Title

Rapamycin-Induced Inhibition of P34(Cdc2) Kinase Activation Is Associated with G1/S-Phase Growth Arrest in T Lymphocytes

Document Type

Article

Publication Date

1-1-1993

Abstract

The macrolide rapamycin (RAP) is a potent inhibitor of interleukin-2 (IL- 2)-induced T-cell proliferation. Current models suggest that RAP, when complexed to its intracellular receptor, FK506-binding protein, interferes with an IL-2 receptor-coupled signaling pathway required for cell-cycle progression from G1- to S-phase. Here we show that RAP treatment inhibits the growth of an IL-2-dependent cytotoxic T-cell line, CTLL-2, in late G1- phase, just prior to entry of the cells into S-phase. In contrast, RAP- treated CTLL-2 cells retained the ability to respond to IL-2 with enhanced cytolytic activity, indicating that RAP was not a general suppressant of cellular responsiveness to IL-2. Subsequent studies revealed that IL-2 stimulation triggered a delayed activation of the p34(cdc2) kinase, the timing of which correlated with the G1- to S-phase transition. The IL-2- dependent increase in p34(cdc2) kinase activity was blocked by RAP. The RAP sensitivity of the p34(cdc2) activation mechanism implicates this signaling pathway in the control of S-phase commitment in IL-2-stimulated T-cells.

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