The Expression of p18INK4 and p27kip1 Cyclin-Dependent Kinase Inhibitors Is Regulated Differently During Human B Cell Differentiation

Abstract

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, p27Kip1 and p18INK4c, are differently expressed and control different steps of human B lymphocyte activation. Resting B cells contain large amounts of p27Kip1 and no p18INK4c. In vitro stimulation by Staphylococcus aureus Cowan 1 strain or CD40 ligand associated with IL-10 and IL-2 induces a rapid decrease in p27Kip1 expression combined with cell cycle entry and progression. In contrast, in vitro Ig production correlates with specific expression of p18INK4c and early G1 arrest. This G1 arrest is associated with inhibition of cyclin D3/cdk6-mediated retinoblastoma protein phosphorylation by p18INK4c. A similar contrasting pattern of p18INK4c and p27Kip1 expression is observed both in B cells activated in vivo and in various leukemic cells. Expression of p18INK4c was also detected in various Ig-secreting cell lines in which both maximum Ig secretion and specific p18INK4c expression were observed during the G1 phase. Our study shows that p27Kip1 and p18INK4c have different roles in B cell activation; p27Kip1 is involved in the control of cell cycle entry, and p18INK4c is involved in the subsequent early G1 arrest necessary for terminal B lymphocyte differentiation.