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A new mode of cell cycle stimulation: cyclin E and CDK2-mediated cytoplasmic retention of repressive E2F complexes.
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PMID:  22874593     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Authors:
Alexandre Blais
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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:  2978     Citation Subset:  IM    
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MeSH Terms
Descriptor/Qualifier:
Animals
Cell Cycle Checkpoints / drug effects*
Cyclin E / metabolism*
Cyclin-Dependent Kinase 2 / metabolism*
Fibroblast Growth Factors / pharmacology*
Retinoblastoma Protein / metabolism*
Chemical
Reg. No./Substance:
0/Cyclin E; 0/Retinoblastoma Protein; 62031-54-3/Fibroblast Growth Factors; EC 2.7.11.22/Cyclin-Dependent Kinase 2
Comments/Corrections
Comment On:
Cell Cycle. 2012 Jul 1;11(13):2557-66   [PMID:  22713240 ]

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

Full Text
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: 2978 Last Page: 2978
PubMed Id: 22874593
ID: 3442905
Publisher Id: 2012NV0741
DOI: 10.4161/cc.21531
Publisher Item Identifier: 21531

A new mode of cell cycle stimulation : Cyclin E and CDK2-mediated cytoplasmic retention of repressive E2F complexes
Alexandre Blais*
Ottawa Institute of Systems Biology; University of Ottawa Faculty of Medicine; Department of Biochemistry, Microbiology and Immunology; Ottawa, Ontario, Canada
*Correspondence to: Alexandre Blais, Email: alexandre.blais@uottawa.ca

FGF, fibroblast growth factor, normally exerts a positive effect on the proliferation of most cell types. Chondrocytes, the cellular constituent of cartilage, can be quite different: in certain settings, they exit the cell cycle and initiate differentiation when exposed to FGF.1 The molecular mechanisms behind this uncommon response to growth factor stimulation are still incompletely understood. The FGF-stimulated chondrocyte cell cycle arrest is highly dependent on the function of two key cell cycle regulators, the retinoblastoma protein sister proteins p107 and p130.2 These two pocket proteins function by binding to “repressor E2F” transcription factors, bringing them to the cell nucleus, and assisting in the downregulation of the expression of genes important for cell cycle progression.3 The crucial role played by p107 and p130 in this setting is manifested in mice knockout for both genes: they have higher proliferation of chondrocytes and display cartilage and skeletal developmental defects.4

Mitogenic stimulation of cells triggers the accumulation of cyclin D, which associates with CDK4 or CDK6 and initiates the phosphorylation, and inactivation, of pocket proteins. Subsequently, the cyclin E gene is de-repressed, and cyclin E can associate to CDK2 to continue the wave of regulatory phosphorylation events. In contrast, the cell cycle arrest of chondrocytes and most other cell types is accompanied by the dephosphorylation of pocket proteins, as it is in this hypophosphorylated state that they can bind to E2F proteins and repress their activity. Kolupaeva et al. have previously shown that following FGF exposure of chondrocytes, dephosphorylation of p107 by the phosphatase PP2A accompanies cell cycle exit.5 They now report on the effect of cyclin E and CDK2 overexpression on p107/p130 phosphorylation and on proliferation.6 The idea was that if the role of cyclin E and CDK2 is to participate in the phosphorylation of p107/p130, the overexpression of cyclin E-CDK2 should counteract the effects of FGF treatment and lead to two consequences: maintaining p107/p130 in a phosphorylated state, and preventing cell cycle exit. The result was surprising, however: the cyclin E-CDK2-expressing cells did continue to cycle, but they did so while p107/p130 were in a hypophosphorylated state.

Repressive E2Fs (E2F4 and E2F5) lack a nuclear localization signal, and instead rely on association to hypophosphorylated pocket proteins to reach the nucleus and repress their target genes.7 Kolupaeva et al. reveal that when cyclin E-CDK2 are ectopically expressed, the repressive E2F4/p130 complex fails to make its way to the nucleus; this prevents the repression of E2F target genes and impairs FGF-stimulated cell cycle exit. Interestingly, Kolupaeva et al. also show that while in the cytoplasm, the E2F-pocket protein complexes are associated to cyclin E-CDK2. These results highlight a novel means to promote proliferation for cyclin E-CDK2 that might be independent of pocket protein phosphorylation. This is interesting in the context of previous findings reported by the authors that cyclin D-CDK4 ectopic expression not only prevents FGF-mediated cell cycle exit, but also leads to p107 phosphorylation. Because, cyclin E expression and associated CDK2 activity are higher following cyclin D-CDK4 overexpression, it will be interesting to determine whether the cytoplasmic association between cyclin E-CDK2 and pocket proteins also occurs in the cyclin D-CDK4-overexpression setting, and if a catalytically inactive CDK2 would still lead to higher proliferation when cyclin E is overexpressed.

As the authors pointed out, cyclin E overexpression is detected in several types of cancers, and it would be interesting to determine the contribution of the cytoplasmic retention of E2F-p107/p130 by cyclin E-CDK2 to tumorigenesis. Moreover, if this function of cyclin E-CDK2 is independent of its kinase activity, this would represent a novel therapeutic target to block, in conjunction with conventional CDK inhibitors. This will await more detailed studies on the precise mode of interaction of cyclin E-CDK2 with the E2F-pocket protein complexes, and on the exact composition of cytoplasmic pocket protein complexes.


Notes

Previously published online: www.landesbioscience.com/journals/cc/article/21531

Notes


References
1. Marie PJ. GeneYear: 20124981410.1016/j.gene.2012.01.08622342254
2. Dailey L,et al. J Cell BiolYear: 200316110536610.1083/jcb.20030207512821644
3. Blais A,et al. Curr Opin Genet DevYear: 2004145273210.1016/j.gde.2004.07.00315380244
4. Cobrinik D,et al. Genes DevYear: 19961016334410.1101/gad.10.13.16338682294
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7. Lindeman GJ,et al. Proc Natl Acad Sci USAYear: 199794509510010.1073/pnas.94.10.50959144196

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