REGULATION OF INSULIN GENE EXPRESSION

Salk Institute For Biological Studies, La Jolla CA

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Abstract

The homeobox protein pdx1 functions importantly in pancreatic development and in glucose homeostasis. Targeted disruption of the pdx1 gene leads to pancreatic agenesis in pdx1 -/- homozygotes, and pdx +/- heterozygotes develop glucose intolerance as adults. Inactivating mutations in the human pdx1 gene are correlated with maturity onset diabetes of the young, further underscoring the importance of this factor for glycemic control. The long term objective of this proposal is to elucidate the mechanism by which pdx1 stimulates the expression of cellular target genes during development and in response to glucose. Two features of the pdx polypeptide appear to be particularly critical in this regard; a conserved pentapeptide motif that mediates cooperative DNA binding with the ubiquitous homeodomain protein pbx, and an N-terminal trans-activation domain whose activity is induced in response to glucose stimulation. The major hypothesis to be tested is that glucose regulates the transcriptional activity of the pdx/pbx complex by promoting complex formation with the co-activator CBP via a phosphorylation dependent mechanism. This hypothesis will be tested in the following specific aims: 1. We will characterize the mechanism by which the conserved pentapeptide motif in pdx promotes interaction with pbx, and we will evaluate the importance of pdx/pbx complex formation for pancreatic development and glucose homeostasis in transgenic mice. 2. We will characterize a glucose responsive trans-activation domain in pdx-1, and we will identify residues in pdx that are phosphorylated in response to glucose stimulation. 3. We will examine the mechanism by which pdx interacts with the signal dependent co-activator CBP, and we will evaluate whether glucose promotes recruitment of CBP to pdx by a phosphorylation dependent mechanism.