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Involvement of p27^Kip1 in the G₁- and S/G₂-phase Lengthening Mediated by Glucocorticoids in Normal Human Lymphocytes¹

Laboratoire de Cytologie Analytique, Faculté de Médecine, 69373 Lyon CEDEX 08 (JE 1879) [N. B., A. P., E. D., P. A. B., M. F.]; and Laboratoire d’Hématologie et de Cytogénétique, Hôpital Edouard-Herriot, 69003 Lyon [P. A. B., M. F.], France

Glucocorticoids inhibit cell proliferation by inducing cell cycle lengthening. In this report, we have analyzed, in normal peripheral blood lymphocytes, the involvement of p27^Kip1in this slowing of proliferation. Following dexamethasone (DXM) treatment, p27^Kip1 expression and regulation varied differently with the level of lymphocyte stimulation. In quiescent cells, DXM inhibited p27^Kip1 protein expression by decreasing its rate of synthesis, whereas its half-life and mRNA steady state remained constant. In contrast, in stimulated lymphocytes, DXM increased p27^Kip1 expression by enhancing its mRNA steady state. This increase is not only a consequence of the DXM-induced interleukin 2 inhibition: we also found an increase in p27^Kip1 mRNA stability that was not observed in quiescent lymphocytes. Cyclin/cyclin-dependent kinase (CDK) complexes immunoprecipitated with p27^Kip1 are differentially modified by DXM addition: (a) G₁ kinasic complexes (cyclin D/CDK4 or CDK6) associated with p27^Kip1 are strongly decreased by DXM, (b) S-phase complexes (CDK2/cyclin E and A) remained stable or increased, and (c) the association of p27^Kip1 with the phosphorylated forms of CDK1 is increased by DXM. In addition, CDK2 kinase activity was decreased in DXM-treated cells: we suggest that p27^Kip1 might participate in inhibiting its catalytic activity. These results indicated that, in normal lymphoid cells, p27^Kip1 may be involved in DXM antiproliferative effects. The increase of p27^Kip1 expression and a decrease in G₁ mitogenic factors, together with the redistribution of p27^Kip1 to S/G₂-M regulatory complexes, may explain the lengthening of G₁ and S/G₂ after DXM treatment in lymphocytes.

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