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

Abstract

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 p27Kip1 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.

FOXO transcription factor-dependent p15INK4b and p19INK4d expression

“…FOXOs suppress cell proliferation with transcription of the apoptosis-related and/or cellcycle inhibitor genes. p27 KIP1 is a target of transcription by FOXOs Stahl et al, 2002), and it induces cell-cycle arrest in any phase. In addition, the functions of p21 CIP1 and p27 KIP1 are inhibited by Aktdependent phosphorylation and translocation from nuclei to cytoplasm (Collado et al, 2000;Rodier et al, 2001;Zhou et al, 2001;Fujita et al, 2002).…”

“…Akt-dependent phosphorylation of FOXOs results in their cytoplasmic localization, possibly by association with 14-3-3 proteins, and inability to exhibit their gene transcriptional activity (Brunet et al, 1999;Woods and Rena, 2002). FOXOs are reported to be involved in apoptosis induction or cell-cycle arrest by transcription of the related genes Rokudai et al, 2002;Stahl et al, 2002;Suhara et al, 2002).…”

Foxo‐mediated Bim transcription is dispensable for the apoptosis of hematopoietic cells that is mediated by this BH3‐only protein

“…As Bim is critical for cytokine deprivation-induced apoptosis in diverse hematopoietic cell subsets [5,16], it was concluded that growth factor withdrawal kills cells through transcriptional upregulation of Bim by Foxo3a [11][12][13][14].…”

“…Previous studies showed that cytokine deprivation activates Foxo3a and that the resulting apoptosis can be inhibited by expression of a dominant-negative Foxo3a [11][12][13]. It was therefore concluded that Foxo3a-mediated transcriptional induction of Bim is essential for cytokine deprivation-induced apoptosis.…”

BimEL is phosphorylated at mitosis by Aurora A and targeted for degradation by βTrCP1

“…At the transcriptional level, the promoter of the Bim gene is activated by stress-inducible transcription factors including activator protein 1 and forkhead box protein O. 4,7,8 Post-transcriptional mechanisms that have been shown to control Bim expression levels include both mRNA stability 9 and protein stability. [10][11][12] Signaling downstream of receptor tyrosine kinases (RTKs) including epidermal growth factor receptor induce the proteasomal degradation of Bim.…”