Vav1 Promotes T Cell Cycle Progression by Linking TCR/CD28 Costimulation to FOXO1 and p27kip1 Expression
| Autor: | Marcel Deckert, Stéphane Bécart, Ana V. Miletic, Ann Janette Canonigo, Céline Charvet, Ulrich Maurer, Amnon Altman, Wojciech Swat |
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| Rok vydání: | 2006 |
| Předmět: |
T-Lymphocytes
T cell Immunology Receptors Antigen T-Cell Down-Regulation FOXO1 Biology Mice CD28 Antigens medicine Animals Guanine Nucleotide Exchange Factors Immunology and Allergy Cytotoxic T cell Phosphorylation Proto-Oncogene Proteins c-vav Protein kinase B Cells Cultured PI3K/AKT/mTOR pathway Forkhead Box Protein O1 Cell Cycle T-cell receptor CD28 Forkhead Transcription Factors Cell cycle Cell biology medicine.anatomical_structure Proto-Oncogene Proteins c-akt Cyclin-Dependent Kinase Inhibitor p27 |
| Zdroj: | The Journal of Immunology. 177:5024-5031 |
| ISSN: | 1550-6606 0022-1767 |
| DOI: | 10.4049/jimmunol.177.8.5024 |
| Popis: | Vav proteins play a critical role in T cell activation and proliferation by promoting cytoskeleton reorganization, transcription factor activation, and cytokine production. In this study, we investigated the role of Vav in T cell cycle progression. TCR/CD28-stimulated Vav1−/− T cells displayed a cell cycle block at the G0-G1 stage, which accounted for their defective proliferation. This defect was associated with impaired TCR/CD28-induced phosphorylation of Akt and the Forkhead family transcription factor, FOXO1. The cytoplasmic localization of FOXO1 and its association with 14–3-3τ were also reduced in Vav1−/− T cells. Consistent with the important role of FOXO1 in p27kip1 transcription, stimulated Vav1−/− T cells failed to down-regulate the expression of p27kip1, explaining their G0-G1 arrest. These defects were more pronounced in Vav1/Vav3 double-deficient T cells, suggesting partial redundancy between Vav1 and Vav3. Importantly, IL-2-induced p27kip1 down-regulation and cyclin D3 up-regulation and FOXO1 phosphorylation were similar in Vav1−/− and wild-type T lymphoblasts, indicating that defective FOXO1 phosphorylation and p27kip1 and cyclin D3 expression do not result from deficient IL-2 signaling in the absence of Vav1. Thus, Vav1 is a critical regulator of a PI3K/Akt/FOXO1 pathway, which controls T cell cycle progression and proliferation. |
| Databáze: | OpenAIRE |
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