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The diabetes-linked transcription factor PAX4 promotes {beta}-cell proliferation and survival in rat and human islets

St-Onge, Luc
Biason-Lauber, Anna
Schoenle, Eugene J
Published in The Journal of Cell Biology. 2004, vol. 167, no. 6, p. 1123-35
Abstract The mechanism by which the beta-cell transcription factor Pax4 influences cell function/mass was studied in rat and human islets of Langerhans. Pax4 transcripts were detected in adult rat islets, and levels were induced by the mitogens activin A and betacellulin. Wortmannin suppressed betacellulin-induced Pax4 expression, implicating the phosphatidylinositol 3-kinase signaling pathway. Adenoviral overexpression of Pax4 caused a 3.5-fold increase in beta-cell proliferation with a concomitant 1.9-, 4-, and 5-fold increase in Bcl-xL (antiapoptotic), c-myc, and Id2 mRNA levels, respectively. Accordingly, Pax4 transactivated the Bcl-xL and c-myc promoters, whereas its diabetes-linked mutant was less efficient. Bcl-xL activity resulted in altered mitochondrial calcium levels and ATP production, explaining impaired glucose-induced insulin secretion in transduced islets. Infection of human islets with an inducible adenoviral Pax4 construct caused proliferation and protection against cytokine-evoked apoptosis, whereas the mutant was less effective. We propose that Pax4 is implicated in beta-cell plasticity through the activation of c-myc and potentially protected from apoptosis through Bcl-xL gene expression.
Keywords Activins/pharmacologyAdenoviridae/chemistryAnimalsCell Proliferation/drug effectsCell Survival/drug effects/physiologyCells, CulturedDiabetes Mellitus/geneticsGenes, myc/genetics/physiologyHomeodomain Proteins/drug effects/genetics/metabolismHumansImmunohistochemistryInhibin-beta Subunits/pharmacologyIntercellular Signaling Peptides and Proteins/pharmacologyIslets of Langerhans/cytology/drug effects/metabolism/physiology/ultrastructurePaired Box Transcription FactorsProto-Oncogene Proteins c-bcl-2/geneticsRatsRats, WistarTranscription Factors/drug effects/genetics/metabolismTranscription, Genetic/physiologyBcl-X Protein
PMID: 15596543
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BRUN, Thierry et al. The diabetes-linked transcription factor PAX4 promotes {beta}-cell proliferation and survival in rat and human islets. In: The Journal of Cell Biology, 2004, vol. 167, n° 6, p. 1123-35. doi: 10.1083/jcb.200405148 https://archive-ouverte.unige.ch/unige:34542

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Deposited on : 2014-03-03

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