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J. Biol. Chem., Vol. 281, Issue 10, 6395-6403, March 10, 2006

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Phosphorylation Marks IPF1/PDX1 Protein for Degradation by Glycogen Synthase Kinase 3-dependent Mechanisms^*

From the Umeå Center for Molecular Medicine, University of Umeå, SE-901 87 Umeå, Sweden

The transcription factor IPF1/PDX1 plays a crucial role in both pancreas development and maintenance of -cell function. Targeted disruption of this transcription factor in -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 -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 -cells. Thus, this current study uncovers a new mechanism that might contribute to diminished levels of IPF1/PDX1 protein and -cell dysfunction during the progression of diabetes.

Received for publication, October 26, 2005 , and in revised form, January 10, 2006.

^* This work was supported by grants from the Swedish Research Council, the Wallenberg Consortium North, European Union regional fund Objective 1 (to H. E.), and a post-doctoral fellowship from the Fonds pour la Recherche en Santé du Québec (to M.-J. B.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹To whom correspondence may be addressed. E-mail: marie-josee.boucher{at}ucmm.umu.se. ²To whom correspondence may be addressed. Tel.: 90-785-4429; Fax: 90-785-4400; E-mail: helena.edlund{at}ucmm.umu.se.

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