AFX-like Forkhead transcription factors mediate cell-cycle regulation by Ras and PKB through p27kip1

Medema, René H.; Kops, Geert J. P. L.; Bos, Johannes L.; Burgering, Boudewijn M.T.

doi:10.1038/35008115

Cited by 1,328 publications

(1,156 citation statements)

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“…In rodent beta cells, FOXO1 controls various cellular responses including proliferation [4,[26][27][28][29]. Our ex vivo analyses demonstrated a progressive decrease in the localisation of nFOXO1 within proliferating cells, suggesting that FOXO1 may be involved in regulating cell cycle progression in the human fetal pancreas after 12 weeks of a c fetal age.…”

Section: Discussionmentioning

confidence: 64%

“…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%

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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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Section: Discussionmentioning

confidence: 64%

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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“…This is very similar to the sequence for a FOXA1 binding site. Other Forkhead transcription factors have been shown to regulate p27 Kip1 in a number of tissues including breast and ovarian tissues (Medema et al, 2000;Castrillon et al, 2003;Cunningham et al, 2004;Jin et al, 2004). These are members of the FOXO family of Forkhead transcription factors, namely AFX (FOXO4), FKHR (FOXO1) and FKHR-L1 (FOXO3a).…”

Section: Discussionmentioning

confidence: 99%

BRCA1 and FOXA1 proteins coregulate the expression of the cell cycle-dependent kinase inhibitor p27Kip1

et al. 2005

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We have previously shown that the breast cancer susceptibility gene, BRCA1, can transcriptionally activate the p27 Kip1 promoter. The BRCA1-responsive element was defined as a 35 bp region from position À545 to À511. We next determined that within this region is also a potential binding site for the transcription factor Forkhead box (FOX)A1. RNA and protein analysis as well as immunohistochemistry showed that expression of FOXA1 correlated with the expression of the estrogen receptor in a panel of breast cancer cell lines and tissues. In transient transfection reporter assays, FOXA1 could activate the p27 Kip1 promoter. Cotransfection of BRCA1 and FOXA1 resulted in a synergistic activation of the p27 Kip1 promoter. Mutation of the FOXA1 DNA-binding site in the p27 Kip1 promoter-luciferase construct significantly diminished the activity of FOXA1 alone or in combination with BRCA1. Cotransfection of FOXA1 and BRCA1 resulted in a greater amount of each protein compared to transfection of each expression vector alone. The half-life of FOXA1 was increased when coexpressed with BRCA1. Electrophoretic mobility shift assay analysis demonstrated that FOXA1 could bind to a wild-type oligonucleotide containing the FOXA1 binding site in the p27 Kip1 promoter, but this binding was lost upon mutation of this FOXA1 binding site. The protein-DNA binding complex could be supershifted with an antibody directed against FOXA1. The activity of the p27 Kip1 promoter as well as FOXA1 expression was reduced in cells treated with BRCA1 siRNA, thus silencing the expression of BRCA1 protein. In summary, we identified a FOXA1 binding site within the BRCA1-responsive element of the p27 Kip1 promoter and showed that FOXA1 activated the promoter alone and in conjunction with BRCA1. Furthermore, we identified high expression of FOXA1 in breast cancer cell lines and tissues, discovered a role for BRCA1 in the regulation of p27 Kip1 transcription and a possible interaction with BRCA1.

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“…PTEN antagonizes PI3K function and prevents PDK1 and Akt from recruiting to the plasma membrane, resulting in inactivation of Akt signaling pathway. (Sherr and Roberts, 1995;Medema et al, 2000), inhibition of Akt signaling upregulated p27 KIP1 expression (Figure 1a). Further, we observed a drastic increase in p15 INK4b and p19 INK4d protein, while inhibition of Akt signaling showed no effect on p16 INK4a and p18 INK4c protein levels (Figure 1a).…”

Section: Introductionmentioning

confidence: 97%

FOXO transcription factor-dependent p15INK4b and p19INK4d expression

et al. 2007

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AFX-like Forkhead transcription factors mediate cell-cycle regulation by Ras and PKB through p27kip1

Cited by 1,328 publications

References 21 publications

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

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

BRCA1 and FOXA1 proteins coregulate the expression of the cell cycle-dependent kinase inhibitor p27Kip1

FOXO transcription factor-dependent p15INK4b and p19INK4d expression

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