title: BCR-ABL induces the expression of Skp2 through the PI3K pathway to promote p27Kip1 degradation and proliferation of chronic myelogenous leukemia cells.
abstract: 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 G(1) 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.
authors.affiliation: Division of Cancer, Area of Cell Therapy and Hematology Service, Clinica Universitaria/School of Medicine, Foundation for Applied Medical Research, University of Navarra, Pamplona, Spain.
authors.forename: Enrique J
authors.initials: EJ
authors.lastname: Andreu
authors.forename: Elisa
authors.initials: E
authors.lastname: Lledó
authors.forename: Enric
authors.initials: E
authors.lastname: Poch
authors.forename: Carmen
authors.initials: C
authors.lastname: Ivorra
authors.forename: M Pilar
authors.initials: MP
authors.lastname: Albero
authors.forename: José Angel
authors.initials: JA
authors.lastname: Martínez-Climent
authors.forename: Cristina
authors.initials: C
authors.lastname: Montiel-Duarte
authors.forename: José
authors.initials: J
authors.lastname: Rifón
authors.forename: Javier
authors.initials: J
authors.lastname: Pérez-Calvo
authors.forename: Cristina
authors.initials: C
authors.lastname: Arbona
authors.forename: Felipe
authors.initials: F
authors.lastname: Prósper
authors.forename: Ignacio
authors.initials: I
authors.lastname: Pérez-Roger
mesh_terms: D001549:Benzamides; D002352:Carrier Proteins / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D002453:Cell Cycle / Q000187:drug effects; D048708:Cell Growth Processes / Q000502:physiology; D050760:Cyclin-Dependent Kinase Inhibitor p27; D016044:Fusion Proteins, bcr-abl / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D006801:Humans; D000068877:Imatinib Mesylate; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000201:enzymology / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D010766:Phosphorylation; D010879:Piperazines; D011743:Pyrimidines / Q000494:pharmacology; D016160:Retinoblastoma Protein / Q000378:metabolism; D044786:S-Phase Kinase-Associated Proteins / Q000096:biosynthesis* / Q000378:metabolism; D014158:Transcription, Genetic
chemical_list: D001549:Benzamides; C436291:CDKN1B protein, human; D002352:Carrier Proteins; D047908:Intracellular Signaling Peptides and Proteins; D010879:Piperazines; D011743:Pyrimidines; D016160:Retinoblastoma Protein; D044786:S-Phase Kinase-Associated Proteins; D050760:Cyclin-Dependent Kinase Inhibitor p27; D000068877:Imatinib Mesylate; D019869:Phosphatidylinositol 3-Kinases; D016044:Fusion Proteins, bcr-abl