Activation of NF-κB by Extracellular Matrix Is Involved in Spreading and Glucose-stimulated Insulin Secretion of Pancreatic Beta Cells

Hammar, Eva; Irminger, Jean-Claude; Rickenbach, Katharina; Parnaud, Géraldine; Ribaux, Pascale; Bosco, Domenico; Rouiller, D.; Halban, Philippe A.

doi:10.1074/jbc.m502493200

Cited by 98 publications

(94 citation statements)

References 54 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…16 (BAY) is known to inhibit IKK, and thereby inhibits IkBa phosphorylation and NF-kB activation. 17,18 Constitutive expression of NF-kB leads to activation of several factors involved in cell cycle progression and cell differentiation for cancer metastasis. Inhibiting NF-kB activity in tumor cells dramatically reduced the cell growth in vitro and in vivo.…”

mentioning

confidence: 99%

Inhibition of RelA phosphorylation sensitizes apoptosis in constitutive NF-kappaB-expressing and chemoresistant cells

Manna

Sarkar

2006

Cell Death Differ

View full text Add to dashboard Cite

The compound 5-(4-methoxyarylimino)-2-N-(3,4-dichlorophenyl)-3-oxo-1,2,4-thiadiazolidine (P 3 -25) is known to possess antibacterial, anti-fungal, anti-tubercular, and local anesthetic activities. We studied the anti-tumorigenic activity of P 3 -25 and the role of nuclear transcription factor kappaB (NF-jB) in this process. In constitutive NF-jB-expressing cells, treatment with P 3 -25 inhibited the expression of NF-jB-dependent reporter gene, adhesion molecules, and cyclooxygenase. It downregulated phosphorylation of p65 by inhibiting upstream kinases, such as protein kinase A and casein kinase II, but did not alter NF-jB DNA-binding activity. Alone, P 3 -25 induced apoptosis in NF-jB-expressing and doxorubicin-resistant breast cancer cells, and in the presence of other chemotherapeutic agents, it potentiated apoptosis. Overall, our results suggest that P 3 -25 exerts antitumorigenic activity by inhibiting phosphorylation of p65, the transcriptionally active subunit of NF-jB by inhibiting its upstream kinases, and potentiates apoptosis mediated by chemotherapeutic agents. These results suggest novel approaches for designing of anticancer drugs for combination chemotherapy.

show abstract

mentioning

confidence: 99%

Inhibition of RelA phosphorylation sensitizes apoptosis in constitutive NF-kappaB-expressing and chemoresistant cells

Manna

Sarkar

2006

Cell Death Differ

View full text Add to dashboard Cite

show abstract

“…Likewise, there are indications that beta cells do not form their own basement membrane, but rely on endothelial cells to form a vascular basement membrane containing LMs next to the beta cell [14]. LM-111 has been demonstrated to promote differentiation of pancreatic precursor cells into beta cells in vitro [24] and to promote glucose-stimulated insulin secretion in vitro [15,25,26]. Prostaglandins exert a number of effects on islet beta cells, although mostly negative [27,28].…”

Section: Discussionmentioning

confidence: 99%

Endothelial cell signalling supports pancreatic beta cell function in the rat

et al. 2009

View full text Add to dashboard Cite

Aims/hypothesis The proximity of endothelial cells and beta cells in islets by necessity means that they are exposed to each other's products. Whereas islet endothelial cells require signals from beta cells to function properly, endothelin-1, thrombospondin-1 and laminins, among others, have been identified as endothelial-derived molecules, although their full effects on beta cells have not been explored. We tested the hypothesis that islet endothelialderived products affect beta cell function. Methods Endothelial cells from rat islets were proliferated and purified. Endothelium-conditioned culture medium (ECCM) was obtained by maintaining the endothelial cells in culture medium. Islet function was evaluated following exposure of cultured islets to standard culture medium or ECCM. Changes in mRNA levels for key beta cell metabolic enzymes were also measured in islets after ECCM exposure.Results Glucose-stimulated insulin release and islet insulin content were markedly enhanced by exposure to ECCM. This was at least partly explained by improved mitochondrial function, as assessed by glucose oxidation and an upregulation of the mitochondrial gene for glycerol-3-phosphate dehydrogenase (mGpdh [also known as Gpd2]), combined with upregulation of the rate-limiting enzyme in the glycolysis, glucokinase, in the islets. The intracellular degradation of insulin was also decreased in the islets. Islet endothelial cells produced laminins, and the positive effects of islet endothelial cells were prevented by addition of a neutralising antibody to the β1-chain of laminin. Addition of exogenous laminin stimulated islet function. Conclusions/interpretation This study provides proof of principle that endothelial cells can affect the function of beta cells in their vicinity and that this is at least partially mediated by laminins.

show abstract

“…One would expect that this constant low inflammatory state reduces beta cell viability. However, recent data obtained in rat beta cells demonstrate that a transient and moderate increase in NF-κB (nuclear factor-κB) activity improves beta cell function and insulin secretion [36]. Furthermore, attenuation of NF-κB activation in transgenic mice impairs GSIS and decreases the expression of genes involved in glucose metabolism and insulin exocytosis [37].…”

Section: Discussionmentioning

confidence: 99%

Increasing uncoupling protein-2 in pancreatic beta cells does not alter glucose-induced insulin secretion but decreases production of reactive oxygen species

Produit-Zengaffinen¹,

Davis-Lameloise²,

Perreten³

et al. 2006

Diabetologia

View full text Add to dashboard Cite

Aims/hypothesis Levels of uncoupling protein-2 (UCP2) are regulated in the pancreatic beta cells and an increase in the protein level has been associated with mitochondrial uncoupling and alteration in glucose-stimulated insulin secretion. However, it is not clear whether an increase in uncoupling protein-2 per se induces mitochondrial uncoupling and affects ATP generation and insulin secretion. Materials and methods Transgenic mice with beta cell-specific overexpression of the human UCP2 gene and INS-1 cells with doxycycline-inducible overproduction of the protein were generated and the consequences of increased levels of UCP2 on glucose-induced insulin secretion and on parameters reflecting mitochondrial uncoupling were determined.Results In transgenic mice, an increase in beta cell UCP2 protein concentration did not significantly modify plasma glucose and insulin levels. Glucose-induced insulin secretion and elevation in the ATP/ADP ratio were unaltered by an increase in UCP2 level. In INS-1 cells, a similar increase in UCP2 level did not modify glucose-induced insulin secretion, cytosolic ATP and ATP/ADP ratio, or glucose oxidation. Increased levels of UCP2 did not modify the mitochondrial membrane potential and oxygen consumption. Increased UCP2 levels decreased cytokine-induced production of reactive oxygen species. Conclusion/interpretation The results obtained in transgenic mice and in the beta cell line do not support the hypothesis that an increase in UCP2 protein per se uncouples the mitochondria and decreases glucose-induced insulin secretion. In contrast, the observation that increased UCP2 levels decrease cytokine-induced production of reactive oxygen species indicates a potential protective effect of the protein on beta cells, as observed in other cell types.

show abstract

Activation of NF-κB by Extracellular Matrix Is Involved in Spreading and Glucose-stimulated Insulin Secretion of Pancreatic Beta Cells

Cited by 98 publications

References 54 publications

Inhibition of RelA phosphorylation sensitizes apoptosis in constitutive NF-kappaB-expressing and chemoresistant cells

Inhibition of RelA phosphorylation sensitizes apoptosis in constitutive NF-kappaB-expressing and chemoresistant cells

Endothelial cell signalling supports pancreatic beta cell function in the rat

Increasing uncoupling protein-2 in pancreatic beta cells does not alter glucose-induced insulin secretion but decreases production of reactive oxygen species

Contact Info

Product

Resources

About