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Scientific article
English

Signaling pathways implicated in the stimulation of beta-cell proliferation by extracellular matrix

Published inMolecular endocrinology, vol. 23, no. 8, p. 1264-1271
Publication date2009
Abstract

Laminin-5-rich extracellular matrix derived from 804G cells (804G-ECM) induces spreading, improves glucose-stimulated insulin secretion, and increases survival and proliferation of rat pancreatic beta-cells. The aim of the study was to determine growth signaling pathways activated by ECM with a particular focus on Ca(2+)-dependent transcription factors. 804G-ECM increased rat beta-cell proliferation, and this stimulation was glucose and Ca(2+) dependent. NF-kappaB nuclear translocation as well as IkappaBalpha gene expression were also Ca(2+) dependent. Inhibition of NF-kappaB almost completely blocked 804G-ECM-stimulated beta-cell proliferation as did the soluble IL-1 receptor antagonist IL-1Ra. 804G-ECM-induced proliferation was also blocked by cyclosporin A and the VIVIT peptide, suggesting involvement of nuclear factor of activated T cells (NFAT)/calcineurin. Use of selective inhibitors further implicated other pathways in this process. Inhibition of phosphatidylinositol 3-kinase and protein kinase A both prevented beta-cell replication stimulated by 804G-ECM. Conversely, inhibition of MAPK, c-Jun N-terminal kinase, p38, and glycogen synthase kinase-3beta increased beta-cell proliferation on 804G-ECM. Our results suggest that Ca(2+) entry, which is necessary for increased beta-cell proliferation on 804G-ECM, is also involved in 804G-ECM-induced NF-kappaB activity. It is proposed that increased cytosolic Ca(2+) leads to activation of the transcription factors NFAT and NF-kappaB that in turn increase beta-cell proliferation. Activation of phosphatidylinositol 3-kinase by 804G-ECM also increases proliferation possibly by synergistic coactivation of NFAT via inhibition of glycogen synthase kinase-3beta, whereas IL-1beta may amplify the process by feed-forward activation of NF-kappaB. Conversely, inhibition of the MAPK pathway increased beta-cell proliferation, indicating a counterregulatory restraining role for this signaling pathway.

Keywords
  • Animals
  • Calcium/metabolism
  • Cell Adhesion Molecules/chemistry
  • Cell Proliferation
  • Extracellular Matrix/ metabolism
  • Glycogen Synthase Kinase 3/metabolism
  • Insulin-Secreting Cells/ cytology
  • JNK Mitogen-Activated Protein Kinases/metabolism
  • MAP Kinase Signaling System
  • Male
  • NF-kappa B/metabolism
  • Rats
  • Rats, Wistar
  • Signal Transduction
  • Transcription Factors/metabolism
  • P38 Mitogen-Activated Protein Kinases/metabolism
Citation (ISO format)
PARNAUD, Géraldine et al. Signaling pathways implicated in the stimulation of beta-cell proliferation by extracellular matrix. In: Molecular endocrinology, 2009, vol. 23, n° 8, p. 1264–1271. doi: 10.1210/me.2009-0008
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ISSN of the journal0888-8809
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