6-Thioguanine is a noncompetitive and slow binding inhibitor of human deubiquitinating protease USP2
Ubiquitin-specific protease 2 (USP2) belongs to the family of deubiquitinases that can rescue protein targets from proteasomal degradation by reversing their ubiquitination. In various cancers, including prostate cancer and ovarian carcinoma, upregulation of USP2 leads to an increase in the levels o...
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| Veröffentlicht in: | Scientific reports 2018-02, Vol.8 (1), p.3102-9, Article 3102 |
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| description | Ubiquitin-specific protease 2 (USP2) belongs to the family of deubiquitinases that can rescue protein targets from proteasomal degradation by reversing their ubiquitination. In various cancers, including prostate cancer and ovarian carcinoma, upregulation of USP2 leads to an increase in the levels of deubiquitinated substrates such as fatty acid synthase, MDM2, cyclin D1 and Aurora-A. USP2 thus plays a critical role in tumor cells’ survival and therefore represents a therapeutic target. Here a leukemia drug, 6-thioguanine, was found to be a potent inhibitor of USP2. Enzyme-kinetic and X-ray crystallographic data suggest that 6-thioguanine displays a noncompetitive and slow-binding inhibitory mechanism against USP2. Our study provides a clear rationale for the clinical evaluation of 6-thioguanine for USP2-upregulated cancers. |
| doi_str_mv | 10.1038/s41598-018-21476-w |
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In various cancers, including prostate cancer and ovarian carcinoma, upregulation of USP2 leads to an increase in the levels of deubiquitinated substrates such as fatty acid synthase, MDM2, cyclin D1 and Aurora-A. USP2 thus plays a critical role in tumor cells’ survival and therefore represents a therapeutic target. Here a leukemia drug, 6-thioguanine, was found to be a potent inhibitor of USP2. Enzyme-kinetic and X-ray crystallographic data suggest that 6-thioguanine displays a noncompetitive and slow-binding inhibitory mechanism against USP2. 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Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Scientific reports</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Chuang, Shang-Ju</au><au>Cheng, Shu-Chun</au><au>Tang, Hui-Chi</au><au>Sun, Chiao-Yin</au><au>Chou, Chi-Yuan</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>6-Thioguanine is a noncompetitive and slow binding inhibitor of human deubiquitinating protease USP2</atitle><jtitle>Scientific reports</jtitle><stitle>Sci Rep</stitle><addtitle>Sci Rep</addtitle><date>2018-02-15</date><risdate>2018</risdate><volume>8</volume><issue>1</issue><spage>3102</spage><epage>9</epage><pages>3102-9</pages><artnum>3102</artnum><issn>2045-2322</issn><eissn>2045-2322</eissn><abstract>Ubiquitin-specific protease 2 (USP2) belongs to the family of deubiquitinases that can rescue protein targets from proteasomal degradation by reversing their ubiquitination. In various cancers, including prostate cancer and ovarian carcinoma, upregulation of USP2 leads to an increase in the levels of deubiquitinated substrates such as fatty acid synthase, MDM2, cyclin D1 and Aurora-A. USP2 thus plays a critical role in tumor cells’ survival and therefore represents a therapeutic target. Here a leukemia drug, 6-thioguanine, was found to be a potent inhibitor of USP2. Enzyme-kinetic and X-ray crystallographic data suggest that 6-thioguanine displays a noncompetitive and slow-binding inhibitory mechanism against USP2. Our study provides a clear rationale for the clinical evaluation of 6-thioguanine for USP2-upregulated cancers.</abstract><cop>London</cop><pub>Nature Publishing Group UK</pub><pmid>29449607</pmid><doi>10.1038/s41598-018-21476-w</doi><tpages>9</tpages><oa>free_for_read</oa></addata></record> |
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| subjects | 631/154/309/555 631/45/607/1164 631/535/1266 82 Cell cycle Crystallization Crystallography Crystallography, X-Ray - methods Cyclin D1 Deubiquitinating Enzymes - antagonists & inhibitors Deubiquitinating Enzymes - metabolism Endopeptidases - metabolism Enzyme kinetics Fatty acids Fatty-acid synthase Genomes Humanities and Social Sciences Humans Kinetics Leukemia MDM2 protein multidisciplinary Ovarian cancer Ovarian carcinoma Prostate Prostate cancer Proteasomes Protein Processing, Post-Translational Proteinase inhibitors Proteins Science Science (multidisciplinary) Thioguanine Thioguanine - metabolism Thioguanine - pharmacokinetics Thioguanine - pharmacology Tumor cells Ubiquitin Ubiquitin-specific proteinase Ubiquitination Ubiquitination - physiology |
| title | 6-Thioguanine is a noncompetitive and slow binding inhibitor of human deubiquitinating protease USP2 |
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