Document Detail


Chk1 suppresses bypass of mitosis and tetraploidization in p53-deficient cancer cells.
MedLine Citation:
PMID:  22433954     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Many cancer cells are unable to maintain a numerically stable chromosome complement. It is well established that aberrant cell division can generate progeny with increased ploidy, but the genetic factors required for maintenance of diploidy are not well understood. Using an isogenic model system derived by gene targeting, we examined the role of Chk1 in p53-proficient and -deficient cancer cells. Targeted inactivation of a single CHK1 allele in stably diploid cells caused an elevated frequency of mitotic bypass if p53 was naturally mutated or experimentally disrupted by homologous recombination. CHK1-haploinsufficient, p53-deficient cells frequently underwent sequential rounds of DNA synthesis without an intervening mitosis. These aberrant cell cycles resulted in whole-genome endoreduplication and tetraploidization. The unscheduled bypass of mitosis could be suppressed by targeted reversion of a p53 mutation or by exogenous expression of Cdk1. In contrast, the number of tetraploid cells was not increased in isogenic cell populations that harbor hypomorphic ATR mutations, suggesting that suppression of unscheduled mitotic bypass is a distinct function of Chk1. These results are consistent with a recently described role for Chk1 in promoting the expression of genes that promote cell cycle transitions and demonstrate how Chk1 might prevent tetraploidization during the cancer cell cycle.
Authors:
Deborah Wilsker; Jon H Chung; Fred Bunz
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't     Date:  2012-04-15
Journal Detail:
Title:  Cell cycle (Georgetown, Tex.)     Volume:  11     ISSN:  1551-4005     ISO Abbreviation:  Cell Cycle     Publication Date:  2012 Apr 
Date Detail:
Created Date:  2012-04-30     Completed Date:  2012-09-14     Revised Date:  2013-06-26    
Medline Journal Info:
Nlm Unique ID:  101137841     Medline TA:  Cell Cycle     Country:  United States    
Other Details:
Languages:  eng     Pagination:  1564-72     Citation Subset:  IM    
Affiliation:
Molecular Radiation Therapeutics Branch, National Cancer Institute, Frederick, MD, USA.
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MeSH Terms
Descriptor/Qualifier:
Alleles
Cell Cycle Proteins / genetics,  metabolism
Cell Line, Tumor
DNA Damage
Diploidy
HCT116 Cells
Haploinsufficiency
Homologous Recombination
Humans
Metaphase
Mitosis*
Mutation
Protein Kinases / metabolism*
Protein-Serine-Threonine Kinases / genetics,  metabolism
RNA Interference
Tetraploidy
Tumor Suppressor Protein p53 / deficiency,  genetics,  metabolism*
Grant Support
ID/Acronym/Agency:
F32CA119724/CA/NCI NIH HHS; R01 CA157535/CA/NCI NIH HHS; R01CA157535/CA/NCI NIH HHS
Chemical
Reg. No./Substance:
0/Cell Cycle Proteins; 0/Tumor Suppressor Protein p53; 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
Comments/Corrections
Comment In:
Cell Cycle. 2012 May 15;11(10):1873   [PMID:  22580458 ]
Cell Cycle. 2012 May 1;11(9):1756   [PMID:  22510558 ]

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


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