Diacylglycerol kinase inhibition prevents IL-2-induced G(1) to S transition through a phosphatidylinositol-3 kinase-independent mechanism

Stimulation via IL-2R ligation causes T lymphocytes to transit through the cell cycle, Previous experiments by our group have demonstrated that, in hu man T cells, IL-2 binding induces phosphatidic acid production through acti vation of the a Isoform of diacylglycerol kinase, In this study, using the IL-2-dependent mouse T cell line CTLL-2, we demonstrate that pharmacologica l inhibition of IL-2-induced diacylglycerol kinase activation is found to b lock IL-2-induced late G(1) to S transition without affecting cell viabilit y. Herein, we demonstrate that diacylglycerol kinase inhibition has a profo und effect on the induction of the protooncogenes c-mp, c-fos, and c-raf by IL-2, whereas expression of bcl-2 and hcl-x, are not affected. When the IL -2-regulated cell cycle control checkpoints are examined in detail, we demo nstrate that inhibition of diacylglycerol kinase activation prevents IL-2 i nduction of cyclin D3 without affecting p27 down-regulation. The strict con trol of cell proliferation exerted by phosphatidic acid through activation of diacylglycerol kinase is independent of other well-characterized IL-2R-d erived signals, such as the phosphatidylinositol-3 kinase/Akt pathway, indi cating the existence of a different and important mechanism to control cell division.