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Molecular and Cellular Biology, April 2000, p. 2411-2422, Vol. 20, No. 7
Division of Biochemistry, Biozentrum of the
University of Basel, CH-4056 Basel, Switzerland
Received 1 November 1999/Returned for modification 12 December
1999/Accepted 3 January 2000
Steroid receptors mediate responses to lipophilic hormones in a
tissue- and ligand-specific manner. To identify nonreceptor proteins
that confer specificity or regulate steroid signaling, we screened a
human cDNA library in a steroid-responsive yeast strain. One of the
identified cDNAs, isolated in the screen as ligand effect modulator 6, showed no homology to yeast or Caenorhabditis elegans
proteins but high similarity to the recently described mouse
coactivator PGC-1 and was accordingly termed hPGC-1. The hPGC-1 DNA
encodes a nuclear protein that is expressed in a tissue-specific manner
and carries novel motifs for transcriptional regulators. The expression
of hPGC-1 in mammalian cells enhanced potently the transcriptional
response to several steroids in a receptor-specific manner.
hPGC-1-mediated enhancement required the receptor hormone-binding domain and was dependent on agonist ligands. Functional analysis of
hPGC-1 revealed two domains that interact with steroid receptors in a
hormone-dependent manner, a potent transcriptional activation function,
and a putative dimerization domain. Our findings suggest a regulatory
function for hPGC-1 as a tissue-specific coactivator for a subset of
nuclear receptors.
Steroid hormones play important
roles in development, growth, glucose and mineral homeostasis, stress
responses, sexual differentiation, and reproduction. The effects of
steroids are mediated by intracellular receptors that, together with
receptors for thyroid hormones, retinoids, vitamin D, and other small
lipophilic molecules, belong to the superfamily of nuclear receptors
(2, 43). Binding of hormone to these receptors triggers a
conformational change that leads to the release of associated proteins,
such as molecular chaperones or corepressors, recruitment of new
proteins, such as coactivators, binding to specific DNA sites termed
hormone response elements (HREs), and regulation of transcription from promoters in the vicinity of the HREs (reviewed in references 2, 47, 61, and 75).
The major determinant of the ability of a cell to respond to a specific
steroid hormone is the presence of the cognate receptor. In addition,
nonreceptor proteins contribute to the cellular response by enabling or
regulating distinct steps in the hormone response pathway. For example,
membrane proteins that regulate the transport of hormone across the
plasma membrane modify the availability of hormone to the intracellular
receptors (32, 63); chaperones such as Hsp90 and p23
interact with steroid receptors in the absence of hormone and support a
receptor conformation competent for hormone binding (reviewed in
reference 61); DNA-binding proteins such as HMG-1
enhance the ability of steroid receptors to bind DNA (3, 57,
80); and the chromatin-remodeling SWI-SNF complex enables steroid
receptors to regulate transcription (6, 14, 49, 78).
Finally, several nuclear proteins are recruited by the receptors in a
hormone-dependent manner and are thought to mediate their
transcriptional regulatory activity (reviewed in references
13, 47, and 75). Among them,
corepressors such as SMRT and NcoR bind to receptors in the absence of
hormone or the presence of an antagonist ligand, connect the receptors
to histone deacetylases, and promote the silencing of neighboring promoters (9, 21, 23, 35, 51). In contrast, coactivators (e.g., SRC-1 [also called NcoA1], TIF2 [the human homologue of mouse
GRIP1, also known as NcoA2], pCIP [also known as AIB1, ACTR, and
RAC3], CREB-binding protein [CBP], p300, pCAF, and others) are
recruited by hormone-activated receptors and enhance transcription (13, 69, 75). At least some of these coactivators are
acetyltransferases that can modify histones or other target proteins
and may increase promoter access to DNA-binding proteins and the
transcriptional machinery (1, 8, 56, 68, 77).
The identification of nonreceptor proteins that participate in hormone
signaling provides insights not just into the mechanism of
receptor-mediated transcription but also into ways in which the
response to hormone can be regulated. Responses to steroid hormones are
often tissue specific and sensitive to other signaling pathways. For
example, the activation of protein kinase A modulates glucocorticoid
responsiveness in a cell type-dependent manner (48, 55).
Proteins that regulate the hormone response may confer tissue
specificity to ubiquitously expressed receptors, if present in only
some cell types, or integrate signaling information, if targeted by
other signaling pathways. However, among the known nonreceptor
proteins, few of them are expressed in a tissue-specific manner (e.g.,
ACTR) (8) or respond to other signals (e.g., CBP) (7,
41, 52).
Functional genetic strategies in easily manipulatable systems are
powerful tools for identifying modulators that act at any step of a
regulatory circuit. Although steroid receptors are not naturally
present in the yeast Saccharomyces cerevisiae, the basic machinery of this organism is permissive to their function (46, 65). We have taken advantage of the ability of steroid receptors to mediate hormone-dependent transcription in yeast to identify proteins that can regulate hormone responsiveness. In previous genetic
screens, we isolated yeast mutants and identified genes (LEM1 to LEM4, for ligand effect modulator) that
negatively regulate responses to hormones (31; R. Sitcheran, R. Emter, A. Kralli, and K. R. Yamamoto, submitted for
publication). In this study, we use a genetic scheme to identify
directly mammalian proteins that enhance responses to glucocorticoid
hormones. In principle, the screen can reveal both conserved proteins,
whose yeast homologues are limiting or do not optimally interact with
the mammalian receptor, and mammal-specific modulators, which may have
evolved to confer specificity and regulation to steroid hormone responses.
Yeast strains and cDNA library screening.
The yeast strain
used in the cDNA library screen, YNK441, is a derivative of YPH499
(67) that has the endogenous HIS3 gene under the
control of three copies of glucocorticoid response elements (GREs) from
the tyrosine aminotransferase gene (26), a
(GRE)×3-LACZ reporter cassette integrated at a disrupted
pdr5::LEU2 locus (31), and a rat
glucocorticoid receptor (GR) expression cassette integrated at the
TRP1 locus. Integrations at the genomic loci were done sequentially, using the one-step replacement method (64) and DNA fragments from plasmids phis3::(GRE)×3-HIS3 (gift of J. Iniguez-Lluhi), pleu2::(GRE)×3-LACZ, and
pBS/trp1::GR. Further information on these plasmids is
available upon request. For the screen, YNK441 was transformed with a
yeast expression HepG2 cDNA library (URA3, 2µm)
(66) by a high-efficiency lithium acetate method (Technical Tips Online [http://tto.trends.com]) and plated on minimal medium lacking histidine and uracil and containing 15 mM 3-aminotriazole and
either 4 µM dexamethasone or 0.5 µM corticosterone. Of 5.5 × 106 transformants, 719 grew and were analyzed for the
Isolation of LEM6 (hPGC-1) cDNA.
Sequencing of the
LEM6H cDNAs isolated in the screen revealed two long open
reading frames (ORFs) that were out of frame with each other and
predicted the expression of a 272-amino-acid (aa) protein from the
first ORF. Using oligonucleotides GCAGTGGTCTCAGTACCC and
GTGGAGTTAGGCCTGCAG, which flank the junction where the two ORFs become discontinuous, and a proofreading DNA polymerase (Vent; New
England Biolabs), we amplified by PCR the LEM6 cDNA from first-strand human liver cDNA (gift of R. Skoda). Sequencing of the amplified fragment showed the existence of one long ORF that had been split into
two out-of-frame ORFs in the library isolate by a 32-bp insertion at
nucleotide 804 (relative to the translation initiation site). The
AatII-PstI 261-bp fragment of the liver LEM6 cDNA
was used to replace the corresponding AatII-PstI
293-bp fragment of the library LEM6H isolate, thereby
giving rise to the full-length clone that was used in subsequent
experiments. The origin of the 32-bp insertion, which was present in
all four LEM6 cDNAs isolated in the screen, has not been further
explored. Sequencing also revealed high identity (95%) between LEM6
and the mouse PGC-1 (peroxisome proliferator-activated receptor gamma
[PPAR Plasmids.
The mammalian expression plasmids for rat GR
(p6RGR, p6RN525, and p6R407C) (17, 18), rat
mineralocorticoid receptor (MR) (p6RMR) (59), and the
Gal4-ligand-binding domain (LBD) fusion [p6R.Gal(74/525)GR] are
SP65-based vectors in which the Rous sarcoma virus promoter drives the
expression of the respective genes. The simian virus 40 early promoter
drives the expression of the human estrogen receptor (ER), androgen
receptor (AR), and steroid receptor coactivator 1e (SRC-1e), the mouse
NF-
0270-7306/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.
A Tissue-Specific Coactivator of Steroid Receptors,
Identified in a Functional Genetic Screen
ABSTRACT
Top
Abstract
Introduction
Materials and Methods
Results
Discussion
References
INTRODUCTION
Top
Abstract
Introduction
Materials and Methods
Results
Discussion
References
MATERIALS AND METHODS
Top
Abstract
Introduction
Materials and Methods
Results
Discussion
References
-galactosidase (-gal) response to hormone. Plate and liquid
-gal assays were performed as described previously (25).
Fifteen isolates showed an increased response to hormone that was lost
when the library plasmid was selected against, on medium containing
5-fluoro-orotic acid. Plasmids were rescued, reintroduced to YNK441 to
confirm their activity, and sequenced. The 15 plasmids carried three
types of cDNA, encoding p23 (10×), ligand effect modulator 5 (LEM5) (1×), and the LEM6 HepG2 library isolate (LEM6H) (4×).
] coactivator 1) protein (62). Since LEM6 is the
likely human homologue of PGC-1, it was renamed hPGC-1.
B subunits p50 and p65, and the chimeric activator Gal4-VP16 in
plasmids pSG5ER (72), pSVARo (gift of F. Hamy), pSG5-SRC-1e
(gift of M. Parker) (27), pSG5-p50 and pSG5-RelA(p65) (gift
of R. Nissen), and pSG424/Gal4-VP2, respectively. The luciferase
reporter plasmids pTAT3Luc, pMMTVDLO, and pB3DLO have three copies
of the tyrosine aminotransferase GRE, the mouse mammary tumor virus
(MMTV) long terminal repeat, and three copies of the interleukin 2
receptor NF-B site, respectively, upstream of the minimal alcohol
dehydrogenase promoter (25). The luciferase reporter
plasmids pERE-TK-luc (two copies of the vitellogenin estrogen response
element upstream of the thymidine kinase promoter) and pGK-1 (five Gal4
sites upstream of the E1b minimal promoter) have been described
elsewhere (72).
1 (91-186), EcoRI and
AgeI for hPGC-12L (189-482), EcoRI and
StuI for hPGC-12 (189-293), and NheI and
StuI for hPGC-13 (91-293), treating the DNA ends with
Klenow polymerase and/or mung bean nuclease, and ligating. All
junctions were sequenced.
The full-length or variant HA-hPGC-1 constructs were then subcloned as
BamHI-NotI fragments into the pcDNA3 vector
(Invitrogen) downstream of the cytomegalovirus enhancer, for mammalian
expression; as NcoI-SalI fragments into the pACT2
vector (Clontech) downstream of and in frame to the Gal4 activation
domain (AD) for the expression of AD-hPGC-1 fusions in yeast; and as
NcoI-SalI fragments into the pAS2-1 vector
(Clontech) downstream of and in frame to the Gal4 DNA-binding domain
(DBD), for the expression of Gal4-hPGC-1 fusions in yeast. For
mammalian expression of the chimeric protein Gal4-hPGC-1, the
NdeI-HindIII fragment of pBS/HA-hPGC-1
(lacking the HA epitope sequence and the last three codons of hPGC-1)
was subcloned into vector pA4.7 (gift of Patrick Matthias) downstream of and in frame to the Gal4 DBD and upstream of and in frame to a
C-terminal HA epitope sequence.
Northern analysis.
A human multiple-tissue Northern blot
(Clontech) was hybridized with either a radioactively labeled 0.66-kb
NdeI-PstI fragment of hPGC-1 cDNA or a
-actin-specific probe (Clontech), as recommended by the
manufacturer, and exposed on X-ray film.
Two-hybrid interaction assay.
Plasmids expressing Gal4 DBD
and Gal4 AD fusions (in vectors pAS2-1 and pACT2, respectively) were
introduced by the lithium acetate transformation method (Technical Tips
Online [http://tto.trends.com]) into yeast diploid cells (CG1945 × Y187; Clontech) that carry Gal4-driven LACZ reporters.
Transformants carrying the plasmids were grown to stationary phase in
96-well plates, diluted 1:20 in selective medium (200 µl) containing
either ethanol vehicle (0.25%) or 25 µM hormone (corticosterone or
RU486), grown for an additional 16 to 18 h at 30°C in 96-well
plates, and assayed for -gal activity as described previously
(25).
Cell culture, transient transfections, and reporter gene
assays.
COS7 cells were cultured in Dulbecco's modified Eagle's
medium supplemented with 9% charcoal-stripped fetal bovine serum. For
experiments with the AR or the ER, media lacking phenol red were used.
Cells from subconfluent 10-cm plates were diluted 8- to 10-fold and
seeded in six-well plates 5 h prior to transfection by calcium
phosphate precipitation (25). All transfections included 0.2 µg of p6RlacZ (59) to normalize for transfection
efficiency. Expression vectors for receptors or other DNA-binding
transcription factors were added at either 2 µg (AR and MR), 1 µg
(GR, ER, p50, p65, and Gal4-hPGC-1), or 50 ng (Gal4-VP16) of DNA.
Reporter plasmids were added at either 2 µg (for MR, p50, and p65) or
1 µg (for GR, ER, AR, Gal4-VP16, and Gal4-hPGC-1) of DNA. For the
coactivators, 1 µg of hPGC-1 (or equivalent hPGC-1 variant) or 2 µg
of SRC-1e expression plasmids was used, unless indicated otherwise (1 µg of SRC-1e DNA gave weaker enhancement of steroid receptor activity than 2 µg). After overnight exposure to the DNA-calcium phosphate precipitate, cells were washed with phosphate-buffered saline (PBS)
lacking calcium and magnesium and incubated for an additional 24 h
in fresh media containing either hormone or vehicle (0.1% ethanol).
Cells were then washed with PBS and lysed in 100 µl of reporter lysis
buffer (Promega). Lysates were cleared by centrifugation and assayed
for luciferase activity with the Luciferase Assay System (Promega) and
-gal activity with the substrate chlorophenol red--D-galactopyranoside (25). Luciferase
values normalized to the -gal activity in the extracts are referred
to as luciferase units.
GFP detection and immunofluorescence. COS7 cells were seeded onto 18-mm coverslips and transiently transfected with hPGC-1 expression vectors by use of either the calcium phosphate precipitation method (for green fluorescent protein [GFP]-hPGC-1) or Effectene reagent (for HA-hPGC-1 constructs; used as recommended by the manufacturer, Qiagen). After 48 h, cells were washed with PBS, fixed for 15 min with 3% paraformaldehyde at room temperature, and permeabilized for 10 min with PBS containing 0.1% Triton X-100. Cells were then incubated for 10 min with 1% bovine serum albumin in PBS to block nonspecific binding. For immunodetection, a monoclonal antibody against the HA epitope (HA-11; BabCo) was used at a 1:1,000 dilution in PBS containing 0.5% bovine serum albumin, followed by a rhodamine-conjugated goat anti-mouse antibody (Jackson Immunoresearch Laboratories) at 1:100 in PBS.
Nucleotide sequence accession number. The hPGC-1 sequence has been submitted to the GenBank database under accession no. AF186379.
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RESULTS |
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Top
Abstract
Introduction
Materials and Methods
Results
Discussion
References
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Mammalian modulators of glucocorticoid signaling can be
functionally isolated in yeast.
To identify proteins that enhance
the cellular response to hormone, we exploited a yeast strain whose
growth is dependent on glucocorticoid signaling. For this, the rat GR
was expressed in yeast carrying two reporters under the control of
GREs: the endogenous HIS3 and the bacterial -gal-encoding
gene (Fig. 1A). In the absence of
hormone, the lack of HIS3 expression precludes growth in
selective media. The addition of hormone induces HIS3 and
the -gal gene and restores growth. At suboptimal hormone concentrations insufficient to support growth, the expression of
mammalian proteins that enhance the hormone response will activate HIS3, enable growth in selective media, and induce -gal
production (Fig. 1A).
|
his) and containing the His3 inhibitor 3-aminotriazole (+3AT). The
star-shaped forms indicate some of the possible interaction points for
the mammalian modulators. (B) Mammalian p23, LEM5, and LEM6 (hPGC-1)
enhance the response to corticosterone. Yeast strain YNK441 carrying a
vector alone (control) or expression plasmids for the indicated cDNAs
was incubated overnight with 0, 1, or 10 µM corticosterone and
assayed for -gal response to hormone, in a manner dependent on the presence of
the mammalian cDNA library plasmid (see Materials and Methods). Rescue
of the plasmids and sequencing of the inserts revealed three types of
cDNAs that enhanced the response to hormone in yeast (Fig. 1B). The
first cDNA encoded the molecular chaperone p23, a known component of
the glucocorticoid aporeceptor complex (61), thereby
establishing that the screen can yield factors involved in mammalian
glucocorticoid signaling. The other two cDNAs encoded novel proteins
that we initially named LEM5 and LEM6. This study focuses on LEM6. The
sequence of the LEM6 HepG2 library isolate (LEM6H in Fig.
1B) predicted the expression of a truncated protein. We therefore
isolated additional LEM6 clones from human liver cDNA and constructed a
full-length yeast expression plasmid (see Materials and Methods). As
shown in Fig. 1B, full-length LEM6 also enhanced the receptor-mediated
response to hormone, albeit to a lesser extent.
LEM6 is a tissue-specific nuclear protein and the human homologue
of murine PGC-1.
The full-length LEM6 cDNA sequence predicted a
798-aa protein that shares high identity (95%) with the mouse
coactivator PGC-1 (62), suggesting that it is the human
homologue of PGC-1. We therefore refer to LEM6 as hPGC-1. Like its
mouse homologue, hPGC-1 is characterized by an N-terminal region rich
in acidic amino acids (26.4% of aa 1 to 140), followed by a putative
nuclear receptor interaction motif (LKKLL) at residues 144 to 148 and a
predominantly basic stretch of amino acids at residues 168 to 207 (Fig.
2A). At the C terminus, there are two
serine- and arginine (SR)-rich stretches (aa 566 to 599 and aa 621 to
631) and a putative RNA-binding domain (aa 677 to 753). Putative
nuclear localization signals at residues 326 to 333, 627 to 633, and
651 to 667 predicted a nuclear protein. Indeed, fusion of hPGC-1 to GFP
revealed exclusively nuclear fluorescence in transiently transfected
mammalian cells (Fig. 2B).
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hPGC-1 is a potent activator of receptor-mediated transcription in
mammalian cells.
We isolated hPGC-1 based on its ability to
enhance receptor-mediated transcription in yeast cells. To determine
whether it displays similar activity in mammalian cells, we transiently
transfected COS7 fibroblasts with hPGC-1 and GR expression plasmids and
a GR-responsive luciferase reporter. In the absence of exogenous hPGC-1, the addition of hormones such as corticosterone and
dexamethasone resulted in 50- to 60-fold induction of luciferase
expression (Fig. 3A). Expression of
hPGC-1 enhanced the hormone-induced transcription by another 20- to
60-fold, in a dose-dependent manner with respect to the amount of
hPGC-1 plasmid transfected (Fig. 3A). Similar enhancement profiles were
seen for cells treated with corticosterone, dexamethasone, or
deoxycorticosterone (Fig. 3A and data not shown). Enhancement of
transcription was strictly hormone dependent, as hPGC-1 expression did
not increase luciferase expression in the absence of hormone (Fig. 3B).
|
Specificity of hPGC-1 coactivator function.
We next examined
whether hPGC-1 could enhance hormone responsiveness for other steroid
receptors. As shown in Fig. 4A, hPGC-1 expression enhanced the hormone-dependent transcription mediated by ER
and MR strongly (by ~13- and ~38-fold, respectively) and that by AR
only weakly (~2-fold). The very weak effect of hPGC-1 on AR was
confirmed in three different promoter contexts, the MMTV long terminal
repeat response element (MMTV in Fig. 4A), the tyrosine
aminotransferase HREs, and the probasin promoter (maximal enhancement,
twofold; data not shown). AR activity was responsive to the effects of
another coactivator, SRC-1e (27, 58), indicating that the
lack of enhancement by hPGC-1 was not due to a general inability for
increased transcription (Fig. 4A). Rather, a comparison of the
coactivation conferred by SRC-1e and hPGC-1 on the different receptors
and promoters tested suggests that the two coactivators act in a
receptor- and promoter context-dependent manner. hPGC-1 was weaker than
or equal to SRC-1e in certain contexts (AR on MMTV and TAT3; GR on
MMTV) and considerably stronger in others (ER; MR and GR on TAT3) (Fig.
4A and data not shown).
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B subunits p50 and p65
(RelA) in COS7 cells resulted in a 40-fold induction of a luciferase
reporter under the control of three NF-B sites. hPGC-1 coexpression
did not affect this induction (Fig. 4B). Similarly, hPGC-1 expression
had no effect on the transcriptional activity of the chimeric activator
Gal4-VP16 (Fig. 4B), suggesting that hPGC-1 is not a general
coactivator of transcription.
hPGC-1 acts via the LBD of GR.
Steroid receptors are modular
proteins consisting of an N-terminal domain that carries a strong
transcriptional activation function (AF1), a central domain that binds
DNA, and a C-terminal domain (LBD) that binds hormone and carries a
hormone-dependent transcriptional activation function (AF2). hPGC-1
could increase the response to hormone by interacting with a particular
receptor domain and enhancing one or more of its functions, e.g.,
binding to DNA or activation of transcription. To delineate the
affected receptor function, we measured the activity of truncated or
chimeric variants of GR in the absence or presence of hPGC-1. As shown earlier, hPGC-1 stimulated efficiently the hormone-dependent induction mediated by full-length GR (N795 in Fig.
5). A C-terminal truncation of the
receptor that removes the LBD and gives rise to a constitutively active
transcription factor (18) eliminated the ability of hPGC-1 to enhance transcription (N525 in Fig. 5). In contrast, the receptor variant 407C, which lacks the N-terminal region but contains the DBD
and the LBD, was still responsive to hPGC-1 (Fig. 5). Finally, the
hormone-dependent activity of the chimeric Gal4-LBD protein, which
contains the receptor LBD fused to the heterologous DBD of Gal4, was
enhanced strongly by hPGC-1 (Fig. 5). The Gal4 DBD itself was
unaffected (Fig. 4B). In conclusion, the LBD of the receptor is both
essential and sufficient for a functional interaction with hPGC-1,
suggesting that hPGC-1 is a coactivator of AF2, the hormone-dependent
transcriptional activation function of the LBD.
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The N terminus of hPGC-1 carries a potent transcriptional AD.
One of the hallmarks of transcriptional coactivators is that their
recruitment to a specific promoter, either by protein-protein interactions with DNA-binding transcription factors such as GR or
artificially by direct fusion to a DBD, activates transcription. This
notion implies that coactivators contain transcriptional ADs. To
determine whether hPGC-1 carries such a domain, we examined the ability
of the chimeric Gal4-hPGC-1 protein, in which the coactivator is fused
to the Gal4 DBD, to activate reporters under the control of
Gal4-binding sites. As shown in Fig. 6,
Gal4-hPGC-1 was a potent activator of transcription in both yeast and
mammalian cells, indicating that hPGC-1 indeed harbors a
transcriptional activation function.
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hPGC-1 and GR interact physically in a hormone-dependent
manner.
The ability of hPGC-1 to enhance receptor-mediated
transcription could be the result of its direct, hormone-dependent
interaction with the receptor, leading to the recruitment of its strong
transcriptional AD. To determine if the receptor and hPGC-1 interact
physically, we used the yeast two-hybrid system, where the interaction
between two proteins, one fused to a DBD and another fused to an AD,
leads to the expression of -gal (12). Yeast carrying a
Gal4-responsive -gal reporter was transformed with two vectors: one
expressing the Gal4-LBD, shown above to be sufficient for the
functional interaction with hPGC-1 (Fig. 5), and another expressing the
Gal4 AD, either alone or fused to hPGC-1 (AD and AD-hPGC-1,
respectively). As the transcriptional activation function of the
receptor LBD is weak in yeast, the Gal4-LBD chimera was unable by
itself to activate the -gal reporter, even at high hormone
concentrations (Fig. 7 and data not
shown). In contrast, coexpression of Gal4-LBD and AD-hPGC-1 caused a
strong induction of -gal activity in the presence but not in the
absence of hormone (Fig. 7), suggesting that the GR LBD and hPGC-1
interact physically in a hormone-dependent manner.
|
2
and the minimal domain 91/186) or NID2 (189C, hPGC-11, and the
minimal construct 189/293) showed a hormone-dependent interaction with
the receptor (Fig. 7). In general, interactions mediated by NID1 were
stronger (>250 -gal units) than those mediated by NID2 (35 to 85 -gal units). Deletion of both domains, as in hPGC-13, resulted in
an hPGC-1 variant that was functional in other assays but could no
longer interact with the receptor (Fig. 7 and data not shown).
The interactions between hPGC-1 and GR were dependent on the presence
of corticosterone. To test whether the hormone dependence reflected a
hormone-induced conformational change that enabled the interaction, we
again tested the effect of the antagonist-partial agonist RU486. RU486
was unable to promote the interaction of GR with hPGC-1 (Fig. 7).
Moreover, RU486 could compete with corticosterone for the
hormone-induced interaction, i.e., acted as an antagonist (data not
shown), demonstrating that both RU486 and corticosterone were able to
bind the receptor but that only the full agonist corticosterone could
promote a conformation competent to interact with hPGC-1.
The hPGC-1 AD and NIDs are essential for the coactivation of GR. The functions encoded by hPGC-1 suggest that the mechanism by which it enhances the response to hormone involves first its recruitment by hormone-activated steroid receptors via the identified NIDs and second the enhancement of transcription via the identified AD. If this is the case, we would expect these domains to be essential for the hPGC-1 coactivator function. To test this notion, we assayed the ability of truncation and deletion variants of hPGC-1 to enhance hormone-dependent, receptor-mediated transcription in mammalian cells.
First, we addressed the importance of the AD. As shown before, full-length hPGC-1 enhanced strongly (35-fold) the transcriptional response to hormone (Fig. 8A). An hPGC-1 variant that lacked most of the AD (91C) could no longer enhance GR activity, indicating that the AD is essential for the coactivation function (Fig. 8A). The 91C protein was expressed at levels comparable to those of full-length hPGC-1, as determined by Western blot analysis (data not shown), and properly localized to the nucleus (Fig. 8C). A similar lack of activity was also seen with hPGC-1 constructs that lacked larger parts of the N terminus, such as 189C (Fig. 8A). Next, we determined the role of the two NIDs. Variants of hPGC-1 that lacked just NID1 (hPGC-11) or a region that includes NID2 (hPGC-12L)
displayed reduced activity but were still able to enhance transcription
by 14- to 18-fold (Fig. 8A). In contrast, deletion of both NIDs
(hPGC-13) eliminated hPGC-1 activity (Fig. 8A). Again, constructs
hPGC-11, hPGC-12L, and hPGC-13 expressed proteins that were
properly localized to the nucleus, suggesting that the decrease in
activity was due to the deletion of the interaction domains and not to
changes in protein stability or localization (Fig. 8C and data not
shown). In conclusion, our results indicate that both the AD and the
ability to interact physically with the receptor are essential for the
hPGC-1 coactivation function. While either NID in the context of
full-length hPGC-1 is sufficient, the presence of both domains renders
the coactivator more effective. Finally, the AD and the interaction
with the receptor are sufficient for the coactivation of GR. As shown
in Fig. 8A, an hPGC-1 construct that includes the AD and the stronger
NID, NID1 (N186), enhanced transcription by 15-fold, suggesting that
the first 186 aa form a core domain that, although compromised, can
potentiate GR-mediated transcription.
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The C terminus of hPGC-1 contributes to coactivator function.
The C terminus of hPGC-1 contains two recognizable features, an SR-rich
region and a putative RNA-binding motif. To address a possible role of
these domains in coactivation, we tested the ability of hPGC-1 variants
that lack the C terminus to enhance receptor-mediated transcription.
hPGC-1 constructs with different C-terminal truncations, such as N293
and N408, displayed reduced activity but were still good coactivators
of transcription (Fig. 8B). Interestingly, deletion of the C terminus
in hPGC-1 variants that already lacked NID1 (N4821, N4081, and
N2931) reduced hPGC-1 activity to almost the background level (Fig.
8B), suggesting that in the absence of the C terminus, the AD and the
weaker NID, NID2, are not sufficient to enhance receptor activity. In
conclusion, the hPGC-1 C terminus, although not essential, contributes
to the coactivation function.
-gal reporter
was transformed with vectors expressing the C terminus of hPGC-1 fused
to the Gal4 DBD (Gal4-294C) as bait and hPGC-1 variants fused to the Gal4 AD as prey. As shown in Fig. 9,
coexpression of Gal4-294C and AD-hPGC-1 induced -gal activity,
indicating that hPGC-1 can indeed interact with itself. This
interaction was dependent on the C terminus, since it was detected with
hPGC-1 proteins lacking the N terminus, such as 294C, but was lost in
hPGC-1 variants N408 and N293, which lack the C-terminal region (Fig.
9).
|
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DISCUSSION |
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Top
Abstract
Introduction
Materials and Methods
Results
Discussion
References
|
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In this work, we present a genetic scheme for the identification of mammalian proteins that regulate steroid hormone responses, based on their function in yeast. Using this approach, we have identified hPGC-1 as a protein that enhances glucocorticoid signaling. We show that hPGC-1 is a nuclear protein, expressed in a tissue-specific manner, and a potent coactivator of selective steroid hormone receptors.
The conservation of cellular pathways and molecular mechanisms from yeast to mammals has enabled genetic studies of higher eukaryotic processes in the simple, unicellular yeast. Hence, genes from several species have been cloned in yeasts by complementation of yeast mutants (33, 37, 39, 40, 66, 74) or in gain-of-function screens (44, 76). Since mammalian steroid receptors were first expressed in S. cerevisiae (46, 65), functional genetic screens have revealed yeast proteins participating in steroid signaling and led to the study of some of the conserved mammalian counterparts (6, 24, 29, 31, 32, 45). In parallel, the development and application of yeast two-hybrid screens has identified a number of proteins that interact physically with nuclear receptors (36). The approach that we present here, the functional screening of mammalian cDNA libraries in yeast engineered to reconstitute a mammalian pathway, should identify proteins regulating any step in the pathway, independent of a physical interaction or subcellular localization. We show that this approach can yield proteins of interest. Of the three proteins identified, the molecular chaperone p23 is a known component of steroid aporeceptor complexes. It interacts indirectly, via Hsp90, with the cytoplasmic, hormone-free GR and is thought to stabilize hormone-binding-competent receptors (11, 61). LEM5 is a novel, ubiquitous nuclear protein with a putative yeast homologue (A. Kaul and A. Kralli, unpublished data). In contrast, hPGC-1 (LEM6) is expressed in a tissue-specific manner and has no yeast or nematode homologue, suggesting that it could provide a regulatory function specific for vertebrates. Given our interest in proteins that confer specificity and sensitivity to lipophilic hormone signaling, we focused our studies on hPGC-1.
We show here that the nuclear protein hPGC-1 is a potent, bona fide
coactivator of steroid receptors. It interacts with the hormone-activated form of GR, contains a transcriptional AD, and enhances strongly the transcriptional response mediated by GR, MR, and
ER in mammalian cells. The high sequence identity of hPGC-1 with murine
PGC-1 (95%) suggests that the two proteins are functional homologues.
Murine PGC-1, isolated as a protein that interacts with the nuclear
receptor PPAR, has been shown to enhance transcription by PPAR
and TR and to be expressed in a tissue-specific manner (62).
Taken together, these findings imply a wide role for hPGC-1 and mouse
PGC-1 as tissue-specific regulators of nuclear receptor signaling.
Steroid receptors harbor two transcriptional ADs: the hormone-independent AF1 at the N terminus and the hormone-dependent AF2 at the C-terminal LBD. hPGC-1 enhanced the transcriptional activity of the LBD but not of the N-terminal part of the receptor, suggesting that it operates via AF2. In support of this notion, hPGC-1 enhanced the response to agonists that activate AF2 but not the response to partial agonists or antagonists, such as RU486, that do not induce proper LBD folding. Furthermore, one of the domains of hPGC-1 that interacts with the receptor LBD carries an LXXLL sequence, a motif that mediates the interaction of several proteins with the AF2 surfaces of receptors (20, 70). Altogether, these data suggest that hPGC-1 interacts with and enhances the activity of AF2.
Two adjacent domains in hPGC-1, NID1 and NID2, mediate the
hormone-dependent interaction with the LBD of GR. NID1 (aa 91 to 186),
as mentioned before, contains an LXXLL sequence. Secondary structure
predictions for NID1 suggest that the LXXLL sequence and its flanking
regions adopt a helical conformation, consistent with it being a
nuclear receptor interaction surface. NID2 (aa 186 to 293) does not
contain a consensus LXXLL motif but has a short sequence,
LLKYLTTNDD, that resembles the
third interaction box of the coactivator TIF2 (underlined amino acids
are identical) and is also predicted to be part of an alpha helix.
Future experiments will address the role of these motifs in the
interactions mediated by NID1 and NID2. Finally, two lines of evidence
suggest that NID1 is the major site of interaction with GR. First, the
yeast two-hybrid assays show a stronger interaction of the receptor LBD
with NID1 than with NID2 (Fig. 7). Second, hPGC-1 variants that lack
NID1 display weaker GR coactivation than those that lack NID2,
particularly when the C terminus of hPGC-1 is absent (compare N2931
and N186 in Fig. 8).
Murine PGC-1 has also been reported to have two distinct interaction
domains for PPAR. One of them is in the N-terminal 180 aa and could
be the same as NID1 of hPGC-1 (73). The second seems to be
distinct from hPGC-1 NID2, since it is in a different region (aa 292 to
338 of murine PGC-1) and mediates a hormone-independent interaction
with the DBD of PPAR (62). These findings raise the
interesting possibility that coactivators such as PGC-1 may have one
interaction site (e.g., NID1) that directs them to a family of
transcription factors, such as the nuclear receptors, and auxiliary
sites (e.g., hPGC-1 NID2) that can discriminate among individual
receptors within the large family. The first site could play a role in
the strength of the interaction, and the second one could play a role
in the specificity of the interaction. Interestingly, the coactivator
GRIP1 was recently shown to have a C-terminal auxiliary domain that
selectively enhances interactions with the LBDs of specific receptors
(22).
Recruitment by the hormone-activated receptor would bring hPGC-1 to the vicinity of promoters under hormone regulation. What are the downstream effectors of hPGC-1? The presence of a strong transcriptional AD indicates that hPGC-1 makes direct contacts via its AD with either the basal transcription machinery or other transcription cofactors. The acidic nature of the hPGC-1 AD suggests contacts with targets of other acidic domains, e.g., TFIIA (30), histone acetyltransferase complexes (71), or the Mediator complex (also known as ARC and Srb) (5, 50). An LLXXLXXXL sequence at aa 88 to 96, similar to the CBP interaction motif in the p160 (NCoA) family of coactivators (70), implies possible contacts with CBP. Since Gal4-hPGC-1 is a potent transcriptional activator in both yeast and mammalian cells, it is possible that hPGC-1 can interact with more than one of these effectors, thereby activating multiple steps in transcription initiation and elongation.
Efficient coactivation of GR requires the C terminus of hPGC-1. A
possible reason for this is the ability of this region to mediate
homophilic hPGC-1 interactions. A "dimerization" surface could
stabilize the binding of an hPGC-1 dimer to a receptor dimer, in a
complex where each NID1 contacts one receptor AF2. Dimerization could
also help NID2 to compensate for the loss of NID1. Deletion of the
dimerization function might lead to two alternative complexes: (i) two
hPGC-1 monomers and a receptor dimer, where the stronger NID (NID1)
interacts with each AF2, or (ii) an hPGC-1 monomer and a receptor
dimer, where NID1 and NID2 each interact with one receptor AF2. The
latter case is similar to what has been observed for the crystal
structure of the PPAR LBD with an SRC-1 fragment that has two NIDs;
a single SRC-1 molecule contacts via two LLXXLL motifs the two AF2
surfaces of the receptor dimer (53). In either case, a
deletion of NID1 in the absence of the C terminus may leave the weaker
NID (NID2) unable to mediate a stable interaction with the receptor
dimer. This could explain why hPGC-11, which has both NID2 and the
dimerization interface, but not N4821, which has just NID2, can
enhance GR activity (Fig. 8). A general role for dimerization is also
consistent with the observations that receptor dimerization is
important for other receptor-coactivator interactions (27)
and that two molecules of the coactivator TIF2 bind cooperatively to a
nuclear receptor heterodimer (38).
The C terminus of hPGC-1 also carries novel motifs for transcriptional coactivators, such as the SR-rich sequences and the putative RNA-binding domain. Although such features are often associated with posttranscriptional RNA-processing regulators, they have been found recently in other proteins that interact with transcription factors. The family of CTD-associated SR-like proteins (CASPs) interacts with the C-terminal domain of RNA polymerase II and has been suggested to couple transcription to pre-mRNA processing (10, 79). An RNA-binding protein, TLS, has been purified as a thyroid receptor-interacting protein (60). Although speculative at the moment, interesting roles for these domains can be proposed. First, they may bind an RNA cofactor (e.g., the steroid receptor RNA activator SRA [34]) that could play a structural role in interactions with other transcription factors or regulate hPGC-1 activity. More interestingly, they may enable coactivators such as hPGC-1 to regulate steps other than transcription initiation and elongation, e.g., pre-mRNA processing. Steroid receptors could recruit hPGC-1 and deliver it to the splicing machinery, possibly via RNA polymerase II, thereby providing hormone-regulated, gene-specific RNA splicing.
The identification of hPGC-1 establishes one more member of an already
large group of coactivators for steroids and other nuclear receptors:
the p160 family (represented by SRC-1, TIF2, and pCIP]), the histone
acetyltransferases CBP and pCAF, and the multisubunit Mediator (also
called SMCC, DRIP, TRAP, ARC, CRSP, and Srb) (reviewed in references
13, 28, 69, and 75). One of the
challenges in transcriptional regulation by nuclear receptors is to
understand how specificity (such as tissue, receptor, signal, or
promoter specificity) and sensitivity to regulation (i.e., sensing and
adapting to changes in cell state) are established. The existence of
multiple coactivators could confer these properties, if the
coactivators were expressed tissue specifically, showed selectivity for
different receptors, affected different limiting steps in the control
of gene expression, and were subject to regulation. hPGC-1 and murine
PGC-1 display many of these properties. First, they are expressed
tissue specifically. The predominant expression in heart, skeletal
muscle, kidney, liver, and brown fat overlaps the expression of GR, MR,
TR, and PPAR and correlates with the sensitivity of these receptors
to PGC-1. Second, a comparison of hPGC-1 and SRC-1e highlights receptor
selectivity. The efficiency of the two coactivators is reversed on
different receptors, SRC-1e being more potent with AR and hPGC-1 being
stronger with ER, GR, and MR. Third, the effects of hPGC-1 and murine
PGC-1 may depend on promoter context. Enhancement of GR activity by
hPGC-1 but not by SRC1e was stronger at the TAT3 reporter than at the
MMTV reporter. Similarly, Wu et al. reported that murine PGC-1
coactivation is promoter dependent, affecting the transcription of
selective PPAR-targeted genes in muscle (73). Finally,
hPGC-1 and murine PGC-1 are good candidates for integrating other
signaling pathways. Exposure of mice to cold and activation of
-adrenergic receptors lead to increased expression of murine PGC-1
(4, 62). The presence of putative phosphorylation sites
suggests additional levels of regulation. We have observed that the
ability of hPGC-1 to enhance GR activity is cell type dependent (data
not shown). Understanding the regulatory mechanisms and the specificity
of coactivator function will be the next challenge.
| |
ACKNOWLEDGMENTS |
|---|
We thank F. Hamy, J. Iniguez-Lluhi, P. Matthias, R. Nissen, M. Parker, D. Picard, and B. Starr for sharing plasmids; Chiron and Tony Brake for the HepG2 cDNA library; R. Skoda for the human liver cDNA; Exelgyn for mifepristone (RU486); and M. Hall, J. Iniguez-Lluhi, U. Müller, D. Picard, R. Sitcheran, M. Spiess, and B. Starr for discussions and helpful comments on the manuscript.
This work was supported by the Swiss National Science Foundation (A.K.), the Basel Chemical Industry (D.K.), and the Max Cloëtta Foundation (A.K.).
| |
FOOTNOTES |
|---|
* Corresponding author. Mailing address: Division of Biochemistry, Biozentrum of the University of Basel, Klingelbergstrasse 70, CH-4056 Basel, Switzerland. Phone: 41 61 267 2162. Fax: 41 61 267 2149. E-mail: anastasia.kralli{at}unibas.ch.
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Top
Abstract
Introduction
Materials and Methods
Results
Discussion
References
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