Phosphorylation marks IPF1/PDX1 protein for degradation by glycogen synthase kinase 3-dependent mechanisms

Abstract

The transcription factor IPF1/PDX1 plays a crucial role in both pancreas development and maintenance of β-cell function. Targeted disruption of this transcription factor in β-cells leads to diabetes, whereas reduced expression levels affect insulin expression and secretion. Therefore, it is essential to determine molecular mechanisms underlying the regulation of this key transcription factor on mRNA levels and, most importantly, on protein levels. Here we show that a minor portion of IPF1/PDX1 is phosphorylated on serine 61 and/or serine 66 in pancreatic β-cells. This phosphorylated form of IPF1/PDX1 preferentially accumulates following proteasome inhibition, an effect that is prevented by inhibition of glycogen synthase kinase 3 (GSK3) activity. Oxidative stress, which is associated with the diabetic state, (i) increases IPF1/PDX1 Ser61 and/or Ser66 phosphorylation and (ii) increases the degradation rate and decreases the half-life of IPF-1/PDX-1 protein. In addition, we provide evidence that GSK3 activity participates in oxidative stressinduced effects on β-cells. Thus, this current study uncovers a new mechanism that might contribute to diminished levels of IPF1/ PDX1 protein and β-cell dysfunction during the progression of diabetes. © 2006 by The American Society for Biochemistry and Molecular Biology, Inc.