Document Detail

A theoretical model for p53 dynamics: identifying optimal therapeutic strategy for its activation and stabilization.
MedLine Citation:
PMID:  19844169     Owner:  NLM     Status:  MEDLINE    
The activation and stabilization of tumor suppressor p53 are very important in preventing cells from becoming cancerous. Hence, many experimental works have been carried out to investigate p53's dynamics through its interactions with other proteins and its therapeutic applications for the treatment of cancers. In this work, by analyzing a theoretical model, we attempt to search for an optimal therapeutic strategy that guarantees the activation and stabilization of p53. For this purpose, we introduce a new mathematical model including oncogene activation and ARF, which are recognized as crucial for tumor suppression but have not yet been considered in most theoretical works. Through mathematical modeling and numerical simulations, we confirm several important properties of p53 dynamics: the role of the oncogene-mediated activation of ARF as an important factor for the activation and stabilization of p53, the necessity of time delays in negative feedback loops to guarantee sustained p53 oscillations, and the digital behavior of p53 pulses. Furthermore, we propose that the binding of ARF to Mdm2 and enhancing the degradation of Mdm2 is an efficient strategy for therapeutic targeting, which may assure the activation and stabilization of p53.
Do-Hyun Kim; Kyoohyoung Rho; Sunghoon Kim
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2009-11-08
Journal Detail:
Title:  Cell cycle (Georgetown, Tex.)     Volume:  8     ISSN:  1551-4005     ISO Abbreviation:  Cell Cycle     Publication Date:  2009 Nov 
Date Detail:
Created Date:  2009-11-10     Completed Date:  2010-03-01     Revised Date:  2011-11-02    
Medline Journal Info:
Nlm Unique ID:  101137841     Medline TA:  Cell Cycle     Country:  United States    
Other Details:
Languages:  eng     Pagination:  3707-16     Citation Subset:  IM    
Information Center for Bio-Pharmacological Network, Seoul National University, Suwon, Korea.
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MeSH Terms
Cell Cycle Proteins / metabolism
Computer Simulation
Cyclin-Dependent Kinase Inhibitor p16 / metabolism*
DNA-Binding Proteins / metabolism
Drug Discovery / methods*
Gene Expression Regulation / physiology*,  radiation effects
Models, Biological*
Neoplasms / drug therapy*
Phosphoprotein Phosphatases / metabolism
Protein-Serine-Threonine Kinases / metabolism
Proto-Oncogene Proteins c-mdm2 / metabolism*
Radiation, Ionizing
Tumor Suppressor Protein p53 / metabolism*,  therapeutic use
Tumor Suppressor Proteins / metabolism
Reg. No./Substance:
0/Cell Cycle Proteins; 0/Cyclin-Dependent Kinase Inhibitor p16; 0/DNA-Binding Proteins; 0/Tumor Suppressor Protein p53; 0/Tumor Suppressor Proteins; EC kinase 2; EC Kinases; EC telangiectasia mutated protein; EC Phosphatases; EC phosphatase 2C; EC protein, human; EC Proteins c-mdm2

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

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