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Cyclin-Dependent Kinase 2/Cyclin E Complex Is Involved in p120 Catenin (p120ctn)–Dependent Cell Growth Control: A New Role for p120ctn in Cancer

INSERM U823, Institut Albert Bonniot, Equipe DySAD Site Santé, Grenoble; Université Joseph Fourier, Grenoble; CNRS, Grenoble, France

Requests for reprints: Muriel R. Jacquier-Sarlin, Equipe de la Dynamique des Systèmes d'Adhérence et de la Différenciation, Centre de Recherche Institut National de la Sante et de la Recherche Medicale/Université Joseph Fourier U823, Institut Albert Bonniot, Site Santé BP 170, 38042 Grenoble, France. Phone: 33-476-54-95-52; Fax: 33-476-54-94-25; E-mail: jacquier-sarlin{at}ujf-grenoble.fr.

Depending on its cellular localization, p120 catenin (p120ctn) can participate in various processes, such as cadherin-dependent cell-cell adhesion, actin cytoskeleton remodeling, and intracellular trafficking. Recent studies also indicate that p120ctn could regulate cell proliferation and contact inhibition. This report describes a new function of p120ctn in the regulation of cell cycle progression. Overexpression of the p120ctn isoform 3A in human colon adenocarcinoma cells (HT-29) results in cytoplasmic accumulation of the protein, as observed in many tumors. This cytoplasmic increase is correlated with a reduction in proliferation and inhibition of DNA synthesis. Under these conditions, experiments on synchronized cells revealed a prolonged S phase associated with cyclin E stabilization. Both confocal microscopy and biochemical analysis showed that cyclin E and cyclin-dependent kinase 2 colocalized with p120ctn in centrosomes during mitosis. These proteins are associated in a functional complex evidenced by coimmunoprecipitation experiments and the emergence of Thr¹⁹⁹-phosphorylated nucleophosmin/B23. Such post-translational modification of this centrosomal target has been shown to trigger the initiation of centrosome duplication. Therefore, p120ctn-mediated accumulation of cyclin E in centrosomes may participate in abnormal amplification of centrosomes and the inhibition of DNA replication, thus leading to aberrant mitosis and polyploidy. Because these modifications are often observed in cancer, p120ctn may represent a new therapeutic target for future therapy. [Cancer Res 2007;67(20):9781–90]