The expression of p18INK4 and p27kip1 cyclin-dependent kinase inhibitors is regulated differently during human B cell differentiation.
Cell cycle progression is under the control of cyclin-dependent kinases (cdks), the activity of which is dependent on the expression of specific cdk inhibitors. In this paper we report that the two cdk inhibitors, p27(Kip1) and p18(INK4c), are differently expressed and control different steps of human B lymphocyte activation. Resting B cells contain large amounts of p27(Kip1) and no p18(INK4c). In vitro stimulation by Staphylococcus aureus Cowan 1 strain or CD40 ligand associated with IL-10 and IL-2 induces a rapid decrease in p27(Kip1) expression combined with cell cycle entry and progression. In contrast, in vitro Ig production correlates with specific expression of p18(INK4c) and early G(1) arrest. This G(1) arrest is associated with inhibition of cyclin D3/cdk6-mediated retinoblastoma protein phosphorylation by p18(INK4c). A similar contrasting pattern of p18(INK4c) and p27(Kip1) expression is observed both in B cells activated in vivo and in various leukemic cells. Expression of p18(INK4c) was also detected in various Ig-secreting cell lines in which both maximum Ig secretion and specific p18(INK4c) expression were observed during the G(1) phase. Our study shows that p27(Kip1) and p18(INK4c) have different roles in B cell activation; p27(Kip1) is involved in the control of cell cycle entry, and p18(INK4c) is involved in the subsequent early G(1) arrest necessary for terminal B lymphocyte differentiation.
Schrantz
N
N
Institut National de la Santé et de la Recherche Médicale, Unité 131, and Centre de Recherche Claude Bernard, Clamart, France.
Beney
G E
GE
Auffredou
M T
MT
Bourgeade
M F
MF
Leca
G
G
Vazquez
A
A
D001402:B-Lymphocytes / Q000166:cytology* / Q000201:enzymology*; D019013:CD40 Antigens / Q000502:physiology; D002352:Carrier Proteins / Q000096:biosynthesis* / Q000378:metabolism; D018797:Cell Cycle Proteins; D002454:Cell Differentiation / Q000276:immunology; D002478:Cells, Cultured; D056743:Cyclin D3; D051361:Cyclin-Dependent Kinase 6; D050763:Cyclin-Dependent Kinase Inhibitor p18; D050760:Cyclin-Dependent Kinase Inhibitor p27; D018844:Cyclin-Dependent Kinases / Q000037:antagonists & inhibitors*; D016213:Cyclins / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D015536:Down-Regulation / Q000276:immunology; D004791:Enzyme Inhibitors / Q000378:metabolism*; D016193:G1 Phase / Q000276:immunology; D006801:Humans; D015448:Leukemia, B-Cell / Q000276:immunology / Q000378:metabolism; D008213:Lymphocyte Activation; D046911:Macromolecular Substances; D008869:Microtubule-Associated Proteins / Q000096:biosynthesis; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000378:metabolism; D016160:Retinoblastoma Protein / Q000037:antagonists & inhibitors / Q000378:metabolism; D014407:Tumor Cells, Cultured; D025521:Tumor Suppressor Proteins; D015854:Up-Regulation / Q000276:immunology
C534696:CCND3 protein, human; D019013:CD40 Antigens; C493971:CDKN2C protein, human; D002352:Carrier Proteins; D018797:Cell Cycle Proteins; D056743:Cyclin D3; D050763:Cyclin-Dependent Kinase Inhibitor p18; D016213:Cyclins; D004791:Enzyme Inhibitors; D046911:Macromolecular Substances; D008869:Microtubule-Associated Proteins; D016160:Retinoblastoma Protein; D025521:Tumor Suppressor Proteins; D050760:Cyclin-Dependent Kinase Inhibitor p27; D017346:Protein Serine-Threonine Kinases; C495911:CDK6 protein, human; D051361:Cyclin-Dependent Kinase 6; D018844:Cyclin-Dependent Kinases