Pancreatic beta-cell-specific repression of insulin gene transcription by CCAAT/enhancer-binding protein beta. Inhibitory interactions with basic helix-loop-helix transcription factor E47.
Chronic exposure of beta-cells to supraphysiologic glucose concentrations results in decreased insulin gene transcription. Here we identify the basic leucine zipper transcription factor, CCAAT/enhancer-binding protein beta (C/EBPbeta), as a repressor of insulin gene transcription in conditions of supraphysiological glucose levels. C/EBPbeta is expressed in primary rat islets. Moreover, after exposure to high glucose concentrations the beta-cell lines HIT-T15 and INS-1 express increased levels of C/EBPbeta. The rat insulin I gene promoter contains a consensus binding motif for C/EBPbeta (CEB box) that binds C/EBPbeta. In non-beta-cells C/EBPbeta stimulates the activity of the rat insulin I gene promoter through the CEB box. Paradoxically, in beta-cells C/EBPbeta inhibits transcription, directed by the promoter of the rat insulin I gene by direct protein-protein interaction with a heptad leucine repeat sequence within activation domain 2 of the basic helix-loop-helix transcription factor E47. This interaction leads to the inhibition of both dimerization and DNA binding of E47 to the E-elements of the insulin promoter, thereby reducing functionally the transactivation potential of E47 on insulin gene transcription. We suggest that the induction of C/EBPbeta in pancreatic beta-cells by chronically elevated glucose levels may contribute to the impaired insulin secretion in severe type II diabetes mellitus.
Lu
M
M
Laboratory of Molecular Endocrinology, Massachusetts General Hospital, Howard Hughes Medical Institute, Harvard Medical School, Boston, Massachusetts 02114, USA.
Seufert
J
J
Habener
J F
JF
D000818:Animals; D001665:Binding Sites / Q000235:genetics; D022762:CCAAT-Enhancer-Binding Proteins; D019556:COS Cells; D002460:Cell Line; D002478:Cells, Cultured; D006224:Cricetinae; D003470:Culture Media; D004247:DNA / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism* / Q000494:pharmacology*; D005947:Glucose / Q000494:pharmacology; D006367:HeLa Cells; D018257:Helix-Loop-Helix Motifs; D006801:Humans; D007328:Insulin / Q000235:genetics*; D007515:Islets of Langerhans / Q000187:drug effects / Q000378:metabolism*; D007930:Leucine / Q000378:metabolism; D016350:Leucine Zippers; D008297:Male; D009687:Nuclear Proteins / Q000494:pharmacology*; D011401:Promoter Regions, Genetic; D051381:Rats; D017207:Rats, Sprague-Dawley; D017422:Sequence Analysis, DNA; D051820:TCF Transcription Factors; D058125:Transcription Factor 7-Like 1 Protein; D014157:Transcription Factors; D014158:Transcription, Genetic / Q000187:drug effects*; D015533:Transcriptional Activation / Q000187:drug effects; D015854:Up-Regulation / Q000187:drug effects
D022762:CCAAT-Enhancer-Binding Proteins; D003470:Culture Media; D004268:DNA-Binding Proteins; D007328:Insulin; D009687:Nuclear Proteins; D051820:TCF Transcription Factors; C544912:TCF7L1 protein, human; C553060:Tcf7l1 protein, rat; D058125:Transcription Factor 7-Like 1 Protein; D014157:Transcription Factors; D004247:DNA; D007930:Leucine; D005947:Glucose