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Scientific article
Open access
English

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

Published inThe Journal of cell biology, vol. 167, no. 6, p. 1123-1135
Publication date2004
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/pharmacology
  • Adenoviridae/chemistry
  • Animals
  • 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
Citation (ISO format)
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. 1123–1135. doi: 10.1083/jcb.200405148
Main files (1)
Article (Published version)
accessLevelPublic
Identifiers
ISSN of the journal0021-9525
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623downloads

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