Document Detail


An overactivated ATR/CHK1 pathway is responsible for the prolonged G2 accumulation in irradiated AT cells.
MedLine Citation:
PMID:  12791699     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Induction of checkpoint responses in G1, S, and G2 phases of the cell cycle after exposure of cells to ionizing radiation (IR) is essential for maintaining genomic integrity. Ataxia telangiectasia mutated (ATM) plays a key role in initiating this response in all three phases of the cell cycle. However, cells lacking functional ATM exhibit a prolonged G2 arrest after IR, suggesting regulation by an ATM-independent checkpoint response. The mechanism for this ataxia telangiectasia (AT)-independent G2-checkpoint response remains unknown. We report here that the G2 checkpoint in irradiated human AT cells derives from an overactivation of the ATR/CHK1 pathway. Chk1 small interfering RNA abolishes the IR-induced prolonged G2 checkpoint and radiosensitizes AT cells to killing. These results link the activation of ATR/CHK1 with the prolonged G2 arrest in AT cells and show that activation of this G2 checkpoint contributes to the survival of AT cells.
Authors:
Xiang Wang; Jay Khadpe; Baocheng Hu; George Iliakis; Ya Wang
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Publication Detail:
Type:  Journal Article; Research Support, U.S. Gov't, Non-P.H.S.; Research Support, U.S. Gov't, P.H.S.     Date:  2003-06-04
Journal Detail:
Title:  The Journal of biological chemistry     Volume:  278     ISSN:  0021-9258     ISO Abbreviation:  J. Biol. Chem.     Publication Date:  2003 Aug 
Date Detail:
Created Date:  2003-08-11     Completed Date:  2003-11-10     Revised Date:  2013-05-24    
Medline Journal Info:
Nlm Unique ID:  2985121R     Medline TA:  J Biol Chem     Country:  United States    
Other Details:
Languages:  eng     Pagination:  30869-74     Citation Subset:  IM; S    
Affiliation:
Department of Radiation Oncology, Kimmel Cancer Center of Jefferson Medical College, Thomas Jefferson University, Philadelphia, Pennsylvania 19107, USA.
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MeSH Terms
Descriptor/Qualifier:
Alkaloids / pharmacology
Caffeine / pharmacology
Cell Cycle Proteins / antagonists & inhibitors,  metabolism*
Cell Line, Transformed
Cell Survival / physiology,  radiation effects
Enzyme Inhibitors / pharmacology
Fibroblasts / cytology*,  metabolism,  radiation effects
G2 Phase / physiology,  radiation effects*
Humans
Phosphodiesterase Inhibitors / pharmacology
Protein Kinase Inhibitors
Protein Kinases / genetics,  metabolism*
Protein-Serine-Threonine Kinases*
RNA, Small Interfering
Radiation, Ionizing
Staurosporine / analogs & derivatives
Grant Support
ID/Acronym/Agency:
CA42026/CA/NCI NIH HHS; CA56706/CA/NCI NIH HHS; CA76203/CA/NCI NIH HHS; P30-CA56036/CA/NCI NIH HHS; R25 CA48010/CA/NCI NIH HHS
Chemical
Reg. No./Substance:
0/Alkaloids; 0/Cell Cycle Proteins; 0/Enzyme Inhibitors; 0/Phosphodiesterase Inhibitors; 0/Protein Kinase Inhibitors; 0/RNA, Small Interfering; 58-08-2/Caffeine; 62996-74-1/Staurosporine; 7BU5H4V94A/7-hydroxystaurosporine; EC 2.7.-/Protein Kinases; EC 2.7.1.-/ATR protein, human; EC 2.7.11.1/Checkpoint kinase 1; EC 2.7.11.1/Protein-Serine-Threonine Kinases
Investigator
Investigator/Affiliation:
G Iliakis / Thomas Jefferson U, Philadelphia, PA

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