A Pancreatic β-Cell-specific Enhancer in the HumanPDX-1 Gene Is Regulated by Hepatocyte Nuclear Factor 3β (HNF-3β), HNF-1α, and SPs Transcription Factors

Ben-Shushan, Etti; Marshak, Sonya; Shoshkes, Michal; Cerasi, Erol; Melloul, Danielle

doi:10.1074/jbc.m009088200

Cited by 96 publications

(70 citation statements)

References 45 publications

(46 reference statements)

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“…We have shown that rosiglitazone promotes elevated nuclear levels of FOXA2 over 24 h. FOXA2 is a known regulator of the Ipf1 gene promoter and plays a key role in Ipf1 gene expression both during pancreas development and in adult islets [19,20]. Nuclear/cytosolic localisation of FOXA2 in hepatocytes is regulated through Akt-mediated phosphorylation events [36].…”

Section: Discussionmentioning

confidence: 98%

“…Expression of the Ipf1 gene is also regulated in response to glucose [16]. The complex 4.5 kb Ipf1 gene promoter contains binding sites for many beta cell transcription factors, including hepatocyte nuclear factor 1α (HNF1α), IPF1 and FOXA2 [17][18][19][20]. FOXA2 is a member of the forkhead/winged helix family and has been identified as a key regulator of Ipf1 gene expression.…”

Section: Introductionmentioning

confidence: 99%

“…FOXA2 is produced at the onset of pancreatic development in the foregut endoderm. Its expression pattern is similar to that of IPF1, and it has been shown to bind key regulatory elements within the Ipf1 gene promoter, regulating expression both during pancreas development and in adult islets [19,20]. Although the key role of FOXA2 in regulating Ipf1 gene expression is becoming clear, at present little is known about the stimuli regulating FOXA2 production itself in adult beta cells.…”

Section: Introductionmentioning

confidence: 99%

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Effects of rosiglitazone and metformin on pancreatic beta cell gene expression

et al. 2006

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Aims/hypothesis: Rosiglitazone and metformin are two oral antihyperglycaemic drugs used to treat type 2 diabetes. While both drugs have been shown to improve insulin-sensitive glucose uptake, the direct effects of these drugs on pancreatic beta cells is only now beginning to be clarified. The aim of the present study was to determine the direct effects of these agents on beta cell gene expression. Methods: We used reporter gene analysis to examine the effects of rosiglitazone and metformin on the activity of the proinsulin and insulin promoter factor 1 (IPF1) gene promoters in the glucose-responsive mouse beta cell line Min6. Western blot and gel retardation analyses were used to examine the effects of both drugs on the regulation of IPF1 protein production, nuclear accumulation and DNA binding activity in both Min6 cells and isolated rat islets of Langerhans. Results: Over 24 h, rosiglitazone promoted the nuclear accumulation of IPF1 and forkhead homeobox A2 (FOXA2), independently of glucose concentration, and stimulated a two-fold increase in the activity of the Ipf1 gene promoter (p<0.01). Stimulation of the Ipf1 promoter by rosiglitazone was unaffected by the presence of the peroxisome proliferator activated receptor γ antagonist GW9662. No effect of either rosiglitazone or metformin was observed on proinsulin promoter activity. Metformin stimulated IPF1 nuclear accumulation and DNA binding activity in a time-dependent manner, with maximal effects observed after 2 h. Conclusions/interpretation: Metformin and rosiglitazone have direct effects on beta cell gene expression, suggesting that these agents may play a previously unrecognised role in the direct regulation of pancreatic beta cell function.

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Section: Discussionmentioning

confidence: 98%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Effects of rosiglitazone and metformin on pancreatic beta cell gene expression

et al. 2006

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“…A plasmid construct containing the human pdx-1 gene promoter linked to a luciferase reporter gene was kindly provided by Dr D. Melloul, Department of Endocrinology, Hadassah University Hospital, Jerusalem, Israel [44]. Transfected beta cells were exposed to cytokines and/or PIC for 24 h (same concentrations as above).…”

Section: Rt-pcr and Real Time Rt-pcrmentioning

confidence: 99%

Global profiling of double stranded RNA- and IFN-?-induced genes in rat pancreatic beta cells

et al. 2003

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Aims/hypothesis. Viral infections and local production of IFN-γ might contribute to beta-cell dysfunction/ death in Type 1 Diabetes. Double stranded RNA (dsRNA) accumulates in the cytosol of viral-infected cells, and exposure of purified rat beta cells to dsRNA (tested in the form of polyinosinic-polycytidylic acid, PIC) in combination with IFN-γ results in beta-cell dysfunction and apoptosis. To elucidate the molecular mechanisms involved in PIC + IFN-γ-effects, we determined the global profile of genes modified by these agents in primary rat beta cells. Methods. FACS-purified rat beta cells were cultured for 6 or 24 h in control condition or with IFN-γ, PIC or a combination of both agents. The gene expression profile was analysed in duplicate by high-density oligonucleotide arrays representing 5000 full-length genes and 3000 EST's. Changes of greater than or equal to 2.5-fold were considered as relevant.Results. Following a 6-or 24-h treatment with IFN-γ, PIC or IFN-γ and PIC, we observed changes in the expression of 51 to 189 genes. IFN-γ modified the expression of MHC-related genes, and also of genes involved in beta-cell metabolism, protein processing, cytokines and signal transduction. PIC affected preferentially the expression of genes related to cell adhesion, cytokines and dsRNA signal transduction, transcription factors and MHC. PIC and/or IFN-γ up-regulated the expression of several chemokines and cytokines that could contribute to mononuclear cell homing and activation during viral infection, while IFN-γ induced a positive feedback on its own signal transduction. PIC + IFN-γ inhibited insulin and GLUT-2 expression without modifying pdx-1 mRNA expression. Conclusion/interpretation. This study provides the first comprehensive characterization of the molecular responses of primary beta cells to dsRNA + IFN-γ, two agents that are probably present in the beta cell milieu during the course of virally-induced insulitis and Type 1 Diabetes. Based on these findings, we propose an integrated model for the molecular mechanisms involved in dsRNA + IFN-γ induced beta-cell dysfunction and death. [Diabetologia (2003[Diabetologia ( ) 46:1641[Diabetologia ( -1657

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“…Islet nuclear protein extraction and DNA-binding assays were performed as described in ref. 47. The NF-B binding mixture contained 30 mM Hepes, pH 7.9͞100 mM NaCl͞0.3 mM EDTA͞ 2.5 mM DTT͞1.5 mM MgCl 2 ͞2 g of poly (dI-dC)͞10% glycerol.…”

Section: Methodsmentioning

confidence: 99%

Conditional and specific NF-κB blockade protects pancreatic beta cells from diabetogenic agents

Eldor¹,

Yeffet²,

Baum³

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

239

211

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Type 1 diabetes is characterized by the infiltration of inflammatory cells into pancreatic islets of Langerhans, followed by the selective and progressive destruction of insulin-secreting beta cells. Isletinfiltrating leukocytes secrete cytokines such as IL-1␤ and IFN-␥, which contribute to beta cell death. In vitro evidence suggests that cytokine-induced activation of the transcription factor NF-B is an important component of the signal triggering beta cell apoptosis. To study the in vivo role of NF-B in beta cell death, we generated a transgenic mouse line expressing a degradation-resistant NF-B protein inhibitor (⌬NI B␣), acting specifically in beta cells, in an inducible and reversible manner, by using the tet-on regulation system. In vitro, islets expressing the ⌬NI B␣ protein were resistant to the deleterious effects of IL-1␤ and IFN-␥, as assessed by reduced NO production and beta-cell apoptosis. This effect was even more striking in vivo, where nearly complete protection against multiple low-dose streptozocin-induced diabetes was observed, with reduced intraislet lymphocytic infiltration. Our results show in vivo that beta cell-specific activation of NF-B is a key event in the progressive loss of beta cells in diabetes. Inhibition of this process could be a potential effective strategy for beta-cell protection.apoptosis ͉ cytokine ͉ diabetes ͉ transgenic mice ͉ insulin

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A Pancreatic β-Cell-specific Enhancer in the HumanPDX-1 Gene Is Regulated by Hepatocyte Nuclear Factor 3β (HNF-3β), HNF-1α, and SPs Transcription Factors

Cited by 96 publications

References 45 publications

Effects of rosiglitazone and metformin on pancreatic beta cell gene expression

Effects of rosiglitazone and metformin on pancreatic beta cell gene expression

Global profiling of double stranded RNA- and IFN-?-induced genes in rat pancreatic beta cells

Conditional and specific NF-κB blockade protects pancreatic beta cells from diabetogenic agents

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