Phosphorylation marks IPF1/PDX1 protein for degradation by glycogen synthase kinase 3-dependent mechanisms.
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.
Boucher
Marie-Josée
MJ
Umeå Center for Molecular Medicine, University of Umeå, SE-901 87 Umeå, Sweden.
Selander
Lars
L
Carlsson
Lennart
L
Edlund
Helena
H
D000818:Animals; D002460:Cell Line; D005786:Gene Expression Regulation / Q000502:physiology; D038362:Glycogen Synthase Kinase 3 / Q000502:physiology*; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D050417:Insulin-Secreting Cells / Q000378:metabolism; D051379:Mice; D018384:Oxidative Stress / Q000502:physiology; D010179:Pancreas / Q000166:cytology / Q000378:metabolism; D010766:Phosphorylation; D061988:Proteasome Inhibitors; D012694:Serine / Q000378:metabolism; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism*
D018398:Homeodomain Proteins; D061988:Proteasome Inhibitors; D015534:Trans-Activators; C084010:pancreatic and duodenal homeobox 1 protein; D012694:Serine; D038362:Glycogen Synthase Kinase 3