Document Detail


USP7 and Daxx regulate mitosis progression and taxane sensitivity by affecting stability of Aurora-A kinase.
MedLine Citation:
PMID:  23348568     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
A large number of patients are resistant to taxane-based chemotherapy. Functional mitotic checkpoints are essential for taxane sensitivity. Thus, mitotic regulators are potential markers for therapy response and could be targeted for anticancer therapy. In this study, we identified a novel function of ubiquitin (Ub)-specific processing protease-7 (USP7) that interacts and cooperates with protein death domain-associated protein (Daxx) in the regulation of mitosis and taxane resistance. Depletion of USP7 impairs mitotic progression, stabilizes cyclin B and reduces stability of the mitotic E3 Ub ligase, checkpoint with forkhead and Ring-finger (CHFR). Consequently, cells with depleted USP7 accumulate Aurora-A kinase, a CHFR substrate, thus elevating multipolar mitoses. We further show that these effects are independent of the USP7 substrate p53. Thus, USP7 and Daxx are necessary to regulate proper execution of mitosis, partially via regulation of CHFR and Aurora-A kinase stability. Results from colony formation assay, in silico analysis across the NCI60 platform and in breast cancer patients suggest that USP7 levels inversely correlate with response to taxanes, pointing at the USP7 protein as a potential predictive factor for taxane response in cancer patients. In addition, we demonstrated that inhibition of Aurora-A attenuates USP7-mediated taxane resistance, suggesting that combinatorial drug regimens of Taxol and Aurora-A inhibitors may improve the outcome of chemotherapy response in cancer patients resistant to taxane treatment. Finally, our study offers novel insights on USP7 inhibition as cancer therapy.
Authors:
S Giovinazzi; V M Morozov; M K Summers; W C Reinhold; A M Ishov
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, N.I.H., Intramural; Research Support, Non-U.S. Gov't     Date:  2013-01-25
Journal Detail:
Title:  Cell death and differentiation     Volume:  20     ISSN:  1476-5403     ISO Abbreviation:  Cell Death Differ.     Publication Date:  2013 May 
Date Detail:
Created Date:  2013-04-08     Completed Date:  2013-09-30     Revised Date:  2014-03-19    
Medline Journal Info:
Nlm Unique ID:  9437445     Medline TA:  Cell Death Differ     Country:  England    
Other Details:
Languages:  eng     Pagination:  721-31     Citation Subset:  IM    
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MeSH Terms
Descriptor/Qualifier:
Adaptor Proteins, Signal Transducing / metabolism*
Antineoplastic Agents / pharmacology*,  therapeutic use
Aurora Kinases
Benzazepines / pharmacology
Breast Neoplasms / drug therapy,  metabolism
Bridged Compounds / pharmacology*,  therapeutic use
Cell Cycle Proteins / metabolism
Cell Line, Tumor
Cyclin B / metabolism
Drug Resistance, Neoplasm
Female
Humans
Mitosis
Neoplasm Proteins / metabolism
Nuclear Proteins / metabolism*
Protein-Serine-Threonine Kinases / antagonists & inhibitors,  metabolism*
RNA Interference
RNA, Small Interfering
Taxoids / pharmacology*,  therapeutic use
Tumor Suppressor Protein p53
Ubiquitin Thiolesterase / genetics,  metabolism*
Grant Support
ID/Acronym/Agency:
R01 CA127378/CA/NCI NIH HHS; R01CA127378-01A1/CA/NCI NIH HHS; T32 CA009151/CA/NCI NIH HHS
Chemical
Reg. No./Substance:
0/Adaptor Proteins, Signal Transducing; 0/Antineoplastic Agents; 0/Benzazepines; 0/Bridged Compounds; 0/CHFR protein, human; 0/Cell Cycle Proteins; 0/Cyclin B; 0/DAXX protein, human; 0/MLN8054; 0/Neoplasm Proteins; 0/Nuclear Proteins; 0/RNA, Small Interfering; 0/Taxoids; 0/Tumor Suppressor Protein p53; 1605-68-1/taxane; EC 2.7.11.1/Aurora Kinases; EC 2.7.11.1/Protein-Serine-Threonine Kinases; EC 3.1.2.15/USP7 protein, human; EC 3.1.2.15/Ubiquitin Thiolesterase

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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