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J. Biol. Chem., Vol. 278, Issue 14, 12443-12451, April 4, 2003

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MAP Kinase-dependent Degradation of p27^Kip1 by Calpains in Choroidal Melanoma Cells
REQUIREMENT OF p27^Kip1 NUCLEAR EXPORT^*

Christelle Delmas, Nathalie Aragou, Sylvie Poussard, Patrick Cottin, Jean-Marie Darbon, and Stéphane Manenti^§

From the Laboratoire de Biologie Cellulaire et Moléculaire du Contrôle de la Prolifération, CNRS UMR 5088, IFR 109, Université Paul Sabatier, 118 Route de Narbonne, 31062 Toulouse Cedex, France and the  Laboratoire Biochimie et Technologie des Aliments USC-INRA 429, Université Bordeaux I, Avenue des Facultés, 33405 Talence Cedex, France

We investigated the status and the regulation of the cyclin-dependent kinases (CDK) inhibitor p27^Kip1 in a choroidal melanoma tumor-derived cell line (OCM-1). By contrast to normal choroidal melanocytes, the expression level of p27^Kip1 was low in these cells and the mitogen-activated protein (MAP) kinase pathway was constitutively activated. Genetic or chemical inhibition of this pathway induced p27^Kip1 accumulation, whereas MAP kinase reactivation triggered a down-regulation of p27^Kip1 that could be partially reversed by calpain inhibitors. In good accordance, ectopic expression of the cellular calpain inhibitor calpastatin led to an increase of endogenous p27^Kip1 expression. In vitro, p27^Kip1 was degraded by calpains, and OCM-1 cell extracts contained a calcium-dependent p27^Kip1 degradation activity. MAP kinase inhibition partially inhibited both calpain activity and calcium-dependent p27^Kip1 degradation by cellular extracts. Immunofluorescence labeling and subcellular fractionation revealed that p27^Kip1 was in part localized in the cytoplasmic compartment of OCM-1 cells but not of melanocytes, and accumulated into the nucleus upon MAP kinase inhibition. MAP kinase activation triggered a cytoplasmic translocation of the protein, as well as a change in its phosphorylation status. This CRM-1-dependent cytoplasmic translocation was necessary for MAP kinase- and calpain-dependent degradation. Taken together, these data suggest that in tumor-derived cells, p27^Kip1 could be degraded by calpains through a MAP kinase-dependent process, and that abnormal cytoplasmic localization of the protein, probably linked to modifications of its phosphorylation state, could be involved in this alternative mechanism of degradation.

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