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.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Activins / pharmacology
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Adenoviridae / chemistry
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Animals
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Betacellulin
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Cell Proliferation / drug effects
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Cell Survival / drug effects
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Cell Survival / physiology
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Cells, Cultured
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Diabetes Mellitus / genetics*
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Genes, myc / genetics
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Genes, myc / physiology
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Homeodomain Proteins / drug effects
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Homeodomain Proteins / genetics
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Homeodomain Proteins / metabolism*
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Humans
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Immunohistochemistry
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Inhibin-beta Subunits / pharmacology
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Intercellular Signaling Peptides and Proteins / pharmacology
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Islets of Langerhans / cytology
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Islets of Langerhans / drug effects
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Islets of Langerhans / metabolism*
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Islets of Langerhans / physiology*
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Islets of Langerhans / ultrastructure
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Paired Box Transcription Factors
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Proto-Oncogene Proteins c-bcl-2 / genetics
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Rats
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Rats, Wistar
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Transcription Factors / drug effects
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Transcription Factors / genetics
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Transcription Factors / metabolism*
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Transcription, Genetic / physiology
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bcl-X Protein
Substances
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BCL2L1 protein, human
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BTC protein, human
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Bcl2l1 protein, rat
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Betacellulin
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Btc protein, rat
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Homeodomain Proteins
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Intercellular Signaling Peptides and Proteins
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PAX4 protein, human
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Paired Box Transcription Factors
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Pax4 protein, rat
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Proto-Oncogene Proteins c-bcl-2
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Transcription Factors
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activin A
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bcl-X Protein
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Activins
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Inhibin-beta Subunits