TY - JOUR
T1 - Vav1 promotes T cell cycle progression by linking TCR/CD28 costimulation to FOXO1 and p27kip1 expression
AU - Charvet, Céline
AU - Canonigo, Ann Janette
AU - Bécart, Stéphane
AU - Maurert, Ulrich
AU - Miletic, Ana V.
AU - Swat, Wojciech
AU - Deckert, Marcel
AU - Altman, Amnon
PY - 2006/10/15
Y1 - 2006/10/15
N2 - 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 tor 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 falled to down-regulate the expression of p27 kip1, 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 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 of Vav1. Thus, Vav1 is a critical regulator of a PI3K/Akt/FOXO1 pathway, which controls T cell cycle progression and proliferation.
AB - 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 tor 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 falled to down-regulate the expression of p27 kip1, 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 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 of Vav1. Thus, Vav1 is a critical regulator of a PI3K/Akt/FOXO1 pathway, which controls T cell cycle progression and proliferation.
UR - http://www.scopus.com/inward/record.url?scp=33749516648&partnerID=8YFLogxK
U2 - 10.4049/jimmunol.177.8.5024
DO - 10.4049/jimmunol.177.8.5024
M3 - Article
C2 - 17015685
AN - SCOPUS:33749516648
VL - 177
SP - 5024
EP - 5031
JO - Journal of Immunology
JF - Journal of Immunology
SN - 0022-1767
IS - 8
ER -