The diabetes-linked transcription factor PAX4 promotes {beta}-cell proliferation and survival in rat and human islets.
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.
Brun
Thierry
T
Department of Cell Physiology and Metabolism, University Medical Center, Geneva, Switzerland. Thierry.brun@medecine.unige.ch
Franklin
Isobel
I
St-Onge
Luc
L
Biason-Lauber
Anna
A
Schoenle
Eugene J
EJ
Wollheim
Claes B
CB
Gauthier
Benoit R
BR
D028341:Activins / Q000494:pharmacology; D000256:Adenoviridae / Q000737:chemistry; D000818:Animals; D066259:Betacellulin; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D003920:Diabetes Mellitus / Q000235:genetics*; D016259:Genes, myc / Q000235:genetics / Q000502:physiology; D018398:Homeodomain Proteins / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007150:Immunohistochemistry; D028322:Inhibin-beta Subunits / Q000494:pharmacology; D036341:Intercellular Signaling Peptides and Proteins / Q000494:pharmacology; D007515:Islets of Langerhans / Q000166:cytology / Q000187:drug effects / Q000378:metabolism* / Q000502:physiology* / Q000648:ultrastructure; D051761:Paired Box Transcription Factors; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics; D051381:Rats; D017208:Rats, Wistar; D014157:Transcription Factors / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D014158:Transcription, Genetic / Q000502:physiology; D051020:bcl-X Protein
C494811:BCL2L1 protein, human; C587851:BTC protein, human; C494813:Bcl2l1 protein, rat; D066259:Betacellulin; C587853:Btc protein, rat; D018398:Homeodomain Proteins; D036341:Intercellular Signaling Peptides and Proteins; C491709:PAX4 protein, human; D051761:Paired Box Transcription Factors; C491708:Pax4 protein, rat; D019253:Proto-Oncogene Proteins c-bcl-2; D014157:Transcription Factors; C422405:activin A; D051020:bcl-X Protein; D028341:Activins; D028322:Inhibin-beta Subunits