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J Biol Chem, Vol. 275, Issue 3, 2199-2204, January 21, 2000
From the Department of Biological Chemistry, Weizmann Institute of
Science, Rehovot, Israel 76100
The insulin gene is efficiently expressed only in
pancreatic beta cells. Using reverse transcriptase-polymerase chain
reaction analysis, we show that insulin mRNA levels are at least
105-fold higher in beta cells than non-beta cells. To
examine the underlying mechanisms, we expressed beta cell transcription
factors by transfection of non-beta cells. Separate expression of
BETA2, E2A, or PDX1 led to modest (<10-fold) activation of the insulin promoter, whereas co-expression of the three proteins produced synergistic, high level activation (160-fold). This level of activity is ~25% that observed in transfected beta cell lines. Of the three factors studied, BETA2 appears to play a dominant role. Efficient transcription required a C-terminal activation domain of BETA2 and an
N-terminal region, which does not function as an independent activation
domain. The myogenic basic helix-loop-helix (bHLH) protein MyoD was
unable to bind and activate the promoter, even when its DNA binding
region was replaced with that of BETA2. Our results demonstrate the
central importance of BETA2 in insulin gene transcription and the
importance of sequences outside the canonical DNA binding domain in
permitting efficient DNA binding and cell-specific activity of the
insulin gene promoter.
Transcription Factor BETA2 Acts Cooperatively with E2A and
PDX1 to Activate the Insulin Gene Promoter*
,
*
This work was supported by grants from the Israel Academy of
Sciences and Humanities and the Kekst Family Foundation for Molecular Genetics (to M. D. W.).The costs of publication of this
article were defrayed in part by the
payment of page charges. The article must therefore be hereby marked
"advertisement" in
accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
Present address: Dept of Pathology and Biochemistry, University of
Washington, Seattle, WA 98195-7705.
§
Present address: QBI Enterprises Ltd., Ness Ziona 70400, Israel.
¶
Holds the Marvin Meyer and Jenny Cyker Chair of Diabetes
Research. To whom correspondence should be addressed. Fax: 972 8 934 4118; E-mail: m.walker@weizmann.ac.il.
Copyright © 2000 by The American Society for Biochemistry and Molecular Biology, Inc.
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