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Cell Growth & Differentiation Vol. 10, 405-412, June 1999
© 1999 American Association for Cancer Research

Involvement of p27Kip1 in the G1- and S/G2-phase Lengthening Mediated by Glucocorticoids in Normal Human Lymphocytes1

Nathalie Baghdassarian, Alexandra Peiretti, Elwire Devaux, Paul André Bryon and Martine Ffrench2

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 p27Kip1in this slowing of proliferation. Following dexamethasone (DXM) treatment, p27Kip1 expression and regulation varied differently with the level of lymphocyte stimulation. In quiescent cells, DXM inhibited p27Kip1 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 p27Kip1 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 p27Kip1 mRNA stability that was not observed in quiescent lymphocytes. Cyclin/cyclin-dependent kinase (CDK) complexes immunoprecipitated with p27Kip1 are differentially modified by DXM addition: (a) G1 kinasic complexes (cyclin D/CDK4 or CDK6) associated with p27Kip1 are strongly decreased by DXM, (b) S-phase complexes (CDK2/cyclin E and A) remained stable or increased, and (c) the association of p27Kip1 with the phosphorylated forms of CDK1 is increased by DXM. In addition, CDK2 kinase activity was decreased in DXM-treated cells: we suggest that p27Kip1 might participate in inhibiting its catalytic activity. These results indicated that, in normal lymphoid cells, p27Kip1 may be involved in DXM antiproliferative effects. The increase of p27Kip1 expression and a decrease in G1 mitogenic factors, together with the redistribution of p27Kip1 to S/G2-M regulatory complexes, may explain the lengthening of G1 and S/G2 after DXM treatment in lymphocytes.




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Cancer Research Clinical Cancer Research
Cancer Epidemiology Biomarkers & Prevention Molecular Cancer Therapeutics
Molecular Cancer Research Cell Growth & Differentiation
Copyright © 1999 by the American Association of Cancer Research.