The coactivator Bridge-1 increases transcriptional activation by pancreas duodenum homeobox-1 (PDX-1).
Well-orchestrated transcriptional regulation of pancreatic beta cells is essential for insulin production and glucose homeostasis. Pancreas duodenum homeobox-1 (PDX-1) is a key regulator of glucose-dependent insulin production and glucose metabolism. We find that PDX-1 interacts with the PDZ-domain coactivator Bridge-1 in yeast interaction trap assays. Rat Bridge-1 and PDX-1 interact directly in GST pull-down assays via Bridge-1 interactions with the amino-terminal transactivation domain of PDX-1. Bridge-1 also interacts with wild-type and mutant human PDX-1 (IPF-1) proteins and strongly interacts with the amino-terminal PDX-1 P63fsdelC (MODY4) mutant protein. Transcriptional activation by PDX-1 is increased by addition of Bridge-1 in multiple contexts, including synergistic activation of a Gal4 reporter by Gal4-Bridge-1 and Gal4-PDX-1 fusion proteins, activation of the somatostatin promoter TAAT1 enhancer, and synergistic activation of the rat insulin I promoter FarFlat enhancer by PDX-1, E12, and E47. We propose that the coactivator Bridge-1 modulates PDX-1 functions in the regulation of its target genes.
Stanojevic
Violeta
V
Laboratory of Molecular Endocrinology, Massachusetts General Hospital, Wellman 340, 50 Blossom Street, Boston, MA 02114, USA.
Yao
Kwok-Ming
KM
Thomas
Melissa K
MK
D000818:Animals; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D024002:HMGB Proteins / Q000235:genetics / Q000378:metabolism; D018398:Homeodomain Proteins / Q000235:genetics* / Q000378:metabolism*; D006801:Humans; D011401:Promoter Regions, Genetic; D025941:Protein Interaction Mapping; D051381:Rats; D012441:Saccharomyces cerevisiae; D013004:Somatostatin / Q000235:genetics; D051820:TCF Transcription Factors; D015534:Trans-Activators / Q000235:genetics* / Q000378:metabolism*; D058125:Transcription Factor 7-Like 1 Protein; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D015533:Transcriptional Activation
D004268:DNA-Binding Proteins; D024002:HMGB Proteins; D018398:Homeodomain Proteins; C402482:Psmd9 protein, rat; D051820:TCF Transcription Factors; C544912:TCF7L1 protein, human; C553060:Tcf7l1 protein, rat; D015534:Trans-Activators; D058125:Transcription Factor 7-Like 1 Protein; D014157:Transcription Factors; C084010:pancreatic and duodenal homeobox 1 protein; D013004:Somatostatin