scholarly journals A Comprehensive Analysis of Cytokine-induced and Nuclear Factor-κB-dependent Genes in Primary Rat Pancreatic β-Cells

2001 ◽  
Vol 276 (52) ◽  
pp. 48879-48886 ◽  
Author(s):  
Alessandra K. Cardozo ◽  
Harry Heimberg ◽  
Yves Heremans ◽  
Ruth Leeman ◽  
Burak Kutlu ◽  
...  
Keyword(s):  
Nuclear Factor Κb ◽  
Comprehensive Analysis ◽  
Nuclear Factor ◽  
Β Cells ◽  
Pancreatic Β Cells

scholarly journals Glycated Albumin Causes Pancreatic β-Cells Dysfunction Through Autophagy Dysfunction

Endocrinology ◽  
2013 ◽  
Vol 154 (8) ◽  
pp. 2626-2639 ◽  
Author(s):  
Young Mi Song ◽  
Sun Ok Song ◽  
Young-Hye You ◽  
Kun-Ho Yoon ◽  
Eun Seok Kang ◽  
...  
Keyword(s):  
Caspase 3 ◽  
Glycated Albumin ◽  
Nuclear Factor Κb ◽  
Nuclear Factor ◽  
Bafilomycin A1 ◽  
Β Cells ◽  
Β Cell ◽  
Pancreatic Β Cells ◽  
Autophagy Induction ◽  
Interfering Rna

Abstract Growing evidence suggests that advanced glycation end-products (AGEs) are cytotoxic to pancreatic β-cells. The aims of this study were to investigate whether glycated albumin (GA), an early precursor of AGEs, would induce dysfunction in pancreatic β-cells and to determine which kinds of cellular mechanisms are activated in GA-induced β-cell apoptosis. Decreased viability and increased apoptosis were induced in INS-1 cells treated with 2.5 mg/mL GA under 16.7mM high-glucose conditions. Insulin content and glucose-stimulated secretion from isolated rat islets were reduced in 2.5 mg/mL GA-treated cells. In response to 2.5 mg/mL GA in INS-1 cells, autophagy induction and flux decreased as assessed by green fluorescent protein–microtubule-associated protein 1 light chain 3 dots, microtubule-associated protein 1 light chain 3-II conversion, and SQSTM1/p62 in the presence and absence of bafilomycin A1. Accumulated SQSTM1/p62 through deficient autophagy activated the nuclear factor-κB (p65)-inducible nitric oxide synthase-caspase-3 cascade, which was restored by treatment with small interfering RNA against p62. Small interfering RNA treatment against autophagy-related protein 5 significantly inhibited the autophagy machinery resulting in a significant increase in iNOS-cleaved caspase-3 expression. Treatment with 500μM 4-phenyl butyric acid significantly alleviated the expression of endoplasmic reticulum stress markers and iNOS in parallel with upregulated autophagy induction. However, in the presence of bafilomycin A1, the decreased viability of INS-1 cells was not recovered. Glycated albumin, an early precursor of AGE, caused pancreatic β-cell death by inhibiting autophagy induction and flux, resulting in nuclear factor-κB (p65)-iNOS-caspase-3 cascade activation as well as by increasing susceptibility to endoplasmic reticulum stress and oxidative stress.

scholarly journals Mechanisms of Glucose-Induced Expression of Pancreatic-Derived Factor in Pancreatic β-Cells

Endocrinology ◽  
2007 ◽  
Vol 149 (2) ◽  
pp. 672-680 ◽  
Author(s):  
Oumei Wang ◽  
Kun Cai ◽  
Shanshan Pang ◽  
Ting Wang ◽  
Dongfei Qi ◽  
...  
Keyword(s):  
Gene Expression ◽  
Protein Kinase ◽  
Signaling Pathways ◽  
Nuclear Factor Κb ◽  
Nuclear Factor ◽  
Phosphatidylinositol 3 Kinase ◽  
Promoter Activation ◽  
Β Cells ◽  
Pancreatic Β Cells ◽  
Phosphatidylinositol 3

Pancreatic-derived factor (PANDER) is a cytokine-like peptide highly expressed in pancreatic β-cells. PANDER was reported to promote apoptosis of pancreatic β-cells and secrete in response to glucose. Here we explored the effects of glucose on PANDER expression, and the underlying mechanisms in murine pancreatic β-cell line MIN6 and primary islets. Our results showed that glucose up-regulated PANDER mRNA and protein levels in a time- and dose-dependent manner in MIN6 cells and pancreatic islets. In cells expressing cAMP response element-binding protein (CREB) dominant-negative construct, glucose failed to induce PANDER gene expression and promoter activation. Treatment of the cells with calcium chelator [EGTA, 1,2-bis(o-aminophenoxy)ethane-N,N,N′,N′-tetraacetic acid tetra(acetoxymethyl)ester (BAPTA/AM)], the voltage-dependent Ca2+ channel inhibitor (nifedipine), the protein kinase A (PKA) inhibitor (H89), the protein kinase C (PKC) inhibitor (Go6976), or the MAPK kinase 1/2 inhibitor (PD98059), all significantly inhibited glucose-induced PANDER gene expression and promoter activation. Further studies showed that glucose induced CREB phosphorylation through Ca2+-PKA-ERK1/2 and Ca2+-PKC pathways. Thus, the Ca2+-PKA-ERK1/2-CREB and Ca2+-PKC-CREB signaling pathways are involved in glucose-induced PANDER gene expression. Wortmannin (phosphatidylinositol 3-kinase inhibitor), ammonium pyrrolidinedithiocarbamate (nuclear factor-κB inhibitor and nonspecific antioxidant), and N-acetylcysteine (antioxidant) were also found to inhibit glucose-induced PANDER promoter activation and gene expression. Because there is no nuclear factor-κB binding site in the promoter region of PANDER gene, these results suggest that phosphatidylinositol 3-kinase and reactive oxygen species be involved in glucose-induced PANDER gene expression. In conclusion, glucose induces PANDER gene expression in pancreatic β-cells through multiple signaling pathways. Because PANDER is expressed by pancreatic β-cells and in response to glucose in a similar way to those of insulin, PANDER may be involved in glucose homeostasis.

scholarly journals Double-Stranded RNA Cooperates with Interferon-γ and IL-1β to Induce Both Chemokine Expression and Nuclear Factor-κB-Dependent Apoptosis in Pancreatic β-Cells: Potential Mechanisms for Viral-Induced Insulitis and β-Cell Death in Type 1 Diabetes Mellitus

Endocrinology ◽  
2002 ◽  
Vol 143 (4) ◽  
pp. 1225-1234 ◽  
Author(s):  
Dongbo Liu ◽  
Alessandra K. Cardozo ◽  
Martine I. Darville ◽  
Décio L. Eizirik
Keyword(s):  
Promoter Activity ◽  
Nuclear Factor Κb ◽  
Interferon Γ ◽  
Nuclear Factor ◽  
Β Cells ◽  
Β Cell ◽  
Pancreatic Β Cells ◽  
Double Stranded Rna ◽  
Ifn Γ

Abstract Viral infections may trigger the autoimmune assault leading to type 1 diabetes mellitus. Double-stranded RNA (dsRNA) is produced by many viruses during their replicative cycle. The dsRNA, tested as synthetic poly(IC) (PIC), in synergism with the proinflammatory cytokines interferon-γ (IFN-γ) and/or IL-1β, results in nitric oxide production, Fas expression, β-cell dysfunction, and death. Activation of the transcription nuclear factor-κB (NF-κB) is required for PIC-induced inducible nitric oxide synthase expression in β-cells, and we hypothesized that this transcription factor may also participate in PIC-induced Fas expression and β-cell apoptosis. This hypothesis, and the possibility that PIC induces expression of additional chemokines and cytokines (previously reported as NF-κB dependent) in pancreatic β-cells, was investigated in the present study. We observed that the PIC-responsive region in the Fas promoter is located between nucleotides −223 and −54. Site-directed mutations at the NF-κB and CCAAT/enhancer binding protein-binding sites prevented PIC-induced Fas promoter activity. Increased Fas promoter activity was paralleled by enhanced susceptibility of PIC + cytokine-treated β-cells to apoptosis induced by Fas ligand. β-Cell infection with the NF-κB inhibitor AdIκB(SA)2 prevented both necrosis and apoptosis induced by PIC + IL-1β or PIC + IFN-γ. Messenger RNAs for several chemokines and one cytokine were induced by PIC, alone or in combination with IFN-γ, in pancreatic β-cells. These included IP-10, interferon-γ-inducible protein-10, IL-15, macrophage chemoattractant protein-1, fractalkine, and macrophage inflammatory protein-3α. There was not, however, induction of IL-1β expression. We propose that dsRNA, generated during a viral infection, may contribute for β-cell demise by both inducing expression of chemokines and IL-15, putative contributors for the build-up of insulitis, and by synergizing with locally produced cytokines to induce β-cell apoptosis. Activation of the transcription factor NF-κB plays a central role in at least part of the deleterious effects of dsRNA in pancreatic β-cells.

scholarly journals Molecular Pathways Involved in the Antineoplastic Effects of Calcitriol on Insulinoma Cells

Endocrinology ◽  
2003 ◽  
Vol 144 (5) ◽  
pp. 1832-1841 ◽  
Author(s):  
Francesca Galbiati ◽  
Luca Polastri ◽  
Bernard Thorens ◽  
Philippe Dupraz ◽  
Paolo Fiorina ◽  
...  
Keyword(s):  
Nuclear Factor Κb ◽  
Molecular Pathways ◽  
Β Cells ◽  
Pancreatic Β Cells ◽  
Protein Levels ◽  
Igf I ◽  
Antitumorigenic Effect ◽  
Induced Apoptosis ◽  
Insulinoma Cells ◽  
Transcription Factor Nuclear Factor

We have previously reported that in tumorigenic pancreatic β-cells, calcitriol exerts a potent antitumorigenic effect by inducing apoptosis, cell growth inhibition, and reduction of solid β-cell tumors. Here we have studied the molecular pathways involved in the antineoplastic activity of calcitriol on mouse insulinoma βTC3 cells, mouse insulinoma βTC expressing or not expressing the oncogene p53, and βTC-tet cells overexpressing or not the antiapoptotic gene Bcl2. Our results indicate that calcitriol-induced apoptosis was dependent on the function of p53 and was associated with a biphasic increase in protein levels of transcription factor nuclear factor-κB. Calcitriol decreased cell viability by about 40% in p53-retaining βTC and in βTC3 cells; in contrast, βTC p53−/− cells were only minimally affected. Calcitriol-induced cell death was regulated by members of the Bcl-2 family of apoptosis regulatory proteins, as shown by calcitriol-induced up-regulation of proapoptotic Bax and Bak and the lack of calcitriol-induced cytotoxicity in Bcl-2-overexpressing insulinoma cells. Moreover, calcitriol-mediated arrest of βTC3 cells in the G1 phase of the cell cycle was associated with the abnormal expression of p21 and G2/M-specific cyclin B2 genes and involved the DNA damage-inducible factor GADD45. Finally, in βTC3 cells, calcitriol modulated the expression of IGF-I and IGF-II genes. In conclusion, these findings contribute to the understanding of the antitumorigenic effects of calcitriol on tumorigenic pancreatic β-cells and further support the rationale of its utilization in the treatment of patients with malignant insulinomas.

scholarly journals Hepatocyte Nuclear Factor-4α Is Essential for Glucose-stimulated Insulin Secretion by Pancreatic β-Cells

2005 ◽  
Vol 281 (8) ◽  
pp. 5246-5257 ◽  
Author(s):  
Atsuko Miura ◽  
Kazuya Yamagata ◽  
Masafumi Kakei ◽  
Hiroyasu Hatakeyama ◽  
Noriko Takahashi ◽  
...  
Keyword(s):  
Insulin Secretion ◽  
Nuclear Factor ◽  
Hepatocyte Nuclear Factor ◽  
Β Cells ◽  
Pancreatic Β Cells ◽  
Hepatocyte Nuclear Factor 4Α ◽  
Glucose Stimulated Insulin Secretion

scholarly journals Nuclear Factor Y in Male Mouse pancreatic β-cells Plays a Crucial Role in Glucose Homeostasis by Regulating β-Cell Mass and Insulin Secretion

2021 ◽  
Author(s):  
Yin Liu ◽  
Siyuan He ◽  
Ruixue Zhou ◽  
Xueping Zhang ◽  
Shanshan Yang ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Insulin Secretion ◽  
Cell Mass ◽  
Physiological Role ◽  
Nuclear Factor ◽  
Β Cells ◽  
Β Cell ◽  
Pancreatic Β Cells ◽  
Nuclear Factor Y

Pancreatic β-cell mass and insulin secretion are determined by the dynamic change of transcription factor expression levels in response to altered metabolic demand. Nuclear factor-Y (NF-Y) is an evolutionarily conserved transcription factor playing critical roles in multiple cellular processes. However, the physiological role of NF-Y in pancreatic β-cells is poorly understood. The present study was undertaken in a conditional knockout of <i>Nf-ya</i> specifically in pancreatic β-cells (<i>Nf-ya </i>βKO) to define the essential physiological role of NF-Y in β-cells. <i>Nf-ya </i>βKO mice exhibited glucose intolerance without changes in insulin sensitivity. Reduced β-cell proliferation resulting in decreased β-cell mass was observed in these mice, which was associated with disturbed actin cytoskeleton. NF-Y-deficient β-cells also exhibited impaired insulin secretion with a reduced Ca<sup>2+</sup> influx in response to glucose, which was associated an inefficient glucose uptake into β-cells due to a decreased expression of glucose transporter 2 and a reduction in ATP production resulting from the disruption of mitochondrial integrity. This study is the first to show that NF-Y is critical for pancreatic islets homeostasis and function through regulation in β-cell proliferation, glucose uptake into β-cells, and mitochondrial energy metabolism. Modulating NF-Y expression in β-cells may therefore offer an attractive approach for therapeutic intervention.

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