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J. Biol. Chem., Vol. 280, Issue 46, 38203-38210, November 18, 2005

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Regulation of the Pancreatic Duodenal Homeobox-1 Protein by DNA-dependent Protein Kinase^*

Patricia Lebrun1, Marc R. Montminy, and Emmanuel Van Obberghen2

From the INSERM U145, Faculty of Medicine, IFR50 Nice, France and The Salk Institute for Biological Studies, La Jolla, California 92037

The transcription factor PDX-1 plays a crucial role during pancreatic development and in the function of insulin-producing beta cells. Disruption of the pdx-1 gene in these cells induces overt diabetes in mice, and this gene is modified in several type 2 diabetic families. It is thus crucial to determine the molecular mechanisms involved in the regulation of PDX-1 expression and/or activation. We identified new proteins associated with PDX-1 by mass spectrometry. These proteins, Ku70 and Ku80, are regulatory subunits of DNA-dependent protein kinase (DNA-PK). We determined that the interaction between PDX-1 and Ku70 or Ku80 is dependent on the homeodomain of PDX-1. Most interestingly, we demonstrated in vitro that the DNA-PK phosphorylates PDX-1 on threonine 11. Although this residue is located in the transactivation domain, this phosphorylation does not seem to be implicated in the transcriptional activation of PDX-1. However, in response to radiation, which activates DNA-PK, a second form of the PDX-1 protein appears rapidly. This form is phosphorylated on threonine and seems to drive PDX-1 degradation by the proteosome. In correlation with this degradation, we observed a subsequent reduction in the activation of the insulin promoter and a decrease in PDX-1-mediated gene expression, i.e. glut2 and glucokinase. Our study demonstrates that radiation, through the activation of DNA-PK, may regulate PDX-1 protein expression.

Received for publication, May 3, 2005 , and in revised form, September 8, 2005.

^* This work was supported in part by the Association pour la Recherche Contre le Cancer, the Catherina Foundation, and the Ligue Nationale Contre le Cancer Grant GL/VP-4457. 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.

¹ Supported by the Philippe Foundation. To whom correspondence may be addressed. Fax: 33-4-93-81-54-32; E-mail: plebrun{at}unice.fr. ² To whom correspondence may be addressed. Fax: 33-4-93-81-54-32; E-mail: vanobbeg{at}unice.fr.

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