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Reports
Confluence-induced cell cycle exit involves pre-mitotic CDK inhibition by p27Kip1 and cyclin D1 downregulation
Anne-Amandine Chassot, Gerald Lossaint, Laurent Turchi, Guerrino Meneguzzi, Daniel Fisher, Gilles Ponzio and Vjekoslav Dulic
volume 7 | issue 13
1 July 2008Subscribe to this journal for $129/year
Tissue homeostasis requires precise control of cell proliferation and arrest in response to environmental cues. In situation such as wound healing, injured cells are stimulated to divide, but as soon as confluence is reached proliferation must be blocked. Such reversible cell cycle exit occurs in G1, requires pRb family members, and is driven by p27Kip1-dependent Cdk inactivation. This implies that, while dividing, cells should simultaneously prepare the exit once mitosis is accomplished. For a long time, the decision to cycle or not was presumed to occur in G1, prior to the restriction point, beyond which the cells were bound to divide even in the absence of mitogens, before finally arresting after mitosis. However, more recent reports suggested that the commitment to cycle in response to serum occurs already in G2 phase and requires the Ras-dependent induction of cyclin D1, which promotes following G1/S transition. To test whether this hypothesis applies to arrest induced by contact inhibition, we used an in vitro wounding model where quiescent human dermal fibroblasts, stimulated to proliferate by mechanical injury, synchronously exit cell cycle after mitosis due to renewed confluence. We show that this exit is preceded by p27-dependent inhibition of cyclin A-Cdk1/2, cyclin D1 downregulation and reduced pre-mitotic pRb pocket protein phosphorylation. Over-expression of cyclin D1 but not p27 depletion reversed this phenotype and compromised confluence-driven cell cycle exit. Thus, a balance between cyclin D1 and p27 may provide sensitive responses to variations in proliferative cues operating throughout the cell cycle.
Authors
Anne-Amandine Chassot
INSERM
Gerald Lossaint
IGMM-CNRS
Laurent Turchi
INSERM
Guerrino Meneguzzi
INSERM
Daniel Fisher
Centre National de la Recherche Scientifique; Montpellier, France
Gilles Ponzio
INSERM
Vjekoslav Dulic
Centre National de la Recherche Scientifique, Montpellier, France