Abstract
Insulin gene expression is regulated by pancreatic beta cell-specific factors, PDX-1 and BETA2/E47. Here we have demonstrated that the insulin promoter is a novel target for SREBPs established as lipid-synthetic transcription factors. Promoter analyses of rat insulin I gene in non-beta cells revealed that nuclear SREBP-1c activates the insulin promoter through three novel SREBP-binding sites (SREs), two of which overlap with E-boxes, binding sites for BETA2/E47. SREBP-1c activation of the insulin promoter was markedly enhanced by co-expression of BETA2/E47. This synergistic activation by SREBP-1c/BETA2/E47 was not mediated through SREs but through the E-boxes on which BETA2/E47 physically interacts with SREBP-1c, suggesting a novel function of SREBP as a co-activator. These two cis-DNA regions, E1 and E2, with an appropriate distance separating them, were mandatory for the synergism, which implicates formation of SREBP-1c.BETA2.E47 complex in a DNA looping structure for efficient recruitment of CREB-binding protein/p300. However, in the presence of PDX1, the synergistic action of SREBP-1c with BETA2/E47 was canceled. SREBP-1c-mediated activation of the insulin promoter and expression became overt in beta cell lines and isolated islets when endogenous PDX-1 expression was low. This cryptic SREBP-1c action might play a compensatory role in insulin expression in diabetes with beta cell lipotoxicity.
Publication types
-
Research Support, Non-U.S. Gov't
MeSH terms
-
Animals
-
Basic Helix-Loop-Helix Transcription Factors / metabolism
-
Basic Helix-Loop-Helix Transcription Factors / physiology*
-
Binding Sites
-
Blotting, Western
-
Cell Nucleus / metabolism
-
Chromatin Immunoprecipitation
-
DNA / chemistry
-
Dose-Response Relationship, Drug
-
Gene Expression Regulation*
-
Genes, Reporter
-
Glutathione Transferase / metabolism
-
Homeodomain Proteins / metabolism
-
Humans
-
Immunoblotting
-
Insulin / genetics*
-
Insulin / metabolism
-
Insulin-Secreting Cells / metabolism
-
Luciferases / metabolism
-
Male
-
Mice
-
Mice, Inbred C57BL
-
Models, Biological
-
Mutagenesis, Site-Directed
-
Pancreas / metabolism
-
Plasmids / metabolism
-
Promoter Regions, Genetic*
-
Protein Binding
-
Protein Biosynthesis
-
Protein Structure, Tertiary
-
Rats
-
Rats, Sprague-Dawley
-
Sterol Regulatory Element Binding Protein 1 / metabolism
-
Sterol Regulatory Element Binding Protein 1 / physiology*
-
Sterol Regulatory Element Binding Proteins / physiology*
-
TCF Transcription Factors / metabolism
-
TCF Transcription Factors / physiology*
-
Trans-Activators / metabolism
-
Transcription Factor 7-Like 1 Protein
Substances
-
Basic Helix-Loop-Helix Transcription Factors
-
Homeodomain Proteins
-
Insulin
-
NEUROD1 protein, human
-
Sterol Regulatory Element Binding Protein 1
-
Sterol Regulatory Element Binding Proteins
-
TCF Transcription Factors
-
TCF7L1 protein, human
-
Tcf7l1 protein, mouse
-
Tcf7l1 protein, rat
-
Trans-Activators
-
Transcription Factor 7-Like 1 Protein
-
pancreatic and duodenal homeobox 1 protein
-
DNA
-
Luciferases
-
Glutathione Transferase