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BCR-ABL Induces the Expression of Skp2 through the PI3K Pathway to Promote p27^Kip1 Degradation and Proliferation of Chronic Myelogenous Leukemia Cells

¹ Division of Cancer, Area of Cell Therapy and Hematology Service, Clinica Universitaria/School of Medicine, Foundation for Applied Medical Research, University of Navarra, Pamplona; ² Departamento de Química, Bioquímica y Biología Molecular, Universidad Cardenal Herrera-CEU, Moncada; and ³ Servicio de Hematología y Oncología Médica, Hospital Clínico de Valencia, Valencia, Spain

Requests for reprints: Ignacio Pérez-Roger, Departamento de Química, Bioquímica y Biología Molecular, Universidad Cardenal Herrera-CEU, av. Seminario s/n, 46113 Moncada, Valencia, Spain. Phone: 34-96-1369000 (1233); Fax: 34-96-139-5272; E-mail: iperez{at}uch.ceu.es or Felipe Prósper, Servicio de Hematología, Area de Terapia Celular, Av Pio XII 36, 31080 Pamplona, Spain. Phone: 34-948-255400; Fax: 34-948-296500; E-mail: fprosper{at}unav.es.

Chronic myelogenous leukemia (CML) is characterized by the expression of the BCR-ABL tyrosine kinase, which results in increased cell proliferation and inhibition of apoptosis. In this study, we show in both BCR-ABL cells (Mo7e-p210 and BaF/3-p210) and primary CML CD34+ cells that STI571 inhibition of BCR-ABL tyrosine kinase activity results in a G₁ cell cycle arrest mediated by the PI3K pathway. This arrest is associated with a nuclear accumulation of p27^Kip1 and down-regulation of cyclins D and E. As a result, there is a reduction of the cyclin E/Cdk2 kinase activity and of the retinoblastoma protein phosphorylation. By quantitative reverse transcription-PCR we show that BCR-ABL/PI3K regulates the expression of p27^Kip1 at the level of transcription. We further show that BCR-ABL also regulates p27^Kip1 protein levels by increasing its degradation by the proteasome. This degradation depends on the ubiquitinylation of p27^Kip1 by Skp2-containing SFC complexes: silencing the expression of Skp2 with a small interfering RNA results in the accumulation of p27^Kip1. We also demonstrate that BCR-ABL cells show transcriptional up-regulation of Skp2. Finally, expression of a p27^Kip1 mutant unable of being recognized by Skp2 results in inhibition of proliferation of BCR-ABL cells, indicating that the degradation of p27^Kip1 contributes to the pathogenesis of CML. In conclusion, these results suggest that BCR-ABL regulates cell cycle in CML cells at least in part by inducing proteasome-mediated degradation of the cell cycle inhibitor p27^Kip1 and provide a rationale for the use of inhibitors of the proteasome in patients with BCR-ABL leukemias.

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