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The Journal of Immunology, 1999, 163: 708-714.
Copyright © 1999 by The American Association of Immunologists

Diacylglycerol Kinase Inhibition Prevents IL-2-Induced G1 to S Transition Through a Phosphatidylinositol-3 Kinase-Independent Mechanism1

Ignacio Flores, David R. Jones, Angel Ciprés, Ernesto Díaz-Flores, Miguel Angel Sanjuan and Isabel Mérida2

Department of Immunology and Oncology, Centro Nacional de Biotecnología, Campus de Cantoblanco, Madrid, Spain

Stimulation via IL-2R ligation causes T lymphocytes to transit through the cell cycle. Previous experiments by our group have demonstrated that, in human T cells, IL-2 binding induces phosphatidic acid production through activation of the {alpha} isoform of diacylglycerol kinase. In this study, using the IL-2-dependent mouse T cell line CTLL-2, we demonstrate that pharmacological inhibition of IL-2-induced diacylglycerol kinase activation is found to block IL-2-induced late G1 to S transition without affecting cell viability. Herein, we demonstrate that diacylglycerol kinase inhibition has a profound effect on the induction of the protooncogenes c-myc, c-fos, and c-raf by IL-2, whereas expression of bcl-2 and bcl-xL are not affected. When the IL-2-regulated cell cycle control checkpoints are examined in detail, we demonstrate that inhibition of diacylglycerol kinase activation prevents IL-2 induction of cyclin D3 without affecting p27 down-regulation. The strict control of cell proliferation exerted by phosphatidic acid through activation of diacylglycerol kinase is independent of other well-characterized IL-2R-derived signals, such as the phosphatidylinositol-3 kinase/Akt pathway, indicating the existence of a different and important mechanism to control cell division.




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