Abstract
Laminin-5-rich extracellular matrix derived from 804G cells (804G-ECM) engages beta1 integrins to induce spreading, improve glucose-stimulated insulin secretion (GSIS), and increase survival of pancreatic beta cells. The present study examines whether 804G-ECM activates the transcriptional activity of NF-kappaB and the involvement of NF-kappaB in those effects of 804G-ECM on pancreatic beta cells. 804G-ECM induces nuclear translocation and the DNA binding activity of the p65 subunit of NF-kappaB. 804G-ECM-induced nuclear translocation of NF-kappaB was weak as compared with that induced by interleukin-1beta. Transient 804G-ECM-induced DNA binding activity of NF-kappaB (peak at 2 h) and overexpression of NF-kappaB target genes IkappaB alpha and NF-kappaB1(p105) (peak at 4 h) were observed. When NF-kappaB was inhibited by an inhibitor of IkappaB alpha phosphorylation (Bay 11-7082) or by a recombinant adenovirus expressing the nonphosphorylatable form of IkappaB alpha, 804G-ECM-induced cell spreading and actin cytoskeleton organization were reduced. GSIS from cells on 804G-ECM was inhibited 5-fold, whereas cell survival was not affected. In summary, the results indicate that 804G-ECM induces a transient and moderate NF-kappaB activity. This study shows for the first time that ECM-induced NF-kappaB activity is necessary in maintaining GSIS, although it does not affect survival of pancreatic beta cells. The effects of ECM-induced NF-kappaB activity contrast with the deleterious effects of cytokine-induced NF-kappaB activity. It is proposed that transient and moderate NF-kappaB activity is essential for proper function of the pancreatic beta cell.
Highlights
Engagement of cells by cognate components of the extracellular matrix (ECM)1 is crucial for various biological processes, including cell adhesion, spreading, proliferation, differentia
The present study examines whether 804G-ECM activates the transcriptional activity of NF-B and the involvement of NF-B in those effects of 804G-ECM on pancreatic beta cells. 804G-ECM induces nuclear translocation and the DNA binding activity of the p65 subunit of NF-B. 804G-ECM-induced nuclear translocation of NF-B was weak as compared with that induced by interleukin-1
We show that 804G-ECM induces transient nuclear translocation of NF-B and its transcriptional activity in pancreatic beta cells, which is followed by overexpression of IB␣ and NF-B mRNAs
Summary
Engagement of cells by cognate components of the extracellular matrix (ECM) is crucial for various biological processes, including cell adhesion, spreading, proliferation, differentia-. It has been shown that its effects on pancreatic beta cells (spreading, glucose-stimulated insulin secretion, and survival) are mediated by the engagement of 1 integrins to laminin-5 [3, 4].2. Engagement of integrins to different ECM molecules (vitronectin, fibronectin, and laminin) has been shown to activate NF-B [5,6,7,8,9] and to promote an NF-B-dependent program of gene expression [10, 11] This has not yet been reported for the pancreatic beta cell nor for primary, nondividing cells. We show that induction of NF-B activity by 804G-ECM is not involved in its control of pancreatic beta cell survival
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