Abstract
The transcription factor IPF1/PDX1 plays a crucial role in both pancreas development and maintenance of beta-cell function. Targeted disruption of this transcription factor in beta-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 beta-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 stress-induced effects on beta-cells. Thus, this current study uncovers a new mechanism that might contribute to diminished levels of IPF1/PDX1 protein and beta-cell dysfunction during the progression of diabetes.
Highlights
The participation of IPF1/PDX1 in the transcription of several genes essential for glucose sensing and insulin synthesis underlines its key role in differentiated -cells
Because phosphorylation has been proposed as a potential post-translational modification for IPF1/ PDX1 [24, 27, 28], we hypothesized that the upper band might correspond to a phosphorylated form of IPF1/PDX1
The IPF1/PDX1 transcription factor plays a crucial role in pancreas development and -cell function
Summary
The participation of IPF1/PDX1 in the transcription of several genes essential for glucose sensing and insulin synthesis underlines its key role in differentiated -cells. Following CIP treatment, the 43-kDa band disappeared, and only the major 42-kDa band could be detected using the anti-pan-IPF1/PDX1 antibody (Fig. 1B), supporting the idea that the 43-kDa protein is a phosphorylated form of IPF1/PDX1. As expected IPF1/PDX1, detected using either the anti-pan-IPF1/PDX1 or the anti-phospho-IPF1/PDX1 antibodies, was nuclear in islets and MIN6 cells cultured at high glucose concentrations (Fig. 1E and data not shown).
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