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Papers In Press, published online ahead of print September 15, 2005
INSERM U145, Nice, Cedex 2 06107
Corresponding Author: plebrun{at}unice.fr
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-PK. We determined that the interaction between PDX-1 and Ku70 or 80 is dependent on the homeodomain of PDX-1. Interestingly, we demonstrated, in vitro, that the DNA-PK phosphorylates PDX-1 on threonine 11. Even though, 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, ie Glut2 and glucokinase. Our study demonstrates that radiation, through the activation of DNA-PK, may regulate PDX-1 protein expression.
J. Biol. Chem, 10.1074/jbc.M504842200
Submitted on May 3, 2005
Revised on September 8, 2005
Accepted on September 15, 2005
Regulation of the pancreatic duodenal homeobox-1 protein by DNA-dependent protein kinase
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