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Unequal Contribution of Akt Isoforms in the Double-Negative to Double-Positive Thymocyte Transition¹

Changchuin Mao^*, Esmerina G. Tili^2,*, Marei Dose^*, Mariëlle C. Haks, Susan E. Bear^3,*, Ioanna Maroulakou^*, Kyoji Horie, George A. Gaitanaris, Vincenzo Fidanza^¶, Thomas Ludwig^||, David L. Wiest, Fotini Gounari^* and Philip N. Tsichlis^4,*

^* Molecular Oncology Research Institute, Tufts-New England Medical Center, Boston, MA 02111; Fox Chase Cancer Center, Philadelphia, PA 19111; Osaka University, Osaka, Japan; Omeros Corporation, Seattle, WA 98104; ^¶ Thomas Jefferson University, Philadelphia, PA 19107; and ^|| Department of Anatomy and Cell Biology, Columbia University, New York, NY 10027

Pre-TCR signals regulate the transition of the double-negative (DN) 3 thymocytes to the DN4, and subsequently to the double-positive (DP) stage. In this study, we show that pre-TCR signals activate Akt and that pharmacological inhibition of the PI3K/Akt pathway, or combined ablation of Akt1 and Akt2, and to a lesser extent Akt1 and Akt3, interfere with the differentiation of DN3 and the accumulation of DP thymocytes. Combined ablation of Akt1 and Akt2 inhibits the proliferation of DN4 cells, while combined ablation of all Akt isoforms also inhibits the survival of all the DN thymocytes. Finally, the combined ablation of Akt1 and Akt2 inhibits the survival of DP thymocytes. Constitutively active Lck-Akt1 transgenes had the opposite effects. We conclude that, following their activation by pre-TCR signals, Akt1, Akt2, and, to a lesser extent, Akt3 promote the transition of DN thymocytes to the DP stage, in part by enhancing the proliferation and survival of cells undergoing -selection. Akt1 and Akt2 also contribute to the differentiation process by promoting the survival of the DP thymocytes.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by National Institutes of Health Grants R01-CA057436 (to P.N.T.) and R01-AI059676 (to F.G.). C.M. was supported by National Institutes of Health Training Grant T32-CA009429.

² Current address: Comprehensive Cancer Center, Ohio State University, Columbus, OH 43210.

³ Current address: Department of Biology, Pine Manor College, Chestnut Hill, MA 02467.

⁴ Address correspondence and reprint requests to Dr. Philip N. Tsichlis, Molecular Oncology Research Institute, Tufts-New England Medical Center, 750 Washington Street, No. 5609, Boston, MA 02111. E-mail address: ptsichlis{at}tufts-nemc.org

⁵ Abbreviations used in this paper: DN, double negative; pT-, pre-T; DP, double positive; LAT, linker for activation of T cells; FTOC, fetal thymic organ culture; PI, propidium iodide; RT, room temperature.

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