| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
|
|
|
|||||||
|
|||||||||
J Biol Chem, Vol. 273, Issue 47, 30847-30850, November 20, 1998
,§, andFrom the Department of Molecular Physiology and Biophysics, Vanderbilt University Medical Center, Nashville, Tennessee 37232-0615
 |
ABSTRACT |
|---|
Top
Abstract
Introduction
Procedures
Results
Discussion
References
|
|---|
Hepatocyte nuclear factor-4 (HNF4), a member of
the nuclear receptor superfamily, plays an important role in
tissue-specific gene expression, including genes involved in hepatic
glucose metabolism. In this study, we show that SRC-1 and GRIP1, which
act as coactivators for various nuclear receptors, associate with HNF4
in vivo and enhance its transactivation potential. The AF-2
domain of HNF4 is required for this interaction and for the
potentiation of transcriptional activity by these coactivators. p300
can also serve as a coactivator with HNF4, and it synergizes with SRC-1
to further augment the activity of HNF4. HNF4 is also a key regulator
of the expression of hepatocyte nuclear factor-1 (HNF1). The
overexpression of SRC-1 or GRIP1 enhances expression from a HNF1 gene
promoter-reporter in HepG2 hepatoma cells, and this requires an intact
HNF4-binding site in the HNF1 gene promoter. Type 1 maturity onset
diabetes of young (MODY), which is characterized by abnormal
glucose-mediated insulin secretion, is caused by mutations of the HNF4
gene. A mutation of the HNF4-binding site in the HNF1 gene promoter has also been associated with MODY. Thus, HNF4 is involved in the regulation of glucose homeostasis at several levels and along with the
SRC-1, GRIP1, and p300 may play an important role in the
pathophysiology of non-insulin-dependent diabetes mellitus.
Hepatocyte nuclear
factor-41
(HNF4),2 a member of the
nuclear receptor superfamily, is primarily expressed in liver, gut,
kidney, and pancreas (1). Fatty acyl-CoA thioesters have recently been identified as ligands of HNF4 (2), a finding of considerable interest
in view of the critical role HNF4 plays in the expression of genes
important in a number of metabolic pathways (1). For example, HNF4
serves as an accessory factor for the glucocorticoid-mediated induction
of the phosphoenolpyruvate carboxykinase gene and is necessary for the
glucose-mediated increase of liver-type pyruvate kinase gene
transcription (3-5). HNF4 also plays an essential role in embryonic
development. Disruption of the HNF4 gene in mice results in an
embryonic lethal phenotype characterized by a failure of the visceral
endoderm to differentiate (6). Furthermore, HNF4 plays a critical role
in the regulation of several liver genes. It also stimulates the
expression of another liver-enriched transcription factor, HNF1, which
itself is required for the expression of several liver genes (7,
8).
Maturity onset diabetes of young (MODY) is a rare form of
non-insulin-dependent diabetes mellitus (NIDDM)
characterized by defective secretion of insulin. It is inherited in an
autosomal dominant pattern. Mutations of the HNF4 and HNF1 genes are
directly associated with MODY types 1 and 3, respectively (9, 10), and
a mutation that disrupts the HNF4-binding site on the HNF1 gene
promoter has been reported in an Italian MODY family (11). Thus,
through their effects in liver and beta cells, HNF4 and HNF1 have
central roles in glucose homeostasis.
In this study we tested whether the transcriptional activity of HNF4
requires an interaction with a coregulator molecule. HNF4 contains two
transactivation domains, designated AF-1 and AF-2. AF-1 is located in
the first 24 amino acids of the N-terminal region of the protein,
whereas AF-2 extends from amino acids 128 to 370 (12). Several
coactivators, including CBP/p300, SRC-1, and members of the
SRC-1-related family such as GRIP1/TIF2 or ACTR/RAC3/P/CIP interact
with the AF-2 domains of other members of the nuclear receptor
superfamily and augment their transactivation potential (13-20). A
physical and functional interaction between CBP and HNF4 has been
recently reported (21). We show that SRC-1 and GRIP1 directly associate
with the AF-2 domain of HNF4 in vivo and that these
coactivators potentiate the transcriptional activity of HNF4.
Furthermore, overexpression of SRC-1 or GRIP1 in HepG2 hepatoma cells
enhances HNF1 gene expression, and this effect is dependent on the
presence of an HNF4-binding site in the promoter. We propose that
HNF4-coactivator interactions play a critical role in the regulation of
glucose homeostasis and thus could be of importance in the
pathophysiology of NIDDM.
Plasmid Construction--
The expression plasmids that encode
the GAL4 DNA-binding domain-HNF4 fusion proteins were generated by
subcloning PCR-amplified DNA fragments into the simian virus 40 (SV40)
promoter-enhancer-driven GAL4 expression plasmid, pSG424 (22). The HNF4
cDNA was provided by Dr. Frances Sladek (University of California
at Riverside). Briefly, the nucleotide sequences of rat HNF4
corresponding to amino acids 1-374, 1-360, and 128-374 were
amplified by the PCR, so that the fragments contained BamHI
and KpnI sites at the 5'- and 3'-ends, respectively. These
distinct PCR fragments were then digested and subcloned into the
BamHI-KpnI site of pSG424. The reporter plasmid
(GAL4)5E1bLuc was provided by Dr. Kazuya Yamada (Fukui
Medical University, Japan) and was constructed by taking the
BamHI/XhoI fragment from
(GAL4)5E1bCAT (23), making it blunt-ended using the Klenow
reaction, and subcloning this into the SmaI site of the pGL3
vector. The expression plasmids that encode p300 and GRIP1 have been
previously described (24, 25) and were obtained from Dr. David
Livingston (Dana Farber Institute, Boston) and Dr. Michael Stallcup
(University of Southern California, Los Angeles), respectively. The
SRC-1 expression plasmid was provided by Dr. Ming-Jer Tsai (Baylor
Collage of Medicine). The HNF1 gene promoter reporter plasmids were
provided by Dr. Naoyuki Miura (Akita University, Japan) and have been
previously described (8).
The yeast expression plasmids encoding the GAL4-HNF4 chimeric proteins
(called pGBT9-HNF4(128-374) and pGBT9-HNF4(128-360)) were generated
by the subcloning of EcoRI-BamHI PCR-amplified DNA fragments into the pGBT9 plasmid (CLONTECH).
The yeast expression vectors that encode fusion proteins of the GAL4 AD
and full-length GRIP1 and SRC-1 (called pGAD424 GRIP1/FL and pGAD424
SRC-1) were described previously (24).
Cell Culture, Transient Transfection, and Luciferase
Assays--
The transient transfection and maintenance of HepG2 and
HeLa cells have been described previously (24, 25). Luciferase activity
was measured by the dual luciferase kit (Promega).
Yeast Two-hybrid Assays--
Protein-protein interaction assays
were performed using the Matchmaker yeast two-hybrid system
(CLONTECH). A yeast plasmid, pGBT9-HNF4(128-374)
or pGBT9-HNF4(128-360), was transformed into the yeast strain SFY526,
and transformants were selected on synthetic dropout medium lacking
Trp. Yeast plasmids, pGAD424 GRIP1/FL and pGAD424 SRC-1, were then
transformed into the yeast strain SFY526 that contained either
pGBT9-HNF4(128-374) or pGBT9-HNF4(128-360). The transformants were
selected on synthetic dropout medium lacking Leu and Trp. The colonies
that grew in these selection media were subjected to colony filter
assays, as described in the technical manual of the Matchmaker yeast
two-hybrid system (CLONTECH).
The GAL4 system, previously used to identify the transactivation
domains of HNF4 (12), was used to determine whether SRC-1 and GRIP1
function as coactivators with HNF4. Expression plasmids that encode
either SRC-1 or GRIP1 were cotransfected into HepG2 hepatoma cells with
plasmids that encode the GAL4-HNF4 fusion proteins described under
"Experimental Procedures" and with a reporter gene,
(GAL4)5E1bLuc, that contains five copies of the GAL4-binding site. The activity of each GAL4-HNF4 chimeric protein was
measured relative to that of the GAL4-DBD. Overexpression of SRC-1 and
GRIP1 did not augment the transcriptional activity provided by GAL4-DBD
in this system (Fig. 1, A and
B). As noted previously, GAL4-HNF4(1-374) and
GAL4-HNF4(128-374) both possess a strong transactivation function,
whereas GAL4-HNF4(1-360), because of the absence of the AF-2 domain,
is a weaker transactivator (Fig. 1A and Ref. 12). The
transcriptional activity of GAL4-HNF4(1-374), which contains both the
AF-1 and AF-2 activation domains but lacks the C-terminal repression
domain, is increased about 3-fold by overexpression of SRC-1 (Fig.
1A). The transcriptional activity of GAL4-HNF4(128-374),
which contains only the AF-2 activation domain, was also augmented
about 3-fold by overexpression of SRC-1 (Fig. 1A). In
contrast, the transcriptional activity of GAL4-HNF4(1-360), which
contains the AF-1 domain but lacks the AF-2 domain, was not influenced
by the overexpression of SRC-1 (Fig. 1A). Overexpression of
GRIP1 also increased the transcriptional activity of GAL4-HNF4(1-374) and GAL4-HNF4(128-374) but had no effect on that of GAL4-HNF4(1-360) (Fig. 1A). The effect of SRC-1 is consistently greater than
that of GRIP-1, although significantly so only in the case of
GAL4-HNF4(1-374). These results show that both SRC-1 and GRIP1 can act
as coactivators with HNF4 and that these effects are dependent on the
presence of the AF-2 domain in HNF4.
INTRODUCTION
Top
Abstract
Introduction
Procedures
Results
Discussion
References
EXPERIMENTAL PROCEDURES
Top
Abstract
Introduction
Procedures
Results
Discussion
References
RESULTS
Top
Abstract
Introduction
Procedures
Results
Discussion
References
View larger version (26K):
[in a new window]
Fig. 1.
SRC-1 and GRIP1 potentiate the activity of
GAL4-HNF4 fusion proteins. A, expression plasmids that
encode SRC-1 or GRIP1 (5 µg) and GAL4-HNF4 fusion proteins (0.5 µg)
were cotransfected into HepG2 cells along with the reporter construct
(GAL4)5E1bLuc (2.5 µg). The transcriptional activity of
each GAL4-HNF4 fusion protein is expressed as the -fold increase
relative to the activity of the GAL4-DBD. The additional increase of
activity provided by SRC-1 or GRIP1 is presented relative to the
activity of the GAL4-HNF4 fusion proteins obtained when equal amounts
of DNA from the control vectors were transfected. These results
represent the mean ± S.E. of at least three experiments.
B, expression plasmids that encode SRC-1 or GRIP1 (10 µg)
and the GAL4-HNF4 fusion proteins (2 µg) were cotransfected into HeLa
cells with (GAL4)5E1bLuc (2 µg). The data are presented
as described above.
We next tested the ability of SRC-1 and GRIP1 to potentiate the transcriptional activities of these three GAL4-HNF4 fusion proteins in HeLa cells to determine whether this phenomenon is cell type-specific. SRC-1 and GRIP1 both increased the transactivation function of GAL4-HNF4(1-374) and GAL4-HNF4(128-374) but had no effect on that of GAL4-HNF4(1-360) (Fig. 1B). Thus, the effect of SRC-1 and GRIP1 on the transcriptional activity of HNF4 is not cell type-specific. SRC-1 was again a more potent coactivator than GRIP-1. These differences could be because of the different expression levels of these two coactivators in the cells or could reflect a difference in the strength of the interactions.
The yeast two-hybrid assay was used to test for an in vivo
interaction between HNF4 and either SRC-1 or GRIP1. The expression of
the GAL4-HNF4(128-374) or the GAL4-HNF4(128-360) fusion proteins in
yeast cells failed to activate reporter gene activity
(
-galactosidase, data not shown). Thus, neither of these chimeric
proteins possesses transcriptional activity in yeast. -Galactosidase
activity was also not observed when a plasmid (pGAD424) that encodes
the GAL4 AD was coexpressed with either of the GAL4-HNF4 fusion
proteins (data not shown). However, -galactosidase activity was
strongly induced when a chimeric protein that contained the GAL4 AD and SRC-1 or GRIP1 was coexpressed with GAL4-HNF4(128-374) (Fig.
2). In colony filter assays, yeast that
contained the GAL4 AD and SRC-1 fusion protein and GAL4-HNF4(128-374)
turned blue 30 min after initiation of the reaction (Fig.
2A). In contrast, yeast that contained the GAL4 AD-GRIP1
fusion protein and GAL4-HNF4(128-374) turned blue 4 h after
initiation of the assay (Fig. 2B). Thus, the interaction
between SRC-1 and HNF4 is stronger than between GRIP1 and HNF4.
Coexpression of the GAL4 AD-SRC-1 or GAL4 AD-GRIP1 fusion proteins with
GAL4-HNF4(128-360) did not induce -galactosidase activity (Fig. 2,
C and D). These results suggest that SRC-1 and GRIP1 both interact with HNF4 and that these interactions are dependent
on the presence of the AF-2 domain of HNF4. These results are consonant
with the functional results shown in Fig. 1.
|
CBP is known to associate with HNF4, and it potentiates the activity of a reporter construct that contains multiple HNF4-binding sites (21). We therefore tested whether p300, another member of the CBP coactivator family, potentiates the transcriptional activity of GAL4-HNF4 chimeric proteins. Overexpression of p300 in HeLa cells does enhance the activity of GAL4-HNF4(128-374) but not that of GAL4-HNF4(1-360) (Fig. 3). Thus, coactivation of HNF4 by p300 also requires an intact AF-2 domain. The transcriptional activity of GAL4-HNF4(128-374) was further enhanced when both p300 and SRC-1 were overexpressed in HeLa cells (Fig. 3), as has been reported in the analysis of other nuclear receptors (20, 28).
|
HNF4 binds to its cognate DNA element in the HNF1 gene promoter and
enhances transcription through this interaction (7, 8). The
coexpression of SRC-1 or GRIP1 should enhance expression from the HNF1
promoter if the HNF4-coregulator interaction is functionally important.
In fact, the overexpression of SRC-1 in HepG2 hepatoma cells increased
HNF1 gene promoter activity by about 3-fold (Fig.
4). Overexpression of GRIP1 was slightly
less effective (Fig. 4). Deletion of the HNF4-binding site in the HNF1 promoter (HNF4
A) resulted in a 90% reduction of
expression, as expected (8), and the overexpression of either SRC-1 or GRIP1 was without effect when a construct containing this element was
used as the promoter in the reporter system (Fig. 4).
|
| |
DISCUSSION |
|---|
|
Top
Abstract
Introduction
Procedures
Results
Discussion
References
|
|---|
The transcription factor HNF4, a member of the nuclear receptor superfamily, is important for tissue-specific gene expression, including several genes involved in hepatic glucose metabolism (1). We now show that both SRC-1 and GRIP1 interact with HNF4 (Fig. 2) and potentiate its transcriptional activity (Fig. 1). Both are presumably active in vivo, and given the high degree of homology between SRC-1, GRIP1, and other SRC-1-related coactivators such as RAC3, ACTR, and P/CIP, it is possible that these proteins can also function as coactivators for HNF4. It is not known why most tissues express all these coactivators, but they could have selective actions. For example, SRC-1 has been implicated in the action of androgens. The expression of GRIP1 is increased about 2-fold in knockout mice that lack the SRC-1 gene, apparently in compensation for the loss of SRC-1, but these mice still display a partial resistance to the action of androgens (29). These coactivators are thus not completely interchangeable. It is possible that specific coactivators, or different ratios of various of these proteins in cells, result in selective interaction with nuclear receptors, including HNF4.
CBP/p300 serves as a coactivator with most members of the nuclear hormone receptor family (13, 17, 30-32). As shown in this paper, p300 enhances the transactivation function of GAL4-HNF4(128-374). This coactivation effect is dependent on an intact AF-2 domain, which is also required for the interaction of SRC-1 and GRIP1 with HNF4. In addition, p300 acts synergistically with SRC-1 or GRIP1 to further enhance the transcriptional activity of HNF4. A similar phenomenon has been observed with other nuclear receptors (20, 28). Recent studies suggest that transactivation by nuclear receptors requires the formation of a complex with coactivators (32-34). These coactivator complexes can contain SRC-1/GRIP1, p300/CBP, and other coactivators such as P/CAF (34, 35). SRC-1 and GRIP1 have both been shown to directly associate with CBP/p300 (13, 34-36). Moreover, many of these proteins possess histone acetyltransferase activity (34, 37-39). The histone acetylase activity of P/CAF is required for the retinoic acid-mediated induction of gene transcription (34, 40). A two-step model that first requires chromatin remodeling by histone acetylation and then an interaction with the general transcription apparatus has been proposed to explain how this coactivator complex mediates the transactivation of nuclear receptors (32). It is possible that a similar mechanism is required for the action of HNF4, which serves as an accessory factor in the glucocorticoid response unit of the phosphoenolpyruvate carboxykinase gene (5).
HNF4 appears to have a pleiotropic effect on the regulation of glucose homeostasis. The mechanism of HNF4 gene mutations in the pathophysiology of MODY (type 1) has not been established, but it is of interest to note that HNF4 is required for expression of HNF1, another MODY gene (type 3) (7-9). Indeed, at least one MODY pedigree is because of a mutation of the HNF4-binding site in the HNF1 gene promoter. The common denominator of MODY type 1 and 3 may be the loss of HNF1 gene function. In this regard, it may be noteworthy that we found that overexpression of both SRC-1 and GRIP1 increases the activity of the HNF1 gene promoter, and a mutation of the HNF4 DNA-binding site in this promoter disrupts this effect.
In addition to its apparent role in insulin secretion (10) and a
demonstrated role in the regulation of hepatic gene expression (1),
HNF4 also regulates the expression of other genes (e.g. glucose transporter 2 (Glut 2), aldolase B, and pyruvate kinase that
are involved in glucose transport and glucose metabolism in embryonic
stem cells and in embryos (41)). The observation that fatty acyl-CoA
thioesters are HNF4 ligands (2) provides support for the connection
between HNF4 and glucose homeostasis because fatty acids affect the
regulation of glucose metabolism by decreasing peripheral glucose
utilization, increasing hepatic gluconeogenesis, and influencing
insulin secretion and pancreatic cell hyperplasia (42-44). Ligands
affect the binding of nuclear receptors to target DNA sequences but
also influence the interactions of these receptors with coactivators or
corepressors (34, 45). This phenomenon, along with the potential role
of these coactivators in NIDDM, is an interesting area for future investigation.
| |
ACKNOWLEDGEMENTS |
|---|
We thank Don Scott and Marc Daniels for a critical reading of this manuscript, Cathy Caldwell for technical assistance, and Deborah C. Brown for helping prepare this manuscript.
| |
FOOTNOTES |
|---|
* This work was supported by National Institutes of Health Grants DK 20593 (the Vanderbilt Diabetes Research and Training Center) and DK 35107.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.
These authors contributed equally to the work presented in this paper.
§ Supported by National Institutes of Health Grant GM07347, the Vanderbilt Medical Scientist Training Program.
¶ To whom correspondence should be addressed. Tel.: 615-322-7004; Fax: 615-322-7236; E-mail: daryl.granner{at}mcmail.vanderbilt.edu.
The abbreviations used are: HNF, hepatocyte nuclear factor; MODY, maturity onset diabetes of young; NIDDM, non-insulin-dependent diabetes mellitus; PCR, polymerase chain reaction; AD, activation domain; DBD, DNA-binding domain.
1
HNF4 and HNF1 exist as multiple isoforms. In
this paper we are referring to the 
isoform of each protein.
| |
REFERENCES |
|---|
|
Top
Abstract
Introduction
Procedures
Results
Discussion
References
|
|---|
CiteULike 
Complore 
Connotea 
Del.icio.us 
Digg 
Reddit 
Technorati What's this?
This article has been cited by other articles:
|
|
 |
|
  L. W. Harries, J. M. Locke, B. Shields, N. A. Hanley, K. P. Hanley, A. Steele, P. R. Njolstad, S. Ellard, and A. T. Hattersley The Diabetic Phenotype in HNF4A Mutation Carriers Is Moderated By the Expression of HNF4A Isoforms From the P1 Promoter During Fetal Development Diabetes, June 1, 2008; 57(6): 1745 - 1752. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. G. Holloway, G. D. Miles, A. A. Dombkowski, and D. J. Waxman Liver-Specific Hepatocyte Nuclear Factor-4{alpha} Deficiency: Greater Impact on Gene Expression in Male than in Female Mouse Liver Mol. Endocrinol., May 1, 2008; 22(5): 1274 - 1286. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T. Onica, K. Nichols, M. Larin, L. Ng, A. Maslen, Z. Dvorak, J.-M. Pascussi, M.-J. Vilarem, P. Maurel, and G. M. Kirby Dexamethasone-Mediated Up-Regulation of Human CYP2A6 Involves the Glucocorticoid Receptor and Increased Binding of Hepatic Nuclear Factor 4{alpha} to the Proximal Promoter Mol. Pharmacol., February 1, 2008; 73(2): 451 - 460. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 G. Schafer, C. Wissmann, J. Hertel, V. Lunyak, and M. Hocker Regulation of Vascular Endothelial Growth Factor D by Orphan Receptors Hepatocyte Nuclear Factor-4{alpha} and Chicken Ovalbumin Upstream Promoter Transcription Factors 1 and 2 Cancer Res., January 15, 2008; 68(2): 457 - 466. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
B. Ponugoti, S. Fang, and J. K. Kemper Functional Interaction of Hepatic Nuclear Factor-4 and Peroxisome Proliferator-Activated Receptor-{gamma} Coactivator 1{alpha} in CYP7A1 Regulation Is Inhibited by a Key Lipogenic Activator, Sterol Regulatory Element-Binding Protein-1c Mol. Endocrinol., November 1, 2007; 21(11): 2698 - 2712. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 G. Benoit, A. Cooney, V. Giguere, H. Ingraham, M. Lazar, G. Muscat, T. Perlmann, J.-P. Renaud, J. Schwabe, F. Sladek, et al. International Union of Pharmacology. LXVI. Orphan Nuclear Receptors Pharmacol. Rev., December 1, 2006; 58(4): 798 - 836. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. P. Martinez-Jimenez, M. J. Gomez-Lechon, J. V. Castell, and R. Jover Underexpressed Coactivators PGC1{alpha} AND SRC1 Impair Hepatocyte Nuclear Factor 4{alpha} Function and Promote Dedifferentiation in Human Hepatoma Cells J. Biol. Chem., October 6, 2006; 281(40): 29840 - 29849. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Miao, S. Fang, Y. Bae, and J. K. Kemper Functional Inhibitory Cross-talk between Constitutive Androstane Receptor and Hepatic Nuclear Factor-4 in Hepatic Lipid/Glucose Metabolism Is Mediated by Competition for Binding to the DR1 Motif and to the Common Coactivators, GRIP-1 and PGC-1{alpha} J. Biol. Chem., May 26, 2006; 281(21): 14537 - 14546. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J.-W. Jeong, I. Kwak, K. Y. Lee, L. D. White, X.-P. Wang, F. C. Brunicardi, B. W. O'Malley, and F. J. DeMayo The Genomic Analysis of the Impact of Steroid Receptor Coactivators Ablation on Hepatic Metabolism Mol. Endocrinol., May 1, 2006; 20(5): 1138 - 1152. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
B. T. Vander Kooi, H. Onuma, J. K. Oeser, C. A. Svitek, S. R. Allen, C. W. Vander Kooi, W. J. Chazin, and R. M. O'Brien The Glucose-6-Phosphatase Catalytic Subunit Gene Promoter Contains Both Positive and Negative Glucocorticoid Response Elements Mol. Endocrinol., December 1, 2005; 19(12): 3001 - 3022. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K. B. Scribner, D. P. Odom, and M. M. McGrane Vitamin A Status in Mice Affects the Histone Code of the Phosphoenolpyruvate Carboxykinase Gene in Liver J. Nutr., December 1, 2005; 135(12): 2774 - 2779. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Rada-Iglesias, O. Wallerman, C. Koch, A. Ameur, S. Enroth, G. Clelland, K. Wester, S. Wilcox, O. M. Dovey, P. D. Ellis, et al. Binding sites for metabolic disease related transcription factors inferred at base pair resolution by chromatin immunoprecipitation and genomic microarrays Hum. Mol. Genet., November 15, 2005; 14(22): 3435 - 3447. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. Iordanidou, E. Aggelidou, C. Demetriades, and M. Hadzopoulou-Cladaras Distinct Amino Acid Residues May Be Involved in Coactivator and Ligand Interactions in Hepatocyte Nuclear Factor-4{alpha} J. Biol. Chem., June 10, 2005; 280(23): 21810 - 21819. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Bhalla, C. Ozalp, S. Fang, L. Xiang, and J. K. Kemper Ligand-activated Pregnane X Receptor Interferes with HNF-4 Signaling by Targeting a Common Coactivator PGC-1{alpha}: FUNCTIONAL IMPLICATIONS IN HEPATIC CHOLESTEROL AND GLUCOSE METABOLISM J. Biol. Chem., October 22, 2004; 279(43): 45139 - 45147. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
E. Aggelidou, P. Iordanidou, P. Tsantili, G. Papadopoulos, and M. Hadzopoulou-Cladaras Critical Role of Residues Defining the Ligand Binding Pocket in Hepatocyte Nuclear Factor-4{alpha} J. Biol. Chem., July 16, 2004; 279(29): 30680 - 30688. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J.-C. Wang, A. Walker, T. K. Blackwell, and K. R. Yamamoto The Caenorhabditis elegans Ortholog of TRAP240, CeTRAP240/let-19, Selectively Modulates Gene Expression and Is Essential for Embryogenesis J. Biol. Chem., July 9, 2004; 279(28): 29270 - 29277. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
B. Herzog, R. K. Hall, X. L. Wang, M. Waltner-Law, and D. K. Granner Peroxisome Proliferator-Activated Receptor {gamma} Coactivator-1{alpha}, as a Transcription Amplifier, Is Not Essential for Basal and Hormone-Induced Phosphoenolpyruvate Carboxykinase Gene Expression Mol. Endocrinol., April 1, 2004; 18(4): 807 - 819. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. Eeckhoute, B. Oxombre, P. Formstecher, P. Lefebvre, and B. Laine Critical role of charged residues in helix 7 of the ligand binding domain in Hepatocyte Nuclear Factor 4{alpha} dimerisation and transcriptional activity Nucleic Acids Res., November 15, 2003; 31(22): 6640 - 6650. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. Hertz, N. Ben-Haim, A. D. Petrescu, B. Kalderon, I. Berman, N. Eldad, F. Schroeder, and J. Bar-Tana Rescue of MODY-1 by Agonist Ligands of Hepatocyte Nuclear Factor-4{alpha} J. Biol. Chem., June 13, 2003; 278(25): 22578 - 22585. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. Eeckhoute, E. Moerman, T. Bouckenooghe, B. Lukoviak, F. Pattou, P. Formstecher, J. Kerr-Conte, B. Vandewalle, and B. Laine Hepatocyte Nuclear Factor 4{alpha} Isoforms Originated from the P1 Promoter Are Expressed in Human Pancreatic {beta}-Cells and Exhibit Stronger Transcriptional Potentials than P2 Promoter-Driven Isoforms Endocrinology, May 1, 2003; 144(5): 1686 - 1694. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 N. Rouleau, S. Turcotte, M.-H. Mondou, P. Roby, and R. Bosse Development of a Versatile Platform for Nuclear Receptor Screening Using AlphaScreenTM J Biomol Screen, April 1, 2003; 8(2): 191 - 197. [Abstract] [PDF]
|
|
|
|
|
|
L. Jackson-Hayes, S. Song, E. N. Lavrentyev, M. S. Jansen, F. B. Hillgartner, L. Tian, P. A. Wood, G. A. Cook, and E. A. Park A Thyroid Hormone Response Unit Formed between the Promoter and First Intron of the Carnitine Palmitoyltransferase-Ialpha Gene Mediates the Liver-specific Induction by Thyroid Hormone J. Biol. Chem., February 28, 2003; 278(10): 7964 - 7972. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Malik, A. E. Wallberg, Y. K. Kang, and R. G. Roeder TRAP/SMCC/Mediator-Dependent Transcriptional Activation from DNA and Chromatin Templates by Orphan Nuclear Receptor Hepatocyte Nuclear Factor 4 Mol. Cell. Biol., August 1, 2002; 22(15): 5626 - 5637. [Abstract] [Full Text] [PDF]
|
|
A) (