Document Detail


DNA damage-induced cell-cycle phase regulation of p53 and p21waf1 in normal and ATM-defective cells.
MedLine Citation:
PMID:  14586414     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
The ATM-dependent accumulation of p53 and induction of p21waf1 are key events for G1 cell-cycle checkpoint arrest following DNA damage. In ATM-null AT cells, even though the p53 and p21waf1 responses are kinetically delayed and quantitatively reduced, the G1 checkpoint is virtually disrupted, suggesting that these proteins arrive too late in G1 to enforce the arrest. As the precise mechanism remains unclear, we examined the response to DNA double-strand breaks generated by gamma-radiation (IR), to determine if ATM deficiency affects the cell-cycle phase regulation of these molecules. We find that, after irradiation, whereas normal LCL-N cells markedly increase their levels of p53 in all phases of the cell cycle, AT cells fail to show any p53 increase in the G1 phase. In addition, whereas in LCL-N p21waf1 is induced in G1 and G2-M, in AT cells this induction is partly seen in G2-M, but not in G1, indicating a different cell-cycle phase regulation of p53 and p21waf1 as a result of ATM deficiency. The levels and catalytic activity of the p53-targeting kinases ATR and DNA-PK in LCL-N and AT cells are very similar throughout the cell cycle, both before and after IR, thus excluding a phase-specific activity for these kinases. Collectively, our findings demonstrate that, in ATM-deficient cells, the p53-dependent p21waf1 response to DNA damage is not only quantitatively reduced, but also specifically suppressed in the G1 phase, thus providing a mechanistic explanation for the severe disruption of the G1 checkpoint in AT cells.
Authors:
Domenico Delia; Enrico Fontanella; Cristina Ferrario; Luciana Chessa; Shuki Mizutani
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  Oncogene     Volume:  22     ISSN:  0950-9232     ISO Abbreviation:  Oncogene     Publication Date:  2003 Oct 
Date Detail:
Created Date:  2003-10-30     Completed Date:  2003-12-03     Revised Date:  2012-06-25    
Medline Journal Info:
Nlm Unique ID:  8711562     Medline TA:  Oncogene     Country:  England    
Other Details:
Languages:  eng     Pagination:  7866-9     Citation Subset:  IM    
Affiliation:
Department of Experimental Oncology, Istituto Nazionale Tumori, Via G. Venezian 1, Milano 20133, Italy. domenico.delia@istitutotumori.mi.it
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MeSH Terms
Descriptor/Qualifier:
Cell Cycle Proteins / physiology
Cyclin-Dependent Kinase Inhibitor p21
Cyclins / physiology*
DNA Damage*
DNA-Activated Protein Kinase
DNA-Binding Proteins*
G1 Phase
Humans
Nuclear Proteins
Phosphorylation
Protein-Serine-Threonine Kinases / physiology*
Tumor Suppressor Protein p53 / physiology*
Tumor Suppressor Proteins
Grant Support
ID/Acronym/Agency:
GP0205Y01//Telethon
Chemical
Reg. No./Substance:
0/CDKN1A protein, human; 0/Cell Cycle Proteins; 0/Cyclin-Dependent Kinase Inhibitor p21; 0/Cyclins; 0/DNA-Binding Proteins; 0/Nuclear Proteins; 0/Tumor Suppressor Protein p53; 0/Tumor Suppressor Proteins; EC 2.7.1.-/ATR protein, human; EC 2.7.11.1/DNA-Activated Protein Kinase; EC 2.7.11.1/PRKDC protein, human; EC 2.7.11.1/Protein-Serine-Threonine Kinases; EC 2.7.11.1/ataxia telangiectasia mutated protein

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