Cyclin D3 - A novel target of rapamycin-mediated growth inhibition in human lymphocytes

Rapamycin is a potent immunosuppressant which is currently undergoing Phase II clinical trials. However, little is known about its mechanism of action at the molecular level. The immunosuppressive activity of rapamycin is currently thought to be due to the restoration of the cyclin dependent kinase inhibitor p27^Kip1 which is eliminated during the IL-2 dependent T cell growth. The widely accepted p27^Kip1 hypothesis of rapamycin action fails to explain why lymphocytes from the p27^Kip1 knockout mice are sensitive to rapamycin. In this study, we present our work that has led us to identify cyclin D₃ as an additional target of rapamycin. Downregulation of cyclin D₃ upon rapamycin treatment was observed only in primary T cells activated with PMA/Ionomycin and not in T cells treated with exogenous IL-2. These results point to a crucial role of cyclin D₃ in G1/S transition of the cell cycle in primary T cells, and suggest that the growth inhibitory effects of rapamycin are mediated by more than one mechanism depending on the type of mitogen stimulation.