title: End-stage differentiation of neutrophil granulocytes in vivo is accompanied by up-regulation of p27kip1 and down-regulation of CDK2, CDK4, and CDK6.
abstract: The in vivo expression profiles of cell-cycle proteins regulating G1-to-S-phase transition were determined in three neutrophil precursor populations from human bone marrow: myeloblasts (MBs) and promyelocytes (PMs); myelocytes (MCs) and metamyelocytes (MMs); and band cells (BCs) and segmented neutrophil cells (SCs) and in mature polymorphonuclear neutrophils (PMNs) from peripheral blood. Complete cell-cycle arrest was observed in BCs/SCs and PMNs. Cyclins D1, D2, and D3 were found to be down-regulated during granulopoiesis, whereas a slight increase of cyclin E was seen. In contrast, cyclin-dependent kinase (CDK)2, -4, and -6 were down-regulated from the MC/MM stages and onward. The transcript levels of CDK2, -4, and -6 were concurrently down-regulated. As the only CDK inhibitor, p27kip1 protein and mRNA expression were up-regulated in MCs/MMs and reached peak levels in PMNs. Protein expression of retinoblastoma protein and the related pocket proteins p107 and p130 was down-regulated from the MC/MM stages and onward. This is the first report to describe expression levels of cell-cycle proteins during granulopoiesis in vivo, and it strongly contrasts the observations made in cell-culture systems in vitro.
authors.affiliation: The Granulocyte Research Laboratory, Department of Hematology, Rigshospitalet, University of Copenhagen, Denmark. pklausen@rh.dk
authors.forename: Pia
authors.initials: P
authors.lastname: Klausen
authors.forename: Malene Digmann
authors.initials: MD
authors.lastname: Bjerregaard
authors.forename: Niels
authors.initials: N
authors.lastname: Borregaard
authors.forename: Jack Bernard
authors.initials: JB
authors.lastname: Cowland
mesh_terms: D042846:CDC2-CDC28 Kinases / Q000096:biosynthesis / Q000235:genetics; D018797:Cell Cycle Proteins / Q000096:biosynthesis / Q000235:genetics*; D002454:Cell Differentiation / Q000235:genetics; D051357:Cyclin-Dependent Kinase 2; D051358:Cyclin-Dependent Kinase 4; D051361:Cyclin-Dependent Kinase 6; D050760:Cyclin-Dependent Kinase Inhibitor p27; D018844:Cyclin-Dependent Kinases / Q000096:biosynthesis / Q000235:genetics*; D016213:Cyclins / Q000235:genetics; D016193:G1 Phase / Q000235:genetics; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D006801:Humans; D019891:Leukopoiesis / Q000235:genetics*; D009504:Neutrophils / Q000166:cytology*; D011518:Proto-Oncogene Proteins; D016196:S Phase / Q000235:genetics; D025521:Tumor Suppressor Proteins / Q000096:biosynthesis / Q000235:genetics*
chemical_list: D018797:Cell Cycle Proteins; D016213:Cyclins; D011518:Proto-Oncogene Proteins; D025521:Tumor Suppressor Proteins; D050760:Cyclin-Dependent Kinase Inhibitor p27; D042846:CDC2-CDC28 Kinases; C495894:CDK2 protein, human; C495900:CDK4 protein, human; C495911:CDK6 protein, human; D051357:Cyclin-Dependent Kinase 2; D051358:Cyclin-Dependent Kinase 4; D051361:Cyclin-Dependent Kinase 6; D018844:Cyclin-Dependent Kinases