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A critical role for TORC1 in cellular senescence.
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PMID:  22874595     Owner:  NLM     Status:  MEDLINE    
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Authors:
Eros Lazzerini Denchi
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Publication Detail:
Type:  Comment; News     Date:  2012-08-09
Journal Detail:
Title:  Cell cycle (Georgetown, Tex.)     Volume:  11     ISSN:  1551-4005     ISO Abbreviation:  Cell Cycle     Publication Date:  2012 Aug 
Date Detail:
Created Date:  2012-08-28     Completed Date:  2013-02-04     Revised Date:  2013-07-12    
Medline Journal Info:
Nlm Unique ID:  101137841     Medline TA:  Cell Cycle     Country:  United States    
Other Details:
Languages:  eng     Pagination:  2976     Citation Subset:  IM    
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MeSH Terms
Descriptor/Qualifier:
Animals
Antibiotics, Antineoplastic / pharmacology*
Cell Aging / drug effects*
Humans
Sirolimus / pharmacology*
Transcription Factors / metabolism*
ras Proteins / metabolism*
Chemical
Reg. No./Substance:
0/Antibiotics, Antineoplastic; 0/Transcription Factors; 53123-88-9/Sirolimus; EC 3.6.5.2/ras Proteins
Comments/Corrections
Comment On:
Cell Cycle. 2012 Jun 15;11(12):2402-7   [PMID:  22672902 ]
Cell Cycle. 2012 Jun 15;11(12):2391-401   [PMID:  22627671 ]

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

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Journal Information
Journal ID (nlm-ta): Cell Cycle
Journal ID (iso-abbrev): Cell Cycle
Journal ID (publisher-id): CC
ISSN: 1538-4101
ISSN: 1551-4005
Publisher: Landes Bioscience
Article Information
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Copyright © 2012 Landes Bioscience
open-access:
Print publication date: Day: 15 Month: 8 Year: 2012
pmc-release publication date: Day: 15 Month: 8 Year: 2012
Volume: 11 Issue: 16
First Page: 2976 Last Page: 2976
ID: 3442903
PubMed Id: 22874595
Publisher Id: 2012NV0748
DOI: 10.4161/cc.21529
Publisher Item Identifier: 21529

A critical role for TORC1 in cellular senescence
Eros Lazzerini Denchi*
Department of Molecular and Experimental Medicine; The Scripps Research Institute; La Jolla, CA USA
*Correspondence to: Eros Lazzerini Denchi, Email: edenchi@scripps.edu

Cellular senescence is a process initiated either when cells proliferate past their potential (replicative senescence) or by activation of an oncogenic stress (oncogene-induced senescence). Both of these events are characterized by the activation of a DNA damage response, which is initiated by eroded telomeres in the case of replicative senescence, and aberrant products of DNA replication in the case of oncogene induced senescence.1 Senescence plays a critical tumor-suppression role in vivo, and alterations in the senescence program are a hallmark of cancer cells. Bypass of senescence is critical for tumor progression and involves the p53 and pRB tumor-suppressor pathways.2 Indeed, expression of DNA tumor virus oncoproteins that target p53 and pRB can bypass senescence in cultured cells,3 and concomitant loss of pRB and p53 bypasses senescence in human diploid fibroblasts.4 In addition to being an obligatory step for tumor progression, bypass of senescence creates a favorable environment in which additional tumor-promoting mutations can be acquired. For example, inactivation of p53 in the context of telomere erosion promotes rampant genomic instability mediated by cycles of aberrant DNA damage/DNA repair events.5

In a new study, Kolesnichenko et al. describe a critical role for the mTOR pathway in senescence induction.6 This work demonstrates that inhibition of mTOR is sufficient to delay RAS-induced senescence as well as replicative senescence. Using a combination of inhibitory molecules, shRNA-mediated knockdown and expression of inhibitory proteins, the authors demonstrate that inhibition of the TORC1 complex is sufficient to delay senescence induction. These findings are further corroborated by the independent work of Pospelova and colleagues showing that rapamycin treatment delays senescence induction in murine fibroblasts.7 These intriguing findings raise the question of why mTOR inhibition inhibits senescence induction. The work of Kolesnchenko and colleagues provides two clues to explain this phenotype. First, mTOR inhibition results in the activation of the pro-survival factor AKT, a factor that could explain how cells can proliferate in the face of an ongoing senescence-inducing signal. In addition, the authors find reduced levels of p53 and its target gene p21 upon mTOR inhibition. These findings are particularly significant considering the critical role for both p53 activation and p21 induction in senescence induction.

In conclusion, the finding that inhibition of the TORC1 complex has a profound effect on the onset of senescence might explain why rapamycin treatment had limited success in the treatment of cancer.8 On the other hand, rapamycin slows aging and thus delays cancer in mice.9


Notes

Previously published online: www.landesbioscience.com/journals/cc/article/21529

Notes


References
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6. Kolesnichenko M,et al. Cell CycleYear: 201211239140110.4161/cc.2068322627671
7. Pospelova TV,et al. Cell CycleYear: 2012112402710.4161/cc.2088222672902
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