Unequal Contribution of Akt Isoforms in the Double-Negative to Double-Positive Thymocyte Transition
| Autor: | Kyoji Horie, Susan E. Bear, George A. Gaitanaris, Philip N. Tsichlis, Ioanna G. Maroulakou, Thomas Ludwig, Esmerina Tili, Marei Dose, Changchuin Mao, Mariëlle C. Haks, Fotini Gounari, David L. Wiest, Vincenzo Fidanza |
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| Rok vydání: | 2007 |
| Předmět: |
Cell Survival
T-Lymphocytes Transgene Immunology Receptors Antigen T-Cell Double negative Gene Expression AKT1 AKT2 Thymus Gland Biology Lymphocyte Activation AKT3 Mice Phosphatidylinositol 3-Kinases Animals Protein Isoforms Immunology and Allergy Transgenes Protein kinase B PI3K/AKT/mTOR pathway Cell Proliferation Phosphoinositide-3 Kinase Inhibitors Mice Knockout Thymocyte embryonic structures Cancer research Proto-Oncogene Proteins c-akt hormones hormone substitutes and hormone antagonists |
| Zdroj: | The Journal of Immunology. 178:5443-5453 |
| ISSN: | 1550-6606 0022-1767 |
| DOI: | 10.4049/jimmunol.178.9.5443 |
| Popis: | 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 β-selection. Akt1 and Akt2 also contribute to the differentiation process by promoting the survival of the DP thymocytes. |
| Databáze: | OpenAIRE |
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