FOXO Transcription Factors as Regulators of Immune Homeostasis: Molecules to Die for?

Birkenkamp, Kim U.; Coffer, Paul J.

doi:10.4049/jimmunol.171.4.1623

Cited by 147 publications

(144 citation statements)

References 44 publications

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“…Although FoxO3a protects quiescent human colon carcinoma cells from oxidative stress via transcriptional induction of the antioxidant enzyme manganese superoxide dismutase (Li et al (39), Kops et al (50)) demonstrated that increased Akt activity in VSMCs from older rats was associated with increased phosphorylation of FoxO3a (at Ser-253) and reduced manganese superoxide dismutase expression. We observed no protective effect of FoxO3a in VSMCs, although it is possible that the protective effect of FoxO3a is only apparent in quiescent cells (40,41). Although overexpression of FoxO3a itself inhibits VSMC proliferation in vitro and neointimal hyperplasia in a balloon carotid arterial injury model, this was associated with increased apoptosis (42,43).…”

Section: Discussionmentioning

confidence: 62%

Akt Regulates the Survival of Vascular Smooth Muscle Cells via Inhibition of FoxO3a and GSK3

Allard

Figg

Bennett

et al. 2008

Journal of Biological Chemistry

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Apoptosis of vascular smooth muscle cells (VSMCs) may lead to atherosclerotic plaque instability and rupture, resulting in myocardial infarction, stroke, and sudden death. However, the molecular mechanisms mediating survival of VSMCs in atherosclerotic plaques remain unknown. Although plaque VSMCs exhibit increased susceptibility to apoptosis and reduced expression of the IGF1 receptor (IGF1R) when compared with normal VSMCs, a causative effect has not been established. Here we show that increased expression of the IGF1R can rescue plaque VSMCs from oxidative stress-induced apoptosis, demonstrating that IGF-1 signaling is a critical regulator of VSMC survival. Akt mediates the majority of the IGF1R survival signaling, and ectopic activation of Akt was sufficient to protect VSMCs in vitro. Both IGF1R and phospho-Akt expression were reduced in human plaque (intimal) VSMCs when compared with medial VSMCs, suggesting that Akt mediates survival signaling in atherosclerosis. Importantly, downstream targets of Akt were identified that mediate its protective effect as inhibition of FoxO3a or GSK3 by Akt-dependent phosphorylation protected VSMCs in vitro. We conclude that Akt and its downstream targets FoxO3a and GSK3 regulate a survival pathway in VSMCs and that their deregulation due to a reduction of IGF1R signaling may promote apoptosis in atherosclerosis.Insulin-like growth factor 1 (IGF1) 2 is a ubiquitous factor exhibiting pleiotropic effects on different cell types. Stimulation of the IGF1 receptor (IGF1R) initiates signaling pathways involved in cell proliferation, differentiation, transformation, and survival. IGF1R-dependent signaling is crucial for the survival of many cell types including vascular smooth muscle cells (VSMCs). VSMCs are the principle source of collagen and extracellular matrix that maintain the tensile strength of atherosclerotic plaques, and VSMC loss induces multiple features of plaque instability (1). In humans, rupture or erosion of the atherosclerotic plaque underlie the majority of myocardial infarctions, stroke, and sudden death (2). We have previously shown that VSMCs derived from atherosclerotic plaques (pVSMCs) are more sensitive to apoptosis than cells derived from non-diseased vessels (3) and exhibit a defect in IGF1-dependent survival signaling (4). Oxidative stress is increasingly implicated in the development of atherosclerosis (5) and increased oxidative damage, and elevated levels of DNA strand breaks occur in human atherosclerotic plaques (6). Oxidative stress reduces IGF1R expression and induces VSMC apoptosis in culture (7-10). Reduced IGF1R expression is also seen within plaques, suggesting that IGF1R-dependent survival regulates apoptosis in vivo (11,12). However, plaque VSMCs also show increased sensitivity to multiple proapoptotic stimuli, including the tumor suppressor gene P53 and death receptor ligation (13,14). It is therefore not known whether defective IGF1R expression alone is an important cause of reduced survival of pVSMCs.A major downstream effector of IGF1R ...

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Section: Discussionmentioning

confidence: 62%

Akt Regulates the Survival of Vascular Smooth Muscle Cells via Inhibition of FoxO3a and GSK3

Allard

Figg

Bennett

et al. 2008

Journal of Biological Chemistry

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“…FOXO transcription factors participate in a diverse range of physiological processes, including the inhibition of cellular proliferation and the promotion of apoptosis and metabolism (2)(3)(4). Although a basic understanding of the mechanisms regulating the subcellular localization and transcriptional activity of these proteins has been achieved, much remains to be learned about the cell-specific effects of FOXOs, as well as their control at the mRNA level.…”

Section: B Cell Receptor Signaling Down-regulates Forkhead Box Transcmentioning

confidence: 99%

“…T he forkhead box family of transcription factors, including forkhead box transcription factor class O 1 (FOXO1), 3 FOXO3a, and FOXO4, has been identified in species ranging from yeast to humans (1). FOXO transcription factors participate in a diverse range of physiological processes, including the inhibition of cellular proliferation and the promotion of apoptosis and metabolism (2)(3)(4).…”

Section: B Cell Receptor Signaling Down-regulates Forkhead Box Transcmentioning

confidence: 99%

B Cell Receptor Signaling Down-Regulates Forkhead Box Transcription Factor Class O 1 mRNA Expression via Phosphatidylinositol 3-Kinase and Bruton’s Tyrosine Kinase

Hinman

Bushanam

Nichols

et al. 2007

The Journal of Immunology

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BCR cross-linking promotes mature B cell proliferation and survival. PI3K-mediated down-regulation of proapoptotic and antimitogenic genes such as forkhead box transcription factor class O 1 (FOXO1) is an important component of this process. Previously, BCR-induced phosphorylation of FOXO1 was shown to lead to a block in nuclear localization and subsequent protein degradation. We demonstrate that the BCR also signals through PI3K to down-regulate FOXO1 mRNA expression. Bruton’s tyrosine kinase (Btk), a downstream effector of PI3K, signals through B cell linker protein (BLNK) and phospholipase C (PLC)γ2 to mediate B cell proliferation and survival in response to BCR cross-linking. BCR-induced down-regulation of FOXO1 mRNA was impaired in murine knockouts of Btk, BLNK, and PLCγ2. Because B cells in these models are predominantly immature, experiments were also performed using mature B cells expressing low levels of Btk and BLNK. Similar results were obtained. Inhibitors of downstream components of the Btk/BLNK/PLCγ2 pathway were used to define the mechanism by which Btk signaling inhibits FOXO1 expression. The protein kinase Cβ inhibitor Gö6850 had minimal effects on BCR-mediated FOXO1 mRNA down-regulation. However, cyclosporin A, an inhibitor of the Ca2+-dependent phosphatase calcineurin, had similar effects on FOXO1 mRNA expression as the PI3K inhibitor LY294002. Neither Btk deficiency nor cyclosporin A prevented FOXO1 protein phosphorylation, indicating that PI3K down-regulates FOXO1 via two independent pathways. We show that the Btk/BLNK/PLCγ2 pathway mediates BCR-induced changes in expression of the FOXO1 target gene cyclin G2. These observations support the hypothesis that Btk mediates BCR-induced proliferation and survival in part via inhibition of FOXO expression.

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“…Over the past few years the mammalian DAF-16-like transcription factors FOXO1, FOXO3 and FOXO4 have been demonstrated to play crucial roles in a plethora of cellular processes including proliferation, apoptosis, differentiation, stress resistance and metabolic responses (Birkenkamp and Coffer, 2003;van der Horst and Burgering, 2007). To ensure that the correct, cell type-specific effect is initiated by these widely expressed factors, FOXOs utilize a wide range of binding partners allowing for a much broader transcriptional response.…”

Section: Introductionmentioning

confidence: 99%

FOXO-binding partners: it takes two to tango

van der Vos,

Coffer

2008

Oncogene

187

161

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Modulation FOXO transcription factor activities can lead to a variety of cellular outputs resulting in changes in proliferation, apoptosis, differentiation and metabolic responses. Although FOXO proteins all contain an identical DNA-binding domain their cellular functions appear to be distinct, as exemplified by differences in the phenotype of Foxo1, Foxo3 and Foxo4 null mutant mice. While some of these differences may be attributable to the differential expression patterns of these transcription factors, many cells and tissues express several FOXO isoforms. Recently it has become clear that FOXO proteins can regulate transcriptional responses independently of direct DNA-binding. It has been demonstrated that FOXOs can associate with a variety of unrelated transcription factors, regulating activation or repression of diverse target genes. The complement of transcription factors expressed in a particular cell type is thus critical in determining the functional end point of FOXO activity. These interactions greatly expand the possibilities for FOXO-mediated regulation of transcriptional programmes. This review details currently described FOXO-binding partners and examines the role of these interactions in regulating cell fate decisions.

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FOXO Transcription Factors as Regulators of Immune Homeostasis: Molecules to Die for?

Cited by 147 publications

References 44 publications

Akt Regulates the Survival of Vascular Smooth Muscle Cells via Inhibition of FoxO3a and GSK3

Akt Regulates the Survival of Vascular Smooth Muscle Cells via Inhibition of FoxO3a and GSK3

B Cell Receptor Signaling Down-Regulates Forkhead Box Transcription Factor Class O 1 mRNA Expression via Phosphatidylinositol 3-Kinase and Bruton’s Tyrosine Kinase

FOXO-binding partners: it takes two to tango

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