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J. Biol. Chem., Vol. 278, Issue 15, 12929-12936, April 11, 2003
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From the The cytosolic form of the phosphoenolpyruvate
carboxykinase (PEPCK-C) gene is selectively expressed in several
tissues, primarily in the liver, kidney, and adipose tissue. The
transcription of the gene is reciprocally regulated by glucocorticoids
in these tissues. It is induced in the liver and kidney but repressed
in the white adipose tissue. To elucidate which adipocyte-specific transcription factors participate in the repression of the gene, DNase
I footprinting analyses of nuclear proteins from 3T3-F442A adipocytes
and transient transfection experiments in NIH3T3 cells were utilized.
Glucocorticoid treatment slightly reduced the nuclear C/EBP
Glucocorticoids Repress Transcription of Phosphoenolpyruvate
Carboxykinase (GTP) Gene in Adipocytes by Inhibiting Its
C/EBP-mediated Activation*
§,§,§,,,
Department of Developmental Biochemistry,
Hebrew University-Hadassah Medical School, Jerusalem, Israel 91120 and the ¶ Department of Biochemistry, Case Western Reserve
University School of Medicine, Cleveland, Ohio 44106-4935
concentration but prominently diminished the binding of adipocyte-derived nuclear proteins to CCAAT/enhancer-binding protein (C/EBP) recognition sites, without affecting the binding to nuclear receptor sites in the PEPCK-C gene promoter. Of members of the C/EBP
family of transcription factors, C/EBP was the strongest trans-activator of the PEPCK-C gene promoter in the NIH3T3 cell line.
The glucocorticoid receptor (GR), in the presence of its hormone
ligand, inhibited the activation of the PEPCK-C gene promoter by
C/EBP or C/EBP
but not by the adipocyte-specific peroxisome proliferator-activated receptor 
2. This inhibition effect was similar using the wild type or mutant GR and did not depend on GR
binding to the DNA. The glucocorticoid response unit (GRU) in the
PEPCK-C gene promoter (
2000 to +73) restrained
C/EBP-mediated trans-activation, because mutation of each single GRU
element increased this activation by 3-4-fold. This series of GRU
mutations were repressed by wild type GR to the same percent as was the nonmutated PEPCK-C gene promoter. In contrast, the repression by
mutant GR depended on the intact AF1 site in the gene promoter, whereby
mutation of the AF1 element abolished the repression.
*
This work was supported by Grants 1999346 and 9600117 from
the United States-Israel Binational Science Foundation, Grant 540197-19 from the Israel Science Foundation, a grant from the Israel Ministry of
Health, and by Grant DK22541 from the National Institutes of Health.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.
To whom correspondence should be addressed: Dept. of
Developmental Biochemistry, Hebrew University-Hadassah Medical School, Jerusalem, Israel 91120. Fax: 972-2-675-7379; E-mail:
reshef@cc.huji.ac.il.
Copyright © 2003 by The American Society for Biochemistry and Molecular Biology, Inc.
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