This Article Full Text Full Text (PDF) Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Copyright Permission Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Stanojevic, V. Articles by Thomas, M. K. Search for Related Content PubMed PubMed Citation Articles by Stanojevic, V. Articles by Thomas, M. K.

Pancreas Duodenum Homeobox-1 Transcriptional Activation Requires Interactions with p300

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.

This article has been cited by other articles:

				M.-J. Boucher, M. Simoneau, and H. Edlund The Homeodomain-Interacting Protein Kinase 2 Regulates Insulin Promoter Factor-1/Pancreatic Duodenal Homeobox-1 Transcriptional Activity Endocrinology, January 1, 2009; 150(1): 87 - 97. [Abstract] [Full Text] [PDF]

				H.-W. Wang, M. Muguira, W.-D. Liu, T. Zhang, C. Chen, R. Aucoin, M. B Breslin, and M. S Lan Identification of an INSM1-binding site in the insulin promoter: negative regulation of the insulin gene transcription J. Endocrinol., July 1, 2008; 198(1): 29 - 39. [Abstract] [Full Text] [PDF]

				L. Chen, H.-X. Yan, J. Chen, W. Yang, Q. Liu, B. Zhai, H.-F. Cao, S.-Q. Liu, M.-C. Wu, and H.-Y. Wang Negative Regulation of c-Myc Transcription by Pancreas Duodenum Homeobox-1 Endocrinology, May 1, 2007; 148(5): 2168 - 2180. [Abstract] [Full Text] [PDF]

				K. Eto, V. Kaur, and M. K. Thomas Regulation of Pancreas Duodenum Homeobox-1 Expression by Early Growth Response-1 J. Biol. Chem., March 2, 2007; 282(9): 5973 - 5983. [Abstract] [Full Text] [PDF]

				T. B. Deramaudt, M. M. Sachdeva, M. P. Wescott, Y. Chen, D. A. Stoffers, and A. K. Rustgi The PDX1 Homeodomain Transcription Factor Negatively Regulates the Pancreatic Ductal Cell-specific Keratin 19 Promoter J. Biol. Chem., December 15, 2006; 281(50): 38385 - 38395. [Abstract] [Full Text] [PDF]

				C. W. Hay and K. Docherty Comparative Analysis of Insulin Gene Promoters: Implications for Diabetes Research Diabetes, December 1, 2006; 55(12): 3201 - 3213. [Abstract] [Full Text] [PDF]

				M. Mirasierra and M. Vallejo The Homeoprotein Alx3 Expressed in Pancreatic ss-Cells Regulates Insulin Gene Transcription by Interacting with the Basic Helix-Loop-Helix Protein E47 Mol. Endocrinol., November 1, 2006; 20(11): 2876 - 2889. [Abstract] [Full Text] [PDF]

				M.-J. Boucher, L. Selander, L. Carlsson, and H. Edlund Phosphorylation Marks IPF1/PDX1 Protein for Degradation by Glycogen Synthase Kinase 3-dependent Mechanisms J. Biol. Chem., March 10, 2006; 281(10): 6395 - 6403. [Abstract] [Full Text] [PDF]

				J. L. Volinic, J. H. Lee, K. Eto, V. Kaur, and M. K. Thomas Overexpression of the Coactivator Bridge-1 Results in Insulin Deficiency and Diabetes Mol. Endocrinol., January 1, 2006; 20(1): 167 - 182. [Abstract] [Full Text] [PDF]

				J. H Lee, J. L Volinic, C. Banz, K.-M. Yao, and M. K Thomas Interactions with p300 enhance transcriptional activation by the PDZ-domain coactivator Bridge-1 J. Endocrinol., November 1, 2005; 187(2): 283 - 292. [Abstract] [Full Text] [PDF]

				T. Iype, J. Francis, J. C. Garmey, J. C. Schisler, R. Nesher, G. C. Weir, T. C. Becker, C. B. Newgard, S. C. Griffen, and R. G. Mirmira Mechanism of insulin Gene Regulation by the Pancreatic Transcription Factor Pdx-1: APPLICATION OF PRE-mRNA ANALYSIS AND CHROMATIN IMMUNOPRECIPITATION TO ASSESS FORMATION OF FUNCTIONAL TRANSCRIPTIONAL COMPLEXES J. Biol. Chem., April 29, 2005; 280(17): 16798 - 16807. [Abstract] [Full Text] [PDF]

				H. Kaneto, T.-a. Matsuoka, Y. Nakatani, T. Miyatsuka, M. Matsuhisa, M. Hori, and Y. Yamasaki A Crucial Role of MafA as a Novel Therapeutic Target for Diabetes J. Biol. Chem., April 15, 2005; 280(15): 15047 - 15052. [Abstract] [Full Text] [PDF]

				M. Brissova, M. Blaha, C. Spear, W. Nicholson, A. Radhika, M. Shiota, M. J. Charron, C. V. E. Wright, and A. C. Powers Reduced PDX-1 expression impairs islet response to insulin resistance and worsens glucose homeostasis Am J Physiol Endocrinol Metab, April 1, 2005; 288(4): E707 - E714. [Abstract] [Full Text] [PDF]