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J. Biol. Chem., Vol. 276, Issue 6, 3811-3819, February 9, 2001
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From the Department of Molecular Physiology and Biophysics,
Vanderbilt University School of Medicine and the Nashville Veterans
Administration Hospital, Nashville, Tennessee 37232
In the liver, glucocorticoids induce a
10-15-fold increase in the rate of transcription of the
phosphoenolpyruvate carboxykinase (PEPCK) gene, which encodes a key
gluconeogenic enzyme. This induction requires a multicomponent
glucocorticoid response unit (GRU) comprised of four glucocorticoid
accessory factor (AF) elements and two glucocorticoid receptor binding
sites. We show that the AFs that bind the gAF1, gAF2, and gAF3 elements
(hepatocyte nuclear factor [HNF]4/chicken ovalbumin upstream
promoter transcription factor 1 and HNF3
Role of Accessory Factors and Steroid Receptor Coactivator
1 in the Regulation of Phosphoenolpyruvate Carboxykinase Gene
Transcription by Glucocorticoids*
) all interact with steroid
receptor coactivator 1 (SRC1). This suggests that the AFs function in
part by recruiting coactivators to the GRU. The binding of a GAL4-SRC1
chimeric protein completely restores the glucocorticoid induction that
is lost when any one of these elements is replaced with a GAL4 binding site. Thus, when SRC1 is recruited directly to gAF1, gAF2, or gAF3, the
requirement for the corresponding AF is bypassed. Surprisingly, glucocorticoid receptor is still required when SRC1 is recruited directly to the GAL4 site, suggesting a role for the receptor in
activating SRC1 in the context of the GRU. Structural variants of
GAL4-SRC1 were used to identify requirements for the
basic-helix-loop-helix and histone acetyltransferase domains of
SRC1, and these are specific to the region of the promoter to which the
coactivator is recruited.
*
This work was supported by National Institutes of Health
Grants DK20593 (Vanderbilt Diabetes Research and Training Center), DK35107, and GM07347 (Vanderbilt Medical Scientist Training Program) and the Veterans Administration Research Service.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 Molecular
Physiology and Biophysics, 707 Light Hall, Vanderbilt University School
of Medicine, Nashville, TN 37232. Tel.: 615-322-7004; Fax: 615-322-7236; E-mail: daryl.granner@mcmail.vanderbilt.edu.
Copyright © 2001 by The American Society for Biochemistry and Molecular Biology, Inc.
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