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rdf:type |
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lifeskim:mentions |
umls-concept:C0007634,
umls-concept:C0017262,
umls-concept:C0023473,
umls-concept:C0033414,
umls-concept:C0044602,
umls-concept:C0169665,
umls-concept:C0185117,
umls-concept:C0205263,
umls-concept:C0243125,
umls-concept:C0285761,
umls-concept:C0699900,
umls-concept:C1150481,
umls-concept:C1332737,
umls-concept:C1335831,
umls-concept:C1368105,
umls-concept:C1451005,
umls-concept:C1514485,
umls-concept:C1704259,
umls-concept:C1705325,
umls-concept:C1705523,
umls-concept:C1705987,
umls-concept:C1977882,
umls-concept:C2911684
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pubmed:issue |
8
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pubmed:dateCreated |
2005-4-18
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pubmed:abstractText |
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.
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pubmed:language |
eng
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pubmed:journal |
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pubmed:citationSubset |
IM
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pubmed:chemical |
http://linkedlifedata.com/resource/pubmed/chemical/CDKN1B protein, human,
http://linkedlifedata.com/resource/pubmed/chemical/Carrier Proteins,
http://linkedlifedata.com/resource/pubmed/chemical/Cyclin-Dependent Kinase Inhibitor...,
http://linkedlifedata.com/resource/pubmed/chemical/Fusion Proteins, bcr-abl,
http://linkedlifedata.com/resource/pubmed/chemical/Intracellular Signaling Peptides...,
http://linkedlifedata.com/resource/pubmed/chemical/Phosphatidylinositol 3-Kinases,
http://linkedlifedata.com/resource/pubmed/chemical/Piperazines,
http://linkedlifedata.com/resource/pubmed/chemical/Pyrimidines,
http://linkedlifedata.com/resource/pubmed/chemical/Retinoblastoma Protein,
http://linkedlifedata.com/resource/pubmed/chemical/S-Phase Kinase-Associated Proteins,
http://linkedlifedata.com/resource/pubmed/chemical/imatinib
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pubmed:status |
MEDLINE
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pubmed:month |
Apr
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pubmed:issn |
0008-5472
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pubmed:author |
pubmed-author:AlberoM PilarMP,
pubmed-author:AndreuEnrique JEJ,
pubmed-author:ArbonaCristinaC,
pubmed-author:IvorraCarmenC,
pubmed-author:LledóElisaE,
pubmed-author:Martínez-ClimentJosé AngelJA,
pubmed-author:Montiel-DuarteCristinaC,
pubmed-author:Pérez-CalvoJavierJ,
pubmed-author:Pérez-RogerIgnacioI,
pubmed-author:PochEnricE,
pubmed-author:PrósperFelipeF,
pubmed-author:RifónJoséJ
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pubmed:issnType |
Print
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pubmed:day |
15
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pubmed:volume |
65
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pubmed:owner |
NLM
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pubmed:authorsComplete |
Y
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pubmed:pagination |
3264-72
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pubmed:dateRevised |
2010-11-18
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pubmed:meshHeading |
pubmed-meshheading:15833859-Carrier Proteins,
pubmed-meshheading:15833859-Cell Cycle,
pubmed-meshheading:15833859-Cell Growth Processes,
pubmed-meshheading:15833859-Cyclin-Dependent Kinase Inhibitor p27,
pubmed-meshheading:15833859-Fusion Proteins, bcr-abl,
pubmed-meshheading:15833859-Humans,
pubmed-meshheading:15833859-Intracellular Signaling Peptides and Proteins,
pubmed-meshheading:15833859-Leukemia, Myelogenous, Chronic, BCR-ABL Positive,
pubmed-meshheading:15833859-Phosphatidylinositol 3-Kinases,
pubmed-meshheading:15833859-Phosphorylation,
pubmed-meshheading:15833859-Piperazines,
pubmed-meshheading:15833859-Pyrimidines,
pubmed-meshheading:15833859-Retinoblastoma Protein,
pubmed-meshheading:15833859-S-Phase Kinase-Associated Proteins,
pubmed-meshheading:15833859-Transcription, Genetic
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pubmed:year |
2005
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pubmed:articleTitle |
BCR-ABL induces the expression of Skp2 through the PI3K pathway to promote p27Kip1 degradation and proliferation of chronic myelogenous leukemia cells.
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pubmed: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.
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pubmed:publicationType |
Journal Article,
Research Support, Non-U.S. Gov't
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