Sterol regulatory element-binding proteins activate insulin gene promoter directly and indirectly through synergy with BETA2/E47.
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.
Amemiya-Kudo
Michiyo
M
Okinaka Memorial Institute for Medical Research, Toranomon Hospital, Toranomon 2-2-2, Minato-ku, Tokyo 105-8470, Japan.
Oka
Junko
J
Ide
Tomohiro
T
Matsuzaka
Takashi
T
Sone
Hirohito
H
Yoshikawa
Tomohiro
T
Yahagi
Naoya
N
Ishibashi
Shun
S
Osuga
Jun-Ichi
J
Yamada
Nobuhiro
N
Murase
Toshio
T
Shimano
Hitoshi
H
D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000378:metabolism / Q000502:physiology*; D001665:Binding Sites; D015153:Blotting, Western; D002467:Cell Nucleus / Q000378:metabolism; D047369:Chromatin Immunoprecipitation; D004247:DNA / Q000737:chemistry; D004305:Dose-Response Relationship, Drug; D005786:Gene Expression Regulation; D017930:Genes, Reporter; D005982:Glutathione Transferase / Q000378:metabolism; D018398:Homeodomain Proteins / Q000378:metabolism; D006801:Humans; D015151:Immunoblotting; D007328:Insulin / Q000235:genetics* / Q000378:metabolism; D050417:Insulin-Secreting Cells / Q000378:metabolism; D008156:Luciferases / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008954:Models, Biological; D016297:Mutagenesis, Site-Directed; D010179:Pancreas / Q000378:metabolism; D010957:Plasmids / Q000378:metabolism; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D014176:Protein Biosynthesis; D017434:Protein Structure, Tertiary; D051381:Rats; D017207:Rats, Sprague-Dawley; D051780:Sterol Regulatory Element Binding Protein 1 / Q000378:metabolism / Q000502:physiology*; D051779:Sterol Regulatory Element Binding Proteins / Q000502:physiology*; D051820:TCF Transcription Factors / Q000378:metabolism / Q000502:physiology*; D015534:Trans-Activators / Q000378:metabolism; D058125:Transcription Factor 7-Like 1 Protein
D051792:Basic Helix-Loop-Helix Proteins; D004247:DNA; D005982:Glutathione Transferase; D018398:Homeodomain Proteins; D007328:Insulin; D008156:Luciferases; D051780:Sterol Regulatory Element Binding Protein 1; D051779:Sterol Regulatory Element Binding Proteins; D051820:TCF Transcription Factors; D015534:Trans-Activators; D058125:Transcription Factor 7-Like 1 Protein; C093970:NEUROD1 protein, human; C544912:TCF7L1 protein, human; C544913:Tcf7l1 protein, mouse; C553060:Tcf7l1 protein, rat; C084010:pancreatic and duodenal homeobox 1 protein