Rapamycin Inhibition of Interleukin-2-Dependent P33(Cdk2) and P34(Cdc2) Kinase Activation in T Lymphocytes
The immunosuppressant rapamycin (RAP) is a potent inhibitor of the entry of interleukin (IL)-2-stimulated T cells into S-phase. Earlier results indicated that RAP treatment arrested the growth of the murine IL-2-dependent T cell line CTLL-2 in late G1-phase. To explore further the interactions of RAP with the cell cycle control machinery in T cells, we examined the effects of RAP treatment on the activation of the cyclin-dependent kinases p34(cdc2) and p33(cdk2) in G1-phase CTLL-2 cells. Stimulation of factor-deprived cells with IL-2 led to the assembly of high molecular weight complexes containing active p34(cdc2) and p33(cdk2). The appearance of these complexes was explained, at least in part, by the association of both cyclin-dependent kinases with IL-2-induced cyclin A. RAP treatment profoundly inhibited both cyclin A expression and the appearance of active cyclin A-cyclin-dependent kinase complexes in IL-2-stimulated, late G1-phase CTLL-2 cells. Although p34(cdc2) activation was largely dependent on association with cyclin A, a significant proportion of the active p33(cdk2) pool was complexed with cyclin E. In contrast to cyclin A, the IL-2-induced accumulation of cyclin E in G1- phase cells was only partially suppressed by RAP, and cyclin E-p33(cdk2) complexes were readily detected in drug-treated cells. These cyclin E- cyclin-dependent kinase complexes were nonetheless devoid of histone H1 kinase activity. The inhibitory effects of RAP on the activation of cyclin E- and cyclin A-associated cyclin-dependent kinases suggest that one or both events participate in the regulation of T cell entry into S-phase.
MSU Digital Commons Citation
Morice, W. G.; Wiederrecht, Gregory; Brunn, Gregory J.; Siekierka, John; and Abraham, R. T., "Rapamycin Inhibition of Interleukin-2-Dependent P33(Cdk2) and P34(Cdc2) Kinase Activation in T Lymphocytes" (1993). Department of Chemistry and Biochemistry Faculty Scholarship and Creative Works. 344.