Document Detail


Uncoupling of S phase and mitosis induced by anticancer agents in cells lacking p21.
MedLine Citation:
PMID:  8649519     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Precise coordination of the S and M phases of the eukaryotic cell cycle is critical not only for normal cell division, but also for effective growth arrest under conditions of stress. When damaged, a cell must communicate signals to both the mitotic and DNA synthesis machineries so that a mitotic block is not followed by an extra S phase, or vice versa. The biochemical mechanisms regulating this coordination, termed checkpoints, have been identified in lower eukaryotes, but are largely unknown in mammalian cells. Here we show that p21 WAF1/CIP1, the prototype inhibitor of cyclin-dependent kinases (CDKs), is required for this coordination in human cells. In the absence of p21, DNA-damaged cells arrest in a G2-like state, but then undergo additional S phases without intervening normal mitoses. They thereby acquire grossly deformed, polyploid nuclei and subsequently die through apoptosis. Perhaps not by coincidence, the DNA-damaging agents that can cause S/M uncoupling are used in the clinic to kill cancer cells preferentially.
Authors:
T Waldman; C Lengauer; K W Kinzler; B Vogelstein
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, P.H.S.    
Journal Detail:
Title:  Nature     Volume:  381     ISSN:  0028-0836     ISO Abbreviation:  Nature     Publication Date:  1996 Jun 
Date Detail:
Created Date:  1996-07-25     Completed Date:  1996-07-25     Revised Date:  2009-11-19    
Medline Journal Info:
Nlm Unique ID:  0410462     Medline TA:  Nature     Country:  ENGLAND    
Other Details:
Languages:  eng     Pagination:  713-6     Citation Subset:  IM    
Affiliation:
The Howard Hughes Medical Institute, Johns Hopkins Oncology Center, and Program in Human Genetics, Baltimore, Maryland 21231, USA.
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MeSH Terms
Descriptor/Qualifier:
Antineoplastic Agents / pharmacology*
Apoptosis
Bisbenzimidazole
Camptothecin / pharmacology
Cyclin-Dependent Kinase Inhibitor p21
Cyclin-Dependent Kinases / antagonists & inhibitors*
Cyclins / physiology*
DNA Damage
Doxorubicin / pharmacology
Enzyme Inhibitors*
Etoposide / pharmacology
Fluorescent Dyes
Gamma Rays
Humans
Mitosis / drug effects,  physiology*
S Phase / drug effects,  physiology*
Tumor Cells, Cultured
Chemical
Reg. No./Substance:
0/Antineoplastic Agents; 0/CDKN1A protein, human; 0/Cyclin-Dependent Kinase Inhibitor p21; 0/Cyclins; 0/Enzyme Inhibitors; 0/Fluorescent Dyes; 23214-92-8/Doxorubicin; 23491-44-3/Bisbenzimidazole; 33419-42-0/Etoposide; 7689-03-4/Camptothecin; EC 2.7.11.22/Cyclin-Dependent Kinases
Comments/Corrections
Comment In:
Nature. 1997 Jan 9;385(6612):123-5   [PMID:  8990112 ]
Nature. 1996 Jun 20;381(6584):643-4   [PMID:  8649505 ]

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