The Many Forks in FOXO's Road

Tran, Hien G.; Brunet, Anne; Griffith, Eric C.; Greenberg, Michael E.

doi:10.1126/scisignal.1722003re5

Cited by 205 publications

(280 citation statements)

References 110 publications

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“…One of the first examples of a Smad-regulated synexpression group has been provided by recent studies on TGFb gene responses mediated by Smad proteins in combination with FoxO transcription factors [49]. FoxO transcription factors are members of the Forkhead family and play a prominent role in the control and integration of cellular and organismal growth, development, metabolism and longevity under caloric restriction [50,51]. Building on the finding that a FoxO-Smad complex mediates the transcriptional activation of p21CIP1 in response to TGFb [52], RNAi-mediated knockdown of FoxO factors (FoxO1, 3 and 4) revealed the requirement of these factors for at least eleven of the 115 rapid gene activation responses triggered by TGFb in cultured human keratinocytes [49].…”

Section: Organization Of the Tgfb Transcriptional Programsmentioning

confidence: 99%

“…For instance, FoxO factors are under the negative control by the PI3Kinase/AKT pathway and other protein kinases [50,51,63]. Phosphorylation of the FoxO proteins leads to their eviction from the nucleus and, in some cases, to their proteosome-mediated degradation [50].…”

Section: Smads As Nodes For Signaling Integrationmentioning

confidence: 99%

“…Glioblastomas typically contain a hyperactive PI3K/Akt pathway due to gene amplification or activating mutations in the phosphatidyl inositol kinase PI3K, or inactivating mutations in the phosphatidyl inositol phosphatase PTEN [100]. Since PI3K through Akt/PKB negative controls the activity of FoxO factors [50,51,63], the hyperactivity of this pathway in glioblastoma inhibits FoxO factors from serving as Smad partners in the induction of p21Cip1 [52]. The activity of FoxO factors as Smad partners can also be inhibited by the telencephalic development factor FoxG1 [52].…”

Section: Selective Evasion Of Tgfb-dependent Cytostasismentioning

confidence: 99%

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The logic of TGFβ signaling

2006

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The identification of the TGFb cytokine signaling pathway, including membrane receptor serine/threonine kinases and Smad transcription factors as their substrates, has allowed the delineation of a process for conversion of these signals into programs of gene activation and repression that underlie critical cell fate and developmental decisions. The deconstruction of one of these responses -the cell cycle arrest response -into its elemental molecular parts has shed light into the mechanisms used by tumors to evade surveillance and cause metastasis.

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Section: Organization Of the Tgfb Transcriptional Programsmentioning

confidence: 99%

Section: Smads As Nodes For Signaling Integrationmentioning

confidence: 99%

Section: Selective Evasion Of Tgfb-dependent Cytostasismentioning

confidence: 99%

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The logic of TGFβ signaling

2006

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“…The majority of studies have demonstrated that FOXO1 inhibits cell proliferation at multiple phases of the cell cycle in various cells and tissues [3,[25][26][27][28][29]. To determine if there is a role for FOXO1 in cell proliferation during human fetal pancreas development, co-localisation of nFOXO1 with Ki67 was assessed (Fig.…”

Section: Presence Of Nfoxo1 In Proliferating (Ki67 + ) Cells During Hmentioning

confidence: 99%

Effect of forkhead box O1 (FOXO1) on beta cell development in the human fetal pancreas

et al. 2009

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Aims/hypothesis Recent studies have demonstrated that in adult murine beta cells the forkhead box O1 (FOXO1) transcription factor regulates proliferation and stress resistance. However, the role of FOXO1 during pancreatic development remains largely unknown. The present study aimed to characterise the expression of the FOXO1 transcription factor in the early to mid-gestation human fetal pancreas and to understand its role in islet cell development. Methods Human (8-21 week fetal age) pancreases were examined using immunohistological, quantitative RT-PCR and western blotting. Isolated human (18-21 week) fetal islet epithelial cell clusters were treated with insulin or glucose, or transfected with FOXO1 small interfering RNA (siRNA). Results Nuclear and cytoplasmic FOXO1 were widely produced during human fetal endocrine pancreatic development, co-localising in cells with the transcription factors pancreatic and duodenal homeobox 1 (PDX-1) and neurogenin 3 (NGN3) as well as cytokeratin 19 (CK19), insulin and glucagon. Treatment with exogenous insulin (50 nmol/l) induced the nuclear exclusion of FOXO1 in both cytokeratin 19 (CK19) + (p<0.01) and insulin + cells (p<0.05) in parallel with increased phospho-Akt (p<0.05) production. siRNA knockdown of FOXO1 significantly increased the number of NGN3 + (p<0.01) and NK6 homeobox 1 (NKX6-1) + (p<0.05) cells in parallel with increases in insulin gene expression (p<0.03) and C-peptide + cells (p<0.05) and reduced levels of hairy and enhancer of split 1 (HES1) (p<0.01). Conclusions/interpretation Our results indicate that FOXO1 may negatively regulate beta cell differentiation in the human fetal pancreas by controlling critical transcription factors, including NGN3 and NKX6-1. These data suggest that the manipulation of FOXO1 levels may be a useful tool for improving cell-based strategies for the treatment of diabetes.Keywords Human fetal pancreas . Human islet epithelial cell clusters . Islet transcription factors . Nuclear FOXO1 . FOXO1 siRNA Electronic supplementary material The online version of this article

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“…Although the specific mechanisms which regulate their cellular activities continue to be elucidated, the transcriptional activity of at least some Fox genes are known to be post-translationally regulated: for instance, members of the FoxO subfamily, which are homologs of the C. elegans longevity gene DAF-16, play key roles in cellular responses to stress, starvation and activation by normally being transcriptionally active in the nucleus in metabolically quiescent cells (reviewed in Tran et al 13 ). Activating stimuli, particularly activators of phosphoinositide-3 kinase (PI3K) pathway, lead to the activation of Akt (protein kinase B, PKB), which phosphorylates the FoxO's, rendering them susceptible to 14-3-3-mediated export from the nucleus and halting their transcriptional activity.…”

mentioning

confidence: 99%

Interplay between the NF-κB and forkhead transcription factors

Peng

2005

Cell Death Differ

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The Many Forks in FOXO's Road

Cited by 205 publications

References 110 publications

The logic of TGFβ signaling

The logic of TGFβ signaling

Effect of forkhead box O1 (FOXO1) on beta cell development in the human fetal pancreas

Interplay between the NF-κB and forkhead transcription factors

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