Document Detail

Mitogenic signalling and the p16INK4a-Rb pathway cooperate to enforce irreversible cellular senescence.
MedLine Citation:
PMID:  17028578     Owner:  NLM     Status:  MEDLINE    
The p16(INK4a) cyclin-dependent kinase inhibitor has a key role in establishing stable G1 cell-cycle arrest through activating the retinoblastoma (Rb) tumour suppressor protein pRb in cellular senescence. Here, we show that the p16(INK4a) /Rb-pathway also cooperates with mitogenic signals to induce elevated intracellular levels of reactive oxygen species (ROS), thereby activating protein kinase Cdelta (PKCdelta) in human senescent cells. Importantly, once activated by ROS, PKCdelta promotes further generation of ROS, thus establishing a positive feedback loop to sustain ROS-PKCdelta signalling. Sustained activation of ROS-PKCdelta signalling irreversibly blocks cytokinesis, at least partly through reducing the level of WARTS (also known as LATS1), a mitotic exit network (MEN) kinase required for cytokinesis, in human senescent cells. This irreversible cytokinetic block is likely to act as a second barrier to cellular immortalization ensuring stable cell-cycle arrest in human senescent cells. These results uncover an unexpected role for the p16(INK4a)-Rb pathway and provide a new insight into how senescent cell-cycle arrest is enforced in human cells.
Akiko Takahashi; Naoko Ohtani; Kimi Yamakoshi; Shin-ichi Iida; Hidetoshi Tahara; Keiko Nakayama; Keiichi I Nakayama; Toshinori Ide; Hideyuki Saya; Eiji Hara
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2006-10-08
Journal Detail:
Title:  Nature cell biology     Volume:  8     ISSN:  1465-7392     ISO Abbreviation:  Nat. Cell Biol.     Publication Date:  2006 Nov 
Date Detail:
Created Date:  2006-11-01     Completed Date:  2006-12-12     Revised Date:  2009-11-19    
Medline Journal Info:
Nlm Unique ID:  100890575     Medline TA:  Nat Cell Biol     Country:  England    
Other Details:
Languages:  eng     Pagination:  1291-7     Citation Subset:  IM    
Institute for Genome Research, University of Tokushima, Tokushima 770-8503, Japan.
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MeSH Terms
Acetophenones / pharmacology
Acetylcysteine / pharmacology
Benzopyrans / pharmacology
Cell Aging / drug effects,  physiology*
Cell Cycle / drug effects,  physiology
Cell Division / drug effects,  physiology
Cell Line
Cyclin-Dependent Kinase Inhibitor p16 / genetics,  metabolism,  physiology*
Dose-Response Relationship, Drug
Models, Biological
Protein Kinase C-delta / genetics,  metabolism
Protein-Serine-Threonine Kinases / genetics,  metabolism
Retinoblastoma Protein / genetics,  metabolism,  physiology*
Signal Transduction / drug effects,  physiology*
Time Factors
Reg. No./Substance:
0/Acetophenones; 0/Benzopyrans; 0/Cyclin-Dependent Kinase Inhibitor p16; 0/Retinoblastoma Protein; 616-91-1/Acetylcysteine; 82-08-6/rottlerin; EC 2.7.1.-/LATS1 protein, human; EC Kinases; EC Kinase C-delta
Comment In:
Nat Cell Biol. 2006 Nov;8(11):1213-5   [PMID:  17077852 ]

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