MECHANISM OF ACTION OF THE IMMUNOSUPPRESSANT RAPAMYCIN

Rapamycin has potent immunosuppressive properties reflecting its abili ty to disrupt cytokine signaling that promotes lymphocyte growth and d ifferentiation. In IL-2-stimulated T cells, rapamycin impedes progress ion through the G1/S transition of the proliferation cycle, resulting in a mid-to-late G1 arrest. Two major biochemical alterations underlie this mode of action. The first one affects the phosphorylation/activa tion of the p70 S6 kinase (p70(s6k)), an early event of cytokine-induc ed mitogenic response. By inhibiting this enzyme, whose major substrat e is the 4DS ribosomal subunit 56 protein, rapamycin reduces the trans lation of certain mRNA encoding for ribosomal proteins and elongation factors, thereby decreasing protein synthesis. A second, later effect of rapamycin in IL-2-stimulated T cells is an inhibition of the enzyma tic activity ofthe cyclin-dependent kinase cdk2-cyclin E complex, whic h functions as a crucial regulator of G1/S transition. This inhibition results from a prevention of the decline of the p27 cdk inhibitor, th at normally follows IL-2 stimulation. To mediate these biochemical alt erations, rapamycin needs to bind to intracellular proteins, termed FK BP, thereby forming a unique effector molecular complex. However, neit her p70(s6k) inhibition, nor p27-induced cdk2-cyclin E inhibition are directly caused by the FKBP-rapamycin complex. Instead, this complex p hysically interacts with a novel protein, designated ''mammalian targe t of rapamycin'' (mTOR), which has sequence homology with the catalyti c domain of phosphatidylinositol kinases and may therefore be itself a kinase. mTOR may act upstream of p70(s6k) and cdk2-cyciin E in a line ar or bifurcated pathway of growth regulation. Molecular dissection of this pathway should further unravel cytokine-mediated signaling proce sses and help devise new immunosuppressants.