Document Detail


Weak p53 permits senescence during cell cycle arrest.
MedLine Citation:
PMID:  21051933     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Cell cycle arrest coupled with hyper-active mTOR leads to cellular senescence. While arresting cell cycle, high levels of p53 can inhibit mTOR (in some cell lines), thus causing reversible quiescence instead of senescence. Nutlin-3a-induced p53 inhibited mTOR and thus caused quiescence in WI-38 cells. In contrast, while arresting cell cycle, the DNA-damaging drug doxorubicin (DOX) did not inhibit mTOR and caused senescence. Super-induction of p53 by either nutlin-3a or high concentrations of DOX (high-DOX) prevented low-DOX-induced senescence, converting it into quiescence. This explains why in order to cause senescence, DNA damaging drugs must be used at low concentrations, which arrest cell cycle but do not induce p53 at levels sufficient to suppress mTOR. Noteworthy, very prolonged treatment with nutlin-3a also caused senescence preventable by rapamycin. In RPE cells, low concentrations of nutlin-3a caused a semi-senescent morphology. Higher concentrations of nutlin-3a inhibited mTOR and caused quiescent morphology. We conclude that low p53 levels during prolonged cell cycle arrest tend to cause senescence, whereas high levels of p53 tend to cause either quiescence or cell death.
Authors:
Olga V Leontieva; Andrei V Gudkov; Mikhail V Blagosklonny
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Publication Detail:
Type:  Journal Article     Date:  2010-11-10
Journal Detail:
Title:  Cell cycle (Georgetown, Tex.)     Volume:  9     ISSN:  1551-4005     ISO Abbreviation:  Cell Cycle     Publication Date:  2010 Nov 
Date Detail:
Created Date:  2010-11-10     Completed Date:  2011-02-22     Revised Date:  2011-03-30    
Medline Journal Info:
Nlm Unique ID:  101137841     Medline TA:  Cell Cycle     Country:  United States    
Other Details:
Languages:  eng     Pagination:  4323-7     Citation Subset:  IM    
Affiliation:
Roswell Park Cancer Institute, Buffalo, NY, USA.
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MeSH Terms
Descriptor/Qualifier:
Antibiotics, Antineoplastic / pharmacology
Cell Aging*
Cell Line
DNA Damage
Doxorubicin / pharmacology
G0 Phase
Humans
Imidazoles / pharmacology
Piperazines / pharmacology
TOR Serine-Threonine Kinases / antagonists & inhibitors,  metabolism
Tumor Suppressor Protein p53 / metabolism*
Chemical
Reg. No./Substance:
0/Antibiotics, Antineoplastic; 0/Imidazoles; 0/Piperazines; 0/Tumor Suppressor Protein p53; 0/nutlin 3; 23214-92-8/Doxorubicin; EC 2.7.1.1/MTOR protein, human; EC 2.7.1.1/TOR Serine-Threonine Kinases
Comments/Corrections
Comment In:
Cell Cycle. 2010 Nov 1;9(21):4262-3   [PMID:  21057199 ]
Cell Cycle. 2010 Nov 1;9(21):4256-7   [PMID:  20980826 ]
Cell Cycle. 2010 Oct 15;9(20):4050-1   [PMID:  21058422 ]

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


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