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Retinoic Acid Induces p27^Kip1 Nuclear Accumulation by Modulating Its Phosphorylation

¹ Department of Biochemistry and Biophysics "F. Cedrangolo," Second University of Naples; ² Medical Genetics, University of Naples Federico II and Centro di Ingegneria Genetica-Advanced Biotechnologies, Naples, Italy

Requests for reprints: Fulvio Della Ragione, Department of Biochemistry and Biophysics "F. Cedrangolo," Second University of Naples, Via Costantinopoli, 16, 80138 Naples, Italy. Phone: 39-81-5665812; Fax: 39-81-441688; E-mail: fulvio.dellaragione{at}unina2.it.

All-trans-retinoic acid (ATRA), the most biologically active metabolite of vitamin A, controls cell proliferation, apoptosis, and differentiation depending on the cellular context. These activities point to ATRA as a candidate for cancer therapy. A pivotal effect of the molecule is the modulation of p27^Kip1, a cyclin-dependent kinase (CDK) inhibitor (CDKI). Here, we investigate the mechanisms by which ATRA regulates p27^Kip1 level in LAN-5, a neuroblastoma cell line. When added to the cells, ATRA causes a rapid nuclear increase of p27^Kip1, which clearly precedes growth arrest. The early buildup is not due to impairment of the CDKI degradation, in contrast to previous observations. Particularly, we did not detect the down-regulation of Skp2 and Cks1, two proteins involved in the nuclear ubiquitin-dependent p27^Kip1 removal. Moreover, the morphogen does not impair the CDKI nuclear export and does not cause CDK2 relocalization. The characterization of CDKI isoforms by two-dimensional PAGE/immunoblotting showed that ATRA induces an early nuclear up-regulation of monophosphorylated p27^Kip1. Immunologic studies established that this isoform corresponds to p27^Kip1 phosphorylated on S10. The buildup of phospho(S10)p27^Kip1 precedes the CDKI accumulation and increases its half-life. Finally, ATRA-treated nuclear LAN-5 extracts showed an enhanced capability of phosphorylating p27^Kip1 on S10, thus explaining the nuclear up-regulation of the isoform. In conclusion, our data suggest a novel mechanism of ATRA antiproliferative activity, in which the morphogen rapidly up-regulates a nuclear kinase activity that phosphorylates p27^Kip1 on S10. In turn, this event causes the stabilization of p27^Kip1 and its accumulation in the nuclear compartment. (Cancer Res 2006; 66(8): 4240-8)

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