Rapamycin-induced inhibition of p34cdc2 kinase activation is associated with G1/S-phase growth arrest in T lymphocytes.
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 p34cdc2 kinase, the timing of which correlated with the G1- to S-phase transition. The IL-2-dependent increase in p34cdc2 kinase activity was blocked by RAP. The RAP sensitivity of the p34cdc2 activation mechanism implicates this signaling pathway in the control of S-phase commitment in IL-2-stimulated T-cells.
Morice
W G
WG
Department of Immunology, Mayo Clinic, Rochester, Minnesota 55905.
Brunn
G J
GJ
Wiederrecht
G
G
Siekierka
J J
JJ
Abraham
R T
RT
D000818:Animals; D016203:CDC2 Protein Kinase / Q000037:antagonists & inhibitors / Q000378:metabolism*; D002455:Cell Division / Q000187:drug effects; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D003602:Cytotoxicity, Immunologic / Q000187:drug effects*; D004261:DNA Replication / Q000187:drug effects; D004789:Enzyme Activation / Q000187:drug effects; D016193:G1 Phase / Q000187:drug effects; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D007376:Interleukin-2 / Q000494:pharmacology; D007700:Kinetics; D051379:Mice; D011090:Polyenes / Q000494:pharmacology*; D016196:S Phase / Q000187:drug effects; D020123:Sirolimus; D013602:T-Lymphocytes, Cytotoxic / Q000166:cytology / Q000187:drug effects* / Q000201:enzymology; D013936:Thymidine / Q000378:metabolism
D007166:Immunosuppressive Agents; D007376:Interleukin-2; D011090:Polyenes; D016203:CDC2 Protein Kinase; D013936:Thymidine; D020123:Sirolimus