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The Expression of p18^INK4 and p27^kip1 Cyclin-Dependent Kinase Inhibitors Is Regulated Differently During Human B Cell Differentiation¹

Institut National de la Santé et de la Recherche Médicale, Unité 131, and Centre de Recherche Claude Bernard, Clamart, France

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 G₁ arrest. This G₁ 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 G₁ 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 G₁ arrest necessary for terminal B lymphocyte differentiation.

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