The Forkhead Transcription Factor FoxO Regulates Transcription of p27Kip1 and Bim in Response to IL-2

The cytokine IL-2 plays a very important role in the proliferation and survival of activated T cells. These effects of IL-2 are dependent on signaling through the phosphatidylinositol 3-kinase (PI3K) pathway. We and others have shown that PI3K, through activation of protein kinase B/Akt, inhibits tr...

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Bibliographic Details
Published in:The Journal of immunology (1950) 2002-05, Vol.168 (10), p.5024-5031
Main Authors: Stahl, Marie, Dijkers, Pascale F, Kops, Geert J. P. L, Lens, Susanne M. A, Coffer, Paul J, Burgering, Boudewijn M. T, Medema, Rene H
Format: Article
Language:English
Subjects:
Animals
Apoptosis - genetics
Apoptosis - immunology
Apoptosis Regulatory Proteins
Bcl-2-Like Protein 11
Carrier Proteins - genetics
Carrier Proteins - metabolism
Cell Cycle Proteins - genetics
Cell Cycle Proteins - metabolism
Cell Line
Cell Survival - genetics
Cell Survival - immunology
Cells, Cultured
Cyclin-Dependent Kinase Inhibitor p27
DNA-Binding Proteins - antagonists & inhibitors
DNA-Binding Proteins - metabolism
DNA-Binding Proteins - physiology
Forkhead Box Protein O1
Forkhead Transcription Factors
Gene Silencing - immunology
Humans
Interleukin-2 - physiology
Lymphocyte Activation - genetics
Membrane Proteins
Mice
Phosphatidylinositol 3-Kinases - physiology
Protein-Serine-Threonine Kinases
Proto-Oncogene Proteins - physiology
Proto-Oncogene Proteins c-akt
Signal Transduction - genetics
Signal Transduction - immunology
T-Lymphocytes - cytology
T-Lymphocytes - enzymology
T-Lymphocytes - immunology
Transcription Factors - antagonists & inhibitors
Transcription Factors - metabolism
Transcription Factors - physiology
Transcription, Genetic - immunology
Tumor Suppressor Proteins - genetics
Tumor Suppressor Proteins - metabolism
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Summary:The cytokine IL-2 plays a very important role in the proliferation and survival of activated T cells. These effects of IL-2 are dependent on signaling through the phosphatidylinositol 3-kinase (PI3K) pathway. We and others have shown that PI3K, through activation of protein kinase B/Akt, inhibits transcriptional activation by a number of forkhead transcription factors (FoxO1, FoxO3, and FoxO4). In this study we have investigated the role of these forkhead transcription factors in the IL-2-induced T cell proliferation and survival. We show that IL-2 regulates phosphorylation of FoxO3 in a PI3K-dependent fashion. Phosphorylation and inactivation of FoxO3 appears to play an important role in IL-2-mediated T cell survival, because mere activation of FoxO3 is sufficient to trigger apoptosis in T cells. Indeed, active FoxO3 can induce expression of IL-2-regulated genes, such as the cdk inhibitor p27(Kip1) and the proapoptotic Bcl-2 family member Bim. Furthermore, we show that IL-2 triggers a rapid, PI3K-dependent, phosphorylation of FoxO1a in primary T cells. Thus, we propose that inactivation of FoxO transcription factors by IL-2 plays a critical role in T cell proliferation and survival.
ISSN:0022-1767
1550-6606