Abnormal integrin-mediated regulation of chronic myelogenous leukemia CD34+ cell proliferation: BCR/ABL up-regulates the cyclin-dependent kinase inhibitor, p27Kip, which is relocated to the cell cytoplasm and incapable of regulating cdk2 activity.
beta(1)-integrin engagement on normal (NL) CD34(+) cells increases levels of the cyclin-dependent kinase inhibitor (cdki), p27(Kip), decreases cdk2 activity, and inhibits G(1)/S-phase progression. In contrast, beta(1)-integrin engagement on chronic myelogenous leukemia (CML) CD34(+) cells does not inhibit G(1)/S progression. We now show that, in CML, baseline p27(Kip) levels are significantly higher than in NL CD34(+) cells, but adhesion to fibronectin (FN) does not increase p27(Kip) levels. p27(Kip) mRNA levels are similar in CML and NL CD34(+) cells and remain unchanged after adhesion, suggesting posttranscriptional regulation. Despite the elevated p27(Kip) levels, cdk2 kinase activity is similar in CML and NL CD34(+) cells. In NL CD34(+) cells, >90% of p27(Kip) is located in the nucleus, where it binds to cdk2 after integrin engagement. In CML CD34(+) cells, however, >80% of p27(Kip) is located in the cytoplasm even in FN-adherent cells, and significantly less p27(Kip) is bound to cdk2. Thus, presence of BCR/ABL induces elevated levels of p27(Kip) and relocation of p27(Kip) to the cytoplasm, which contributes to the loss of integrin-mediated proliferation inhibition, characteristic of CML.
Jiang
Y
Y
Stem Cell Biology Institute and Department of Medicine and Cancer Center, University of Minnesota Medical School, Minneapolis, MN 55455, USA.
Zhao
R C
RC
Verfaillie
C M
CM
D018952:Antigens, CD34 / Q000276:immunology*; D001483:Base Sequence; D001692:Biological Transport; D042846:CDC2-CDC28 Kinases; D002448:Cell Adhesion; D018797:Cell Cycle Proteins; D002455:Cell Division / Q000276:immunology*; D051357:Cyclin-Dependent Kinase 2; D050760:Cyclin-Dependent Kinase Inhibitor p27; D018844:Cyclin-Dependent Kinases / Q000378:metabolism*; D003593:Cytoplasm / Q000378:metabolism; D017931:DNA Primers; D016044:Fusion Proteins, bcr-abl / Q000502:physiology*; D006801:Humans; D016023:Integrins / Q000502:physiology*; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000276:immunology / Q000378:metabolism / Q000473:pathology*; D008869:Microtubule-Associated Proteins / Q000235:genetics / Q000502:physiology*; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D025521:Tumor Suppressor Proteins; D015854:Up-Regulation
D018952:Antigens, CD34; D018797:Cell Cycle Proteins; D017931:DNA Primers; D016023:Integrins; D008869:Microtubule-Associated Proteins; D012333:RNA, Messenger; D025521:Tumor Suppressor Proteins; D050760:Cyclin-Dependent Kinase Inhibitor p27; D016044:Fusion Proteins, bcr-abl; D017346:Protein Serine-Threonine Kinases; D042846:CDC2-CDC28 Kinases; C495894:CDK2 protein, human; D051357:Cyclin-Dependent Kinase 2; D018844:Cyclin-Dependent Kinases