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Published online 13 December 2004. doi:10.1083/jcb.200405148
The Rockefeller University Press, 0021-9525 $8.00
JCB, Volume 167, Number 6, 1123-1135
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Article

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



Thierry Brun1, Isobel Franklin1, Luc St-Onge2, Anna Biason-Lauber3, Eugene J. Schoenle3, Claes B. Wollheim1, and Benoit R. Gauthier1

1 Department of Cell Physiology and Metabolism, University Medical Center, 1211 Geneva 4, Switzerland
2 DeveloGen AG, Göttingen 37079, Germany
3 University Children's Hospital, 8032 Zurich, Switzerland

Correspondence to Benoit R. Gauthier: benoit.gauthier{at}medecine.unige.ch; or Thierry Brun: Thierry.brun{at}medecine.unige.ch

The mechanism by which the ß-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 ß-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 ß-cell plasticity through the activation of c-myc and potentially protected from apoptosis through Bcl-xL gene expression.

L. St-Onge's present address is NeuroNova AG, 80804 Munich, Germany.

Abbreviations used in this paper: AUP, area under peak; EMSA, electrophoretic mobility shift assay; PI3-kinase, phosphatidylinositol 3-kinase; wt, wild type.


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