期刊
JOURNAL OF IMMUNOLOGY
卷 177, 期 8, 页码 5024-5031出版社
AMER ASSOC IMMUNOLOGISTS
DOI: 10.4049/jimmunol.177.8.5024
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资金
- NIGMS NIH HHS [GM50819] Funding Source: Medline
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 G.-G, 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 14-3-3 tau were also reduced in Vav1(-/-) T cells. Consistent with the important role of FOXO1 in p27(kiP1) transcription, stimulated Vav1(-/-) T cells failed to down-regulate the expression of p27(kiP1), explaining their G(0)-G(1) arrest. These defects were more pronounced in Vav1/Vav3 double-deficient T cells, suggesting partial redundancy between Vav1 and Vav3. Importantly, IL-2-induced p27(kiP1) 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 Vav1. Thus, Vav1 is a critical regulator of a PI3K/Akt/FOXO1 pathway, which controls T cell cycle progression and proliferation.
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