Boucher Marie-Josée, Selander Lars, Carlsson Lennart, Edlund Helena
Umeå Center for Molecular Medicine, University of Umeå, SE-901 87 Umeå, Sweden.
J Biol Chem. 2006 Mar 10;281(10):6395-403. doi: 10.1074/jbc.M511597200. Epub 2006 Jan 11.
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.
转录因子IPF1/PDX1在胰腺发育和β细胞功能维持中均发挥着关键作用。在β细胞中靶向破坏该转录因子会导致糖尿病，而其表达水平降低则会影响胰岛素的表达和分泌。因此，确定这一关键转录因子在mRNA水平尤其是蛋白质水平上的调控分子机制至关重要。在此我们表明，胰腺β细胞中一小部分IPF1/PDX1在丝氨酸61和/或丝氨酸66处发生磷酸化。蛋白酶体抑制后，IPF1/PDX1的这种磷酸化形式优先积累，糖原合酶激酶3（GSK3）活性的抑制可阻止这一效应。与糖尿病状态相关的氧化应激，（i）增加IPF1/PDX1丝氨酸61和/或丝氨酸66的磷酸化，（ii）增加IPF-1/PDX-1蛋白的降解速率并缩短其半衰期。此外，我们提供的证据表明，GSK3活性参与了氧化应激对β细胞的诱导作用。因此，本研究揭示了一种新机制，该机制可能导致糖尿病进展过程中IPF1/PDX1蛋白水平降低和β细胞功能障碍。
