Document Detail


Quantitative proteomics reveals a "poised quiescence" cellular state after triggering the DNA replication origin activation checkpoint.
MedLine Citation:
PMID:  20707412     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
An origin activation checkpoint has recently been discovered in the G1 phase of the mitotic cell cycle, which can be triggered by loss of DNA replication initiation factors such as the Cdc7 kinase. Insufficient levels of Cdc7 activate cell cycle arrest in normal cells, whereas cancer cells appear to lack this checkpoint response, do not arrest, and proceed with an abortive S phase, leading to cell death. The differential response between normal and tumor cells at this checkpoint has led to widespread interest in the development of pharmacological Cdc7 inhibitors as novel anticancer agents. We have used RNAi against Cdc7 in combination with SILAC-based high resolution MS proteomics to investigate the cellular mechanisms underlying the maintenance of the origin activation checkpoint in normal human diploid fibroblasts. Bioinformatics analysis identified clear changes in wide-ranging biological processes including altered cellular energetic flux, moderate stress response, reduced proliferative capacity, and a spatially distributed response across the mitochondria, lysosomes, and the cell surface. These results provide a quantitative overview of the processes involved in maintenance of the arrested state, show that this phenotype involves active rather than passive cellular adaptation, and highlight a diverse set of proteins responsible for cell cycle arrest and ultimately for promotion of cellular survival. We propose that the Cdc7-depleted proteome maintains cellular arrest by initiating a dynamic quiescence-like response and that the complexities of this phenotype will have important implications for the continued development of promising Cdc7-targeted cancer therapies.
Authors:
Claire Mulvey; Slavica Tudzarova; Mark Crawford; Gareth H Williams; Kai Stoeber; Jasminka Godovac-Zimmermann
Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  Journal of proteome research     Volume:  9     ISSN:  1535-3907     ISO Abbreviation:  J. Proteome Res.     Publication Date:  2010 Oct 
Date Detail:
Created Date:  2010-10-04     Completed Date:  2010-10-29     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  101128775     Medline TA:  J Proteome Res     Country:  United States    
Other Details:
Languages:  eng     Pagination:  5445-60     Citation Subset:  IM    
Affiliation:
Centre for Molecular Medicine, Rayne Institute, Division of Medicine, University College London, London, U.K.
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MeSH Terms
Descriptor/Qualifier:
Cell Cycle / physiology*
Cell Cycle Proteins / genetics,  metabolism
Cell Line
DNA Replication / physiology*
Humans
Immunoblotting
Mass Spectrometry
Protein-Serine-Threonine Kinases / genetics,  metabolism
Proteomics / methods*
RNA Interference
Replication Origin / physiology*
Grant Support
ID/Acronym/Agency:
081879/z/06/z//Wellcome Trust; C428/A6263//Cancer Research UK
Chemical
Reg. No./Substance:
0/Cell Cycle Proteins; EC 2.7.1.-/CDC7 protein, human; EC 2.7.11.1/Protein-Serine-Threonine Kinases

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


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