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* Division of Cell Biology and
Division of Cellular Immunology, La Jolla Institute for Allergy and Immunology, La Jolla, CA 92037;
Department of Pathology and Immunology, Washington University School of Medicine and Siteman Cancer Center, St. Louis, MO 63110; and
Institut National de la Santé et de la Recherche Médicale U576, Hôpital de l’Archet I, 06202 Nice Cedex 3, France
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 14–3-3
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.
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 Grant GM50819 (to A.A.). This is publication number 728 from La Jolla Institute for Allergy and Immunology. We thank the Philippe Foundation for financial support.
2 Current address: Laboratory of Transplantation Immunology and Nephrology, University Hospital Basel, CH-4031, Basel, Switzerland.
3 Current address: Institute for Molecular Medicine and Cell Research, Stefan Meier Strasse 17, 79104 Freiburg, Germany.
4 Address correspondence and reprint requests to Dr. Amnon Altman, 9420 Athena Circle, La Jolla, CA 92037. E-mail address: amnon{at}liai.org
5 Abbreviations used in this paper: GEF, guanine nucleotide exchange factor; FOXO, Forkhead box class O; 7-AAD, 7-aminoactinomycin D.
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