JQ1 DM1CZSJ Phase 1 (+)-JQ1 decreases the expression of S-phase kinase-associated protein 2 (SKP2). [26]
Leflunomide DMR8ONJ Phase 1 Trial Leflunomide decreases the expression of S-phase kinase-associated protein 2 (SKP2). [27]
PMID28460551-Compound-2 DM4DOUB Patented PMID28460551-Compound-2 decreases the expression of S-phase kinase-associated protein 2 (SKP2). [29]
Bisphenol A DM2ZLD7 Investigative Bisphenol A affects the expression of S-phase kinase-associated protein 2 (SKP2). [31]
Formaldehyde DM7Q6M0 Investigative Formaldehyde decreases the expression of S-phase kinase-associated protein 2 (SKP2). [32]
Coumestrol DM40TBU Investigative Coumestrol increases the expression of S-phase kinase-associated protein 2 (SKP2). [33]
Glyphosate DM0AFY7 Investigative Glyphosate decreases the expression of S-phase kinase-associated protein 2 (SKP2). [34]
Nickel chloride DMI12Y8 Investigative Nickel chloride decreases the expression of S-phase kinase-associated protein 2 (SKP2). [35]
geraniol DMS3CBD Investigative geraniol decreases the expression of S-phase kinase-associated protein 2 (SKP2). [36]
Rapamycin Immunosuppressant Drug DM678IB Investigative Rapamycin Immunosuppressant Drug decreases the expression of S-phase kinase-associated protein 2 (SKP2). [37]
Arachidonic acid DMUOQZD Investigative Arachidonic acid decreases the expression of S-phase kinase-associated protein 2 (SKP2). [38]
GW-3965 DMG60ET Investigative GW-3965 decreases the expression of S-phase kinase-associated protein 2 (SKP2). [39]
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⏷ Show the Full List of 39 Drug(s)

References

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3 Differential modulation of PI3-kinase/Akt pathway during all-trans retinoic acid- and Am80-induced HL-60 cell differentiation revealed by DNA microarray analysis. Biochem Pharmacol. 2004 Dec 1;68(11):2177-86.
4 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.
5 Differential effects of doxorubicin treatment on cell cycle arrest and Skp2 expression in breast cancer cells. Anticancer Drugs. 2007 Nov;18(10):1113-21. doi: 10.1097/CAD.0b013e3282ef4571.
6 Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
7 Estrogen and progesterone regulate p27kip1 levels via the ubiquitin-proteasome system: pathogenic and therapeutic implications for endometrial cancer. PLoS One. 2012;7(9):e46072. doi: 10.1371/journal.pone.0046072. Epub 2012 Sep 27.
8 LncRNA UCA1 attenuates autophagy-dependent cell death through blocking autophagic flux under arsenic stress. Toxicol Lett. 2018 Mar 1;284:195-204. doi: 10.1016/j.toxlet.2017.12.009. Epub 2017 Dec 15.
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10 E2F1 downregulation by arsenic trioxide in lung adenocarcinoma. Int J Oncol. 2014 Nov;45(5):2033-43. doi: 10.3892/ijo.2014.2609. Epub 2014 Aug 19.
11 Effects of 1alpha,25 dihydroxyvitamin D3 and testosterone on miRNA and mRNA expression in LNCaP cells. Mol Cancer. 2011 May 18;10:58.
12 Methotrexate modulates folate phenotype and inflammatory profile in EA.hy 926 cells. Eur J Pharmacol. 2014 Jun 5;732:60-7.
13 Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
14 Cannabidiol enhances cytotoxicity of anti-cancer drugs in human head and neck squamous cell carcinoma. Sci Rep. 2020 Nov 26;10(1):20622. doi: 10.1038/s41598-020-77674-y.
15 S-phase kinase protein 2 is an attractive therapeutic target in a subset of diffuse large B-cell lymphoma. J Pathol. 2008 Dec;216(4):483-94. doi: 10.1002/path.2433.
16 Troglitazone induces p27Kip1-associated cell-cycle arrest through down-regulating Skp2 in human hepatoma cells. Hepatology. 2003 May;37(5):1086-96. doi: 10.1053/jhep.2003.50186.
17 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.
18 A transcriptomics-based in vitro assay for predicting chemical genotoxicity in vivo. Carcinogenesis. 2012 Jul;33(7):1421-9.
19 Apoptosis induced by piroxicam plus cisplatin combined treatment is triggered by p21 in mesothelioma. PLoS One. 2011;6(8):e23569.
20 A fatty acid synthase blockade induces tumor cell-cycle arrest by down-regulating Skp2. J Biol Chem. 2004 Jul 16;279(29):30540-5. doi: 10.1074/jbc.M405061200. Epub 2004 May 11.
21 Antineoplastic effects of gamma linolenic Acid on hepatocellular carcinoma cell lines. J Clin Biochem Nutr. 2010 Jul;47(1):81-90.
22 Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
23 Identifying the differential effects of silymarin constituents on cell growth and cell cycle regulatory molecules in human prostate cancer cells. Int J Cancer. 2008 Jul 1;123(1):41-50. doi: 10.1002/ijc.23485.
24 Novel ATP-competitive Akt inhibitor afuresertib suppresses the proliferation of malignant pleural mesothelioma cells. Cancer Med. 2017 Nov;6(11):2646-2659. doi: 10.1002/cam4.1179. Epub 2017 Sep 27.
25 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.
26 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.
27 Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
28 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.
29 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.
30 Quantitative phosphoproteomics reveal cellular responses from caffeine, coumarin and quercetin in treated HepG2 cells. Toxicol Appl Pharmacol. 2022 Aug 15;449:116110. doi: 10.1016/j.taap.2022.116110. Epub 2022 Jun 7.
31 Comprehensive analysis of transcriptomic changes induced by low and high doses of bisphenol A in HepG2 spheroids in vitro and rat liver in vivo. Environ Res. 2019 Jun;173:124-134. doi: 10.1016/j.envres.2019.03.035. Epub 2019 Mar 18.
32 Gene expression changes in primary human nasal epithelial cells exposed to formaldehyde in vitro. Toxicol Lett. 2010 Oct 5;198(2):289-95.
33 Pleiotropic combinatorial transcriptomes of human breast cancer cells exposed to mixtures of dietary phytoestrogens. Food Chem Toxicol. 2009 Apr;47(4):787-95.
34 Glyphosate-based herbicides at low doses affect canonical pathways in estrogen positive and negative breast cancer cell lines. PLoS One. 2019 Jul 11;14(7):e0219610. doi: 10.1371/journal.pone.0219610. eCollection 2019.
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36 Geraniol suppresses prostate cancer growth through down-regulation of E2F8. Cancer Med. 2016 Oct;5(10):2899-2908.
37 FOXO3a reactivation mediates the synergistic cytotoxic effects of rapamycin and cisplatin in oral squamous cell carcinoma cells. Toxicol Appl Pharmacol. 2011 Feb 15;251(1):8-15. doi: 10.1016/j.taap.2010.11.007. Epub 2010 Nov 16.
38 Arachidonic acid-induced gene expression in colon cancer cells. Carcinogenesis. 2006 Oct;27(10):1950-60.
39 System analysis of cross-talk between nuclear receptors reveals an opposite regulation of the cell cycle by LXR and FXR in human HepaRG liver cells. PLoS One. 2019 Aug 22;14(8):e0220894. doi: 10.1371/journal.pone.0220894. eCollection 2019.
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41 Gene expression profiling of 30 cancer cell lines predicts resistance towards 11 anticancer drugs at clinically achieved concentrations. Int J Cancer. 2006 Apr 1;118(7):1699-712. doi: 10.1002/ijc.21570.