Document Detail

The checkpoint kinase ATM protects against stress-induced elevation of cyclin D1 and potential cell death in neurons.
MedLine Citation:
PMID:  20506465     Owner:  NLM     Status:  MEDLINE    
Quantitative cytometric studies show that cyclin D1 levels must decline during S phase for proper cell cycle progression, and that cyclin D1 decline follows phosphorylation induced by the checkpoint kinases ataxia telangiectasia mutated (ATM) and ATM and Rad3-related (ATR). ATM is mutated in ataxia telangiectasia (AT), a disease characterized by progressive neurodegeneration. Importantly, neurodegeneration in many cases has been linked to the increased expression of cyclin D1 in neurons leading to inappropriate cell cycle entry. These facts prompted us to test the possibility that ATM normally protects against neural degeneration by suppressing cyclin D1 levels, particularly following genotoxic stress. For this purpose, neural stem cells were induced to differentiate into mature neural cells, including neurons. ATM activity in these cultures was inhibited with a specific chemical inhibitor in the presence or absence of hydrogen peroxide treatment, and the effect on cyclin D1 expression was determined by quantitative, single cell cytometric analyses. As predicted, inhibition of ATM did promote elevation of cyclin D1 in differentiated neurons, particularly under conditions of oxidative stress. The survival of differentiated neurons and of neural stem cells was reduced by such treatments. These data support our suggestion that ATM functions to maintain low levels of cyclin D1 expression in differentiated neurons; and may provide important clues in understanding neural degeneration in general.
Masahiro Hitomi; Dennis W Stacey
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  Cytometry. Part A : the journal of the International Society for Analytical Cytology     Volume:  77     ISSN:  1552-4930     ISO Abbreviation:  Cytometry A     Publication Date:  2010 Jun 
Date Detail:
Created Date:  2010-05-27     Completed Date:  2010-09-15     Revised Date:  2011-11-02    
Medline Journal Info:
Nlm Unique ID:  101235694     Medline TA:  Cytometry A     Country:  United States    
Other Details:
Languages:  eng     Pagination:  524-33     Citation Subset:  IM    
Copyright Information:
Copyright 2010 International Society for Advancement of Cytometry.
Department of Molecular Genetics, The Lerner Research Institute, The Cleveland Clinic, Cleveland, Ohio, USA.
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MeSH Terms
Ataxia Telangiectasia* / metabolism
Cell Cycle Proteins / metabolism*
Cell Death*
Cell Line
Cyclin D1 / genetics,  metabolism*
DNA-Binding Proteins / metabolism*
Flow Cytometry
Neurons / cytology,  metabolism*
Oxidative Stress*
Protein-Serine-Threonine Kinases / metabolism*
Tumor Suppressor Proteins / metabolism*
Reg. No./Substance:
0/Cell Cycle Proteins; 0/DNA-Binding Proteins; 0/Tumor Suppressor Proteins; 136601-57-5/Cyclin D1; EC Kinases; EC telangiectasia mutated protein

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