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Laboratory of Molecular Endocrinology (V.S., J.F.H., M.K.T.) and Diabetes Unit (M.K.T.), Massachusetts General Hospital, Howard Hughes Medical Institute (V.S., J.F.H.), and Harvard Medical School (J.F.H., M.K.T.), Boston, Massachusetts 02114
Address all correspondence and requests for reprints to: Melissa K. Thomas, M.D., Ph.D., Laboratory of Molecular Endocrinology and Diabetes Unit, Massachusetts General Hospital, Wellman 340, 50 Blossom Street, Boston, Massachusetts 02114. E-mail: mthomas1{at}partners.org.
The homeodomain transcription factor, pancreas duodenum homeobox (PDX)-1, is essential for pancreas development, insulin production, and glucose homeostasis. Mutations in pdx-1(ipf-1) are associated both with maturity-onset diabetes of the young and type 2 diabetes. PDX-1 interacts with multiple transcription factors and coregulators, including the coactivator p300, to activate the transcription of the insulin gene and other target genes within pancreatic ß-cells. In characterizing the protein-protein interactions of PDX-1 and p300, we identified mutations in PDX-1 that disrupt its function and are associated with increased or decreased interactions with p300. Several mutant PDX-1 proteins that are associated with heritable forms of diabetes in humans, in particular the mutant P63fsdelC, exhibited increased binding to a carboxy-terminal segment of p300 in the setting of decreased DNA-binding activities, suggesting that sequestration of p300 by mutant PDX-1 proteins may be an additional mechanism by which insulin gene expression is reduced in heterozygous carriers of pdx-1(ipf-1) mutations. The introduction of the point mutations S66A/Y68A in the highly conserved amino-terminal PDX-1 transactivation domain reduced the ability of PDX-1 to interact with p300, substantially diminished the transcriptional activation of PDX-1, and reduced the synergistic activation of glucose-responsive insulin promoter enhancer sequences by PDX-1, E12, and E47. We propose that interactions of PDX-1 with p300 are required for the transcriptional activation of PDX-1 target genes. Impairment of interactions between PDX-1 and p300 in pancreatic ß-cells may limit insulin production and lead to the development of diabetes.
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