1: J Cell Biol. 2004 Dec 20;167(6):1123-35. Epub 2004 Dec 13. 

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

Brun T, Franklin I, St-Onge L, Biason-Lauber A, Schoenle EJ, Wollheim CB,
Gauthier BR.

Department of Cell Physiology and Metabolism, University Medical Center, Geneva,
Switzerland. Thierry.brun@medecine.unige.ch

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.

PMID: 15596543 [PubMed - indexed for MEDLINE]


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