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Involvement of p27 Kip1 in the G 1- and S/G 2-phase Lengthening Mediated by Glucocorticoids in Normal Human Lymphocytes 1

By Nathalie Baghdassarian, Ra Peiretti, Elwire Devaux, Paul André Bryon and Martine Ffrench


Glucocorticoids inhibit cell proliferation by inducing cell cycle lengthening. In this report, we have analyzed, in normal peripheral blood lymphocytes, the involvement of p27 Kip1 in 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 DXMinduced interleukin 2 inhibition: we also found an increase in p27 Kip1 mRNA stability that was not observed in quiescent lymphocytes. Cyclin/cyclindependent kinase (CDK) complexes immunoprecipitated with p27 Kip1 are differentially modified by DXM addition: (a) G 1 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 DXMtreated 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 G 1 mitogenic factors, together with the redistribution of p27 Kip1 to S/G 2-M regulatory complexes, may explain the Received 11/10/98; revised 3/4/99; accepted 4/9/99. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact

Year: 1999
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