Document Detail


Restoration of the tumor suppressor p53 by downregulating cyclin B1 in human papillomavirus 16/18-infected cancer cells.
MedLine Citation:
PMID:  20661218     Owner:  NLM     Status:  In-Process    
Abstract/OtherAbstract:
Abrogation of functional p53 is responsible for malignant cell transformation and the maintenance of malignant state of human papillomavirus-infected cancer cells. Thus, restoration of p53 has been regarded as an important strategy for molecular intervention combating papillomavirus-associated malignancies. We show here that depleting cyclin B1 stabilizes and reactivates p53 in papillomavirus-infected cervical cancer cell lines HeLa and CaSki. HeLa cells depleted of cyclin B1 exhibit mitotic defects in spindle formation and chromosome alignment. Downregulation of cyclin B1 increases p14 alternative reading frame of p16, the positive regulator of p53, and decreases phosphorylation of Ser315 in p53. Whereas RO-3306, a selective inhibitor of cyclin-dependent kinase 1 (Cdk1), suppresses this phosphorylation at Ser315 of p53, ZM447439, targeting Aurora A/B kinases, shows no effect. Further analyses in HeLa cells and HCT116 p53(-/-) cells suggest that the Ser315 phosphorylation by Cdk1 regulates negatively the protein stability and the function of p53. Moreover, increased p53 in HeLa cells is functional by showing its increased downstream effectors p21, mouse double minute 2 and Bax. Restoration of p53 and silencing cyclin B1 render cervical carcinoma cells more susceptible to DNA damage agent camptothecin. Taken together, targeting cyclin B1 might be an attractive strategy for preventing and treating papillomavirus-associated cancer by reactivating p53 and by reducing the Cdk1 activity.
Authors:
N N Kreis; M Sanhaji; A Krämer; K Sommer; F Rödel; K Strebhardt; J Yuan
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2010-07-26
Journal Detail:
Title:  Oncogene     Volume:  29     ISSN:  1476-5594     ISO Abbreviation:  Oncogene     Publication Date:  2010 Oct 
Date Detail:
Created Date:  2010-10-14     Completed Date:  -     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  8711562     Medline TA:  Oncogene     Country:  England    
Other Details:
Languages:  eng     Pagination:  5591-603     Citation Subset:  IM    
Affiliation:
Department of Gynecology and Obstetrics, School of Medicine, JW Goethe University, Frankfurt, Germany.
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