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(Received for publication, April 18, 1997, and in revised form, August 6, 1997)
From the Laboratory of Molecular Endocrinology, Massachusetts
General Hospital, Howard Hughes Medical Institute, Harvard Medical
School, Boston, Massachusetts 02114
Chronic exposure of
Volume 272, Number 45,
Issue of November 7, 1997
pp. 28349-28359
©1997 by The American Society for Biochemistry and Molecular Biology, Inc.
Pancreatic
-Cell-specific Repression of Insulin Gene
Transcription by CCAAT/Enhancer-binding Protein
INHIBITORY INTERACTIONS WITH BASIC HELIX-LOOP-HELIX
TRANSCRIPTION FACTOR E47
-cells to supraphysiologic
glucose concentrations results in decreased insulin gene transcription.
Here we identify the basic leucine zipper transcription factor,
CCAAT/enhancer-binding protein (C/EBP), as a repressor of
insulin gene transcription in conditions of supraphysiological
glucose levels. C/EBP is expressed in primary rat islets.
Moreover, after exposure to high glucose concentrations the -cell
lines HIT-T15 and INS-1 express increased levels of C/EBP. The rat
insulin I gene promoter contains a consensus binding motif for C/EBP
(CEB box) that binds C/EBP. In non--cells C/EBP stimulates the
activity of the rat insulin I gene promoter through the CEB box.
Paradoxically, in -cells C/EBP 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/EBP in
pancreatic -cells by chronically elevated glucose levels may
contribute to the impaired insulin secretion in severe type II diabetes
mellitus.
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