Journal of Biological Chemistry
Volume 276, Issue 37, 14 September 2001, Pages 34958-34965
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MECHANISMS OF SIGNAL TRANSDUCTION
The p42/p44 Mitogen-activated Protein Kinase Activation Triggers p27Kip1 Degradation Independently of CDK2/Cyclin E in NIH 3T3 Cells*

https://doi.org/10.1074/jbc.M101714200Get rights and content
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The p42/p44 mitogen-activated protein (MAP) kinase is stimulated by various mitogenic stimuli, and its sustained activation is necessary for cell cycle G1 progression and G1/S transition. G1 progression and G1/S transition also depend on sequential cyclin-dependent kinase (CDK) activation. Here, we demonstrate that MAP kinase inhibition leads to accumulation of the CDK inhibitor p27Kip1 in NIH 3T3 cells. Blocking the proteasome-dependent degradation of p27Kip1impaired this accumulation, suggesting that MAP kinase does not act on p27Kip1 protein synthesis. In the absence of extracellular signals (growth factors or cell adhesion), genetic activation of MAP kinase decreased the expression of p27Kip1 as assessed by cotransfection experiments and by immunofluorescence detection. Importantly, MAP kinase activation also decreased the expression of a p27Kip1 mutant, which cannot be phosphorylated by CDK2, suggesting that MAP kinase-dependent p27Kip1regulation is CDK2-independent. Accordingly, expression of dominant-negative CDK2 did not impair the down-regulation of p27Kip1 induced by MAP kinase activation. These data demonstrate that the MAP kinase pathway regulates p27Kip1expression in fibroblasts essentially through a degradation mechanism, independently of p27Kip1 phosphorylation by CDK2. This strengthens the role of this CDK inhibitor as a key effector of G1 growth arrest, whose expression can be controlled by extracellular stimuli-dependent signaling pathways.

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Published, JBC Papers in Press, June 19, 2001, DOI 10.1074/jbc.M101714200

*

This work was supported by the CNRS and by the Association pour la Recherche contre le Cancer.The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.