The Forkhead Transcription Factor Foxo1 Bridges the JNK Pathway and the Transcription Factor PDX-1 through Its Intracellular Translocation

Kawamori, Dan; Kaneto, Hideaki; Nakatani, Yoichiro; Matsuoka, Tetsuro; Matsuhisa, Munehide; Hori, Masatsugu; Yamasaki, Yoshimitsu

doi:10.1074/jbc.m508510200

Cited by 239 publications

(222 citation statements)

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“…Data are means±SE (n=6). *p<0.05; †p≤0.06; ‡p≤0.07 for difference between genotypes transcription by protecting ROS-induced nuclear localisation of forkhead box O1 (an inhibitor of PDX1 transcription) [46]. The decreased levels of phosphorylated AKT on Thr-308 might attenuate H 2 O 2 -mediated phosphorylation (degradation) of PDX1 [25], but could also inhibit Pdx1 transcription via reduced phosphorylation of forkhead box O1 [9,47].…”

Section: Discussionmentioning

confidence: 99%

Molecular mechanisms for hyperinsulinaemia induced by overproduction of selenium-dependent glutathione peroxidase-1 in mice

et al. 2008

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Aims/hypothesis We previously observed hyperglycaemia, hyperinsulinaemia, insulin resistance and obesity in Gpx1-overexpressing mice (OE). Here we determined whether these phenotypes were eliminated by diet restriction, subsequently testing whether hyperinsulinaemia was a primary effect of Gpx1 overexpression and caused by dysregulation of pancreatic duodenal homeobox 1 (PDX1) and uncoupling protein-2 (UCP2) in islets. Methods First, 24 male OE and wild-type (WT) mice (2 months old) were given 3 g (diet-restricted) or 5 g (fullfed) feed per day for 4 months to compare their glucose metabolism. Thereafter, several mechanistic experiments were conducted with pancreas and islets of the two genotypes (2 or 6 months old) to assay for beta cell mass, reactive oxygen species (ROS) levels, mitochondrial membrane potential (Δ= m ) and expression profiles of regulatory proteins. A functional assay of islets was also performed. Results Diet restriction eliminated obesity but not hyperinsulinaemia in OE mice. These mice had greater pancreatic beta cell mass (more than twofold) and pancreatic insulin content (40%) than the WT, along with an enhanced Δ= m and glucose-stimulated insulin secretion in islets. With diminished ROS production, the OE islets displayed hyperacetylation of H3 and H4 histone in the Pdx1 promoter, elevated PDX1 and decreased UCP2. Conclusions/interpretation Overproduction of the major antioxidant enzyme, glutathione peroxidase 1, caused seemingly beneficial changes in pancreatic PDX1 and UCP2, but eventually led to chronic hyperinsulinaemia by dysregulating islet insulin production and secretion.

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Section: Discussionmentioning

confidence: 99%

Molecular mechanisms for hyperinsulinaemia induced by overproduction of selenium-dependent glutathione peroxidase-1 in mice

et al. 2008

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“…Co-localisation of FOXO1 with transcription factors in the developing human fetal pancreas Several studies have demonstrated opposite nuclear vs cytoplasmic localisation of FOXO1 and PDX-1 in murine adult beta cells [7,8]. To better understand the subcellular distribution of FOXO1 and PDX-1 during human fetal pancreatic development, double immunofluorescence and morphometric analyses of FOXO1 in PDX-1 + cells throughout 8-21 weeks of human fetal pancreatic development were performed.…”

Section: Characterisation Of Foxo1 In the Developing Human Fetal Pancmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

“…Moreover, under oxidative stress conditions, PDX-1 translocates to the cytoplasm of beta cells while FOXO1 moves into the nucleus, resulting in a restriction of beta cell growth and proliferation in order to prevent cellular damage [8]. 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: 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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“…Previous studies have shown that FKHR is a negative regulator of insulin synthesis that acts by decreasing PDX1 production [32]. In addition to its important roles in the development and differentiation of pancreatic islets and in beta cell specific gene expression [33], PDX1, an important downstream target of Foxo transcription factors, functions as an essential mediator of the glucose effect on insulin gene expression on differentiated beta cells [14]. In accord, our study demonstrated that PGE 2 could dephosphorylate Foxo transcription factors, prompting them to enter the nucleus and modulate the expression of target genes.…”

Section: Discussionmentioning

confidence: 99%

Prostaglandin E2 regulates Foxo activity via the Akt pathway: implications for pancreatic islet beta cell dysfunction

et al. 2006

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Aims/hypothesis Prostaglandin E 2 (PGE 2 ) is a well-recognised inhibitor of glucose-stimulated insulin secretion (GSIS). The aim of this study was to investigate the signalling pathway of PGE 2 in beta cell function regulation in HIT-T15 cells and isolated rat islets. Materials and methods mRNA levels of the prostaglandin E receptor 3 (Ptger3) were measured by real-time PCR. Western blot analysis was used to detect changes in the levels of PTGER3, phosphorylated and total Akt, phosphorylated and total forkhead box 'Other' (Foxo). Transient transfection and reporter assays were used to measure Foxo transcriptional activity. The biological significance of PGE 2 in beta cell function was analysed using MTT, flow cytometry and GSIS assays. Results We found that treating HIT-T15 cells with exogenous PGE 2 stimulated Ptger3 gene expression specifically, and diminished cAMP generation. These were accompanied by the downregulation of Akt and Foxo phosphorylation in HIT-T15 cells and isolated rat islets. Moreover, PGE 2 upregulated basal and partially reversed constitutively active Akt-inactivated Foxo transcriptional activity. Furthermore, GSIS was impaired in PGE 2 -treated HIT-T15 cells and isolated islets. However, the dosage used in the above experiments did not affect beta cell viability and apoptosis. In addition, insulin-like growth factor 1 (IGF-1) pretreatment reversed the effects of PGE 2 , and wortmannin treatment abolished the preventive effects of IGF-1. Conclusions/interpretation Our observations strongly suggest that PGE 2 can induce pancreatic beta cell dysfunction through the induction of Ptger3 gene expression and inhibition of Akt/Foxo phosphorylation without impacting beta cell viability. These results shed light on the mechanisms of PGE 2 actions in pancreatic beta cell dysfunction.

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The Forkhead Transcription Factor Foxo1 Bridges the JNK Pathway and the Transcription Factor PDX-1 through Its Intracellular Translocation

Cited by 239 publications

References 62 publications

Molecular mechanisms for hyperinsulinaemia induced by overproduction of selenium-dependent glutathione peroxidase-1 in mice

Molecular mechanisms for hyperinsulinaemia induced by overproduction of selenium-dependent glutathione peroxidase-1 in mice

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

Prostaglandin E2 regulates Foxo activity via the Akt pathway: implications for pancreatic islet beta cell dysfunction

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