FoxO1 protects against pancreatic β cell failure through NeuroD and MafA induction

Kitamura, Yoichi; Kitamura, Tadahiro; Kruse, Jan-Philipp; Raum, Jeffrey C.; Stein, Roland; Gu, Wei; Accili, Domenico

doi:10.1016/j.cmet.2005.08.004

Cited by 516 publications

(549 citation statements)

References 56 publications

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“…These data suggest that FOXO1 may have a significant role in inhibiting beta cell differentiation during human fetal pancreatic development. FOXO1 presence in the nucleus has been shown to be indicative of biological activity [9]. Our immunohistochemical analyses demonstrated relatively constant levels of nFOXO1 in both ductal and islet cell populations of the 8-21 week human fetal pancreas.…”

Section: Discussionmentioning

confidence: 49%

“…This differential nuclear vs cytoplasmic localisation of FOXO1 and PDX-1 has been shown in HIT-T15 cells to work through the c-Jun N-terminal kinase pathway [8]. The presumption that FOXO1 protects against beta cell failure has been further supported by studies demonstrating its ability to increase neurogenic differentiation 1 (NEUROD) and v-maf musculoaponeurotic fibrosarcoma oncogene homologue A (MAFA) production, a compensatory response that preserves beta cell function under metabolic stress conditions [9].…”

Section: Introductionmentioning

confidence: 92%

“…Since FOXO1 levels in the nucleus (nFOXO1) have been shown to be indicative of biological activity [9], the morphometric analyses focused on nFOXO1. To identify co-localisation of nFOXO1 with other pancreatic transcription factors as well as epithelial and endocrine cell markers, double immunofluorescence staining was performed.…”

Section: Immunofluorescent and Morphometric Analysesmentioning

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: 49%

Section: Introductionmentioning

confidence: 92%

Section: Immunofluorescent and Morphometric Analysesmentioning

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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“…In contrast, FOXO1-3KA and FOXO1-3KQ mutants of the same lysine residues have less DNA-binding affinity. Similarly, Kitamura et al (2005) found that FOXO1-6KR mutant (mimicking deacetylated form of FOXO1) has better DNA-binding affinity and stronger transactivation of a FOXO luciferase reporter than the 6KQ mutant (K242R, K245R, K259R, K262R, K271R and K291R), which mimicks acetylated form of FOXO1. We have also found that SIRT2 increases FOXO3 binding to p27 promoter region by chromatin immunoprecipitation assay (Wang et al, 2007).…”

Section: Discussionmentioning

confidence: 90%

Deacetylation of FOXO3 by SIRT1 or SIRT2 leads to Skp2-mediated FOXO3 ubiquitination and degradation

et al. 2011

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Sirtuin deacetylases and FOXO (Forkhead box, class O) transcription factors have important roles in many biological pathways, including cancer development. SIRT1 and SIRT2 deacetylate FOXO factors to regulate FOXO function. Because acetylation and ubiquitination both modify the e-amino group of lysine residues, we investigated whether FOXO3 deacetylation by SIRT1 or SIRT2 facilitates FOXO3 ubiquitination and subsequent proteasomal degradation. We found that SIRT1 and SIRT2 promote FOXO3 poly-ubiquitination and degradation. Proteasome-inhibitor treatment prevented sirtuininduced FOXO3 degradation, indicating that this process is proteasome dependent. In addition, we demonstrated that E3 ubiquitin ligase subunit Skp2 binds preferentially to deacetylated FOXO3. Overexpression of Skp2 caused poly-ubiquitination of FOXO3 and degradation, whereas knockdown of Skp2 increased the amount of FOXO3 protein. We also present evidence that SCF-Skp2 ubiquitinates FOXO3 directly in vitro. Furthermore, mutating four known acetylated lysine residues (K242, K259, K290 and K569) of FOXO3 into arginines to mimic deacetylated FOXO3 resulted in enhanced Skp2 binding but with inhibition of FOXO3 ubiquitination; this suggests that some or all of these four lysine residues are likely the sites for ubiquitination. In the livers of mice deficient in SIRT1, we detected increased expression of FOXO3, indicating SIRT1 regulates FOXO3 protein levels in vivo. Furthermore, we found that the elevation of SIRT1 and Skp2 expression in malignant PC3 and DU145 prostate cells is responsible for the downregulation of FOXO3 protein levels in these cells. Taken together, our data support the notion that deacetylation of FOXO3 by SIRT1 or SIRT2 facilitates Skp2-mediated FOXO3 poly-ubiquitination and proteasomal degradation.

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“…Published evidence suggests that SirT1 prevents ageassociated diseases such as metabolic disorders (Picard et al, 2004;Kitamura et al, 2005;Moynihan et al, 2005;Bordone et al, 2006;Gerhart-Hines et al, 2007;Rodgers and Puigserver, 2007), neurodegenerative diseases (Araki et al, 2004;Parker et al, 2005;Chen et al, 2005a;Qin et al, 2006;Kim et al, 2007) and atherosclerosis . Accumulating evidence also point to SirT1 as having a function in cancer; however, inferences from the literature are that SirT1 has both oncogenic and tumor-suppressor activities.…”

Section: Introductionmentioning

confidence: 99%

SirT1-null mice develop tumors at normal rates but are poorly protected by resveratrol

et al. 2009

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The function of the class III histone deacetylase, Sir2, in promoting lifespan extension is well established in small model organisms. By analogy, SirT1, the mammalian orthologue of Sir2, is a candidate gene to slow down aging and forestall the onset of age-associated diseases. We have used SirT1-null mice to study the function of SirT1 in susceptibility to tumorigenesis. The number of intestinal polyps induced in mice carrying the Apc min mutation was unaffected by the SirT1 genotype although the average polyp size was slightly smaller in the SirT1-null animals. Similarly, the presence or absence of SirT1 had no effect on incidence and tumor load of skin papillomas induced by the classical two-stage carcinogenesis protocol. We found that resveratrol topically applied to the skin profoundly reduced tumorigenesis. This chemoprotective effect was significantly reduced but not ablated in SirT1-null mice, suggesting that part of the protection afforded by resveratrol requires the SirT1-encoded protein. Thus, our results suggest that SirT1 does not behave like a classical tumor-suppressor gene but the antitumor activity of resveratrol is mediated at least in part by SirT1.

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FoxO1 protects against pancreatic β cell failure through NeuroD and MafA induction

Cited by 516 publications

References 56 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

Deacetylation of FOXO3 by SIRT1 or SIRT2 leads to Skp2-mediated FOXO3 ubiquitination and degradation

SirT1-null mice develop tumors at normal rates but are poorly protected by resveratrol

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