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PMID: 15596543 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, P.H.S.

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

The Journal of cell biology ·Vol. 167 ·No. 6 ·2004-12-20 ·Pages 1123-35

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

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.

MeSH Terms
Activins/pharmacology Adenoviridae/chemistry Animals Betacellulin Cell Proliferation/drug effects Cell Survival/drug effects,physiology Cells, Cultured Diabetes Mellitus/genetics Genes, myc/genetics,physiology Homeodomain Proteins/drug effects,genetics,metabolism Humans Immunohistochemistry Inhibin-beta Subunits/pharmacology Intercellular Signaling Peptides and Proteins/pharmacology Islets of Langerhans/cytology,drug effects,metabolism,physiology,ultrastructure Paired Box Transcription Factors Proto-Oncogene Proteins c-bcl-2/genetics Rats Rats, Wistar Transcription Factors/drug effects,genetics,metabolism Transcription, Genetic/physiology bcl-X Protein
Chemicals
BCL2L1 protein, human BTC protein, human Bcl2l1 protein, rat Betacellulin Btc protein, rat Homeodomain Proteins Intercellular Signaling Peptides and Proteins PAX4 protein, human Paired Box Transcription Factors Pax4 protein, rat Proto-Oncogene Proteins c-bcl-2 Transcription Factors activin A bcl-X Protein Activins Inhibin-beta Subunits
Authors & Affiliations
7 authors, click to expand affiliations / ORCID
Brun Thierry
Department of Cell Physiology and Metabolism, University Medical Center, Geneva, Switzerland. [email protected]
Franklin Isobel
St-Onge Luc
Biason-Lauber Anna
Schoenle Eugene J
Wollheim Claes B
Gauthier Benoit R
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Article Info
Journal
The Journal of cell biology
Abbr.
J Cell Biol
ISSN
0021-9525
DOI
10.1083/jcb.200405148
Email
[email protected]
Published
2004-12-20
Epub
2004-00-13
Pages
1123-35
Language
English
Region
United States
NLM ID
0375356
PMCID
PMC2172618
Subset
IM
External Links
PubMed source DOI: 10.1083/jcb.200405148 PMC Full Text View journal details
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