UNIGE document Scientific Article
previous document  unige:8956  next document
add to browser collection

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

Hammar, Eva
Ribaux, Pascale
Donath, M. Y.
Published in Molecular Endocrinology. 2009, vol. 23, no. 8, p. 1264-1271
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 AnimalsCalcium/metabolismCell Adhesion Molecules/chemistryCell ProliferationExtracellular Matrix/ metabolismGlycogen Synthase Kinase 3/metabolismInsulin-Secreting Cells/ cytologyJNK Mitogen-Activated Protein Kinases/metabolismMAP Kinase Signaling SystemMaleNF-kappa B/metabolismRatsRats, WistarSignal TransductionTranscription Factors/metabolismP38 Mitogen-Activated Protein Kinases/metabolism
PMID: 19443607
Full text
Article - document accessible for UNIGE members only Limited access to UNIGE
Other version: http://mend.endojournals.org/cgi/reprint/23/8/1264.pdf
Research group La transplantation d'îlots de Langerhans (623)
(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 https://archive-ouverte.unige.ch/unige:8956

418 hits

0 download


Deposited on : 2010-07-12

Export document
Format :
Citation style :