Nuclear Hormone Receptor Coregulators In Action: Diversity For Shared Tasks
Daniel Robyr1,
Alan P. Wolffe and
Walter Wahli
Institut de Biologie animale (D.R., W.W.) Université de
Lausanne Bâtiment de Biologie CH-1015 Lausanne,
Switzerland
Laboratory of Molecular Embryology (A.P.W.)
National Institute of Child Health and Human Development National
Institutes of Health Bethesda, Maryland 20892-5431
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INTRODUCTION
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The nuclear hormone receptors are
transcriptional regulators that activate gene expression upon binding
of their respective ligands. A new class of protein, termed
coregulators, has emerged during the last few years. These proteins
have the faculty to repress (corepressors) or to enhance (coactivators)
the activity of genes regulated by nuclear hormone receptors in a
ligand-dependent fashion. In this review we describe most of these
coregulators and discuss their mode of action. In particular, we
comment on the link between coregulators and histone acetylation, which
is a crucial event in the transcriptional response within chromatin. We
describe novel alternative pathways, which elicit the recruitment of
coregulators independently of the presence of any ligand and speculate
on how the convergence of ligand-dependent and -independent mechanisms
might enhance the transcriptional response of target genes.
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DESCRIPTION OF THE NUCLEAR HORMONE RECEPTORS
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Nuclear hormone receptors are ligand-inducible transcription
factors that are involved in a number of physiological and cellular
events (see Table 1
for nuclear receptor
nomenclature). Together, they form a superfamily, which includes the
classic steroid receptors (androgen, estrogen, glucocorticoid,
mineralocorticoid, and progesterone receptors), the thyroid, vitamin
D, and retinoid receptors, as well as many others that
have been characterized more recently. All of them share common
functional domains named A to F. The N-terminal A/B region is weakly
conserved among the members of the superfamily, has a variable length,
and contains an autonomous activation function (AF-1). The conserved C
domain is the DNA-binding domain, which consists of two
zinc-finger-like motifs. The D domain is a variable hinge. The
multifunctional C-terminal half of the protein (domain E) encompasses
the ligand-binding domain (LBD), a second activation function (AF-2), a
dimerization domain, and a region involved in nuclear localization. The
AF-2 autonomous activation domain (AF-2 AD) is composed of an
amphipathic
-helix that is highly conserved among nuclear receptors
and is critical for transcriptional activation (1, 2, 3, 4). The most
C-terminal region (domain F) is variable and has no known function.
This domain is absent in some receptors such as the progesterone
receptor (PR), peroxisome proliferator-activated receptors (PPAR), and
retinoid receptors [retinoic acid receptor (RAR), retinoid X receptor
(RXR)].
Transcriptional activation by both AF-1 and AF-2 of the estrogen
receptor (ER) is cell type specific and relies on the promoter context
of the hormone-response element (HRE) (5). This suggests the
existence of different mediating or coactivating proteins, several of
which have been identified to date (see below). These mediators
interact with the LBD and some are capable of increasing the AF-2
response in a ligand-dependent fashion. On certain promoters, AF-1 and
AF-2 must synergize to reach efficient transactivation.
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NUCLEAR RECEPTOR COACTIVATORS
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The observation of transcriptional interference or squelching
between steroid hormone receptors provided evidence for the existence
of limiting common transcriptional cofactors that mediate AF-2 function
(6, 7). The subsequent biochemical identification of several nuclear
receptor-interacting proteins in a ligand-dependent manner supported
this hypothesis (8) (Table 2



).
These mediators or coactivators are required to achieve efficient
transcription (reviewed in Refs. 9, 10, 11).
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COACTIVATORS, A GROWING FAMILY
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Numerous potential receptor-interacting proteins were
identified and described in the past few years (Table 2



), and
many others will certainly be discovered in the near future. This rapid
increase has led to some confusion in the nomenclature and raised
questions about the definition of a coactivator. A real coactivator
must fulfill certain requirements. First it must interact
directly with the activation domain of a nuclear receptor in an
agonist-dependent manner (but not in the presence of an antagonist),
leading to enhancement of the receptor activation function. Most of the
potential cofactors meet this definition. A coactivator should also
interact with components of the basal transcription machinery. Finally,
coactivators should not enhance the basal transcriptional activity by
their own, although they contain an autonomous activation function (12, 13). Indeed, in the absence of a nuclear hormone receptor, coactivators
cannot be recruited to promoters and therefore cannot coactivate
transcription. Here, we will first discuss some well characterized
coactivators and then we will comment on proteins whose coactivator
status is not clearly established.
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SRC-1/CBP/p300/pCAF: A COACTIVATION COMPLEX?
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Among all the described coactivators to date, SRC-1 (steroid
receptor coactivator 1) has attracted much attention. The human
SRC-1 was first discovered as a ligand-dependent interacting protein
for the progesterone receptor (14). It appeared, however, that the
original cDNA clone was truncated at the N terminus (15, 16). In
addition to the full-length SRC-1 (mSRC-1a, NCoA-1), several splice
variants have been described, e.g. SRC-1b, -c, -d, and -e
(15, 17).
The isoform SRC-1e is a more potent coactivator for ER than SRC-1a
(13). For instance, the estrogen-regulated rat oxytocin promoter
(-363/+16) is coactivated by SRC-1e but not by SRC-1a, as analyzed by
transient transfection assay in Cos-1 cells. On the other hand, both
SRC-1 isoforms stimulate ER-mediated transcription from an artificial
ERE-containing promoter. Thus, coactivation by SRC-1a appears to rely
on the promoter context of the receptor target gene. Both isoforms
contain three nuclear receptor-interacting motifs (LXXLL) found in many
co-factors (18). SRC-1a however possesses a fourth LXXLL motif at its C
terminus (13). The function of this additional motif is unclear since
its mutation does not affect transcription. The difference in activity
results most likely from the presence of two distinct activation
domains in SRC-1. The first domain interacts with the mediator
CREB-binding protein (CBP)/p300, whereas the second domain
activates transcription independently of CBP/p300. It seems that the
extra C-terminal portion of SRC-1a, which is not present in
SRC-1e, represses this CBP/p300-independent activation domain. The fact
that the promoter context influences the ability of SRC-1a to
coactivate ER suggests strongly that the recruitment of p300/CBP by
SRC-1 is not always sufficient on some promoters. The target factor of
the second activation domain is not known to date.
The interaction of SRC-1 with the estrogen receptors depends on ligand
and the integrity of helix 12 within the LBD and requires the presence
of two functional AF-2 domains in a receptor dimer (13). The
ligand-dependent interaction between SRC-1 and TR was analyzed in
detail (19). Five independent mutations within the LBD of TR abolished
SRC-1a binding. These mutations include residues from helix 3, 5, and
12, which form a small interaction surface encircling a hydrophobic
cleft. A similar mutation (K366 in helix 3) in the mouse ER was shown
to interfere with SRC-1 recruitment (20). More recently, a complex
containing the liganded PPAR-
LBD (homodimer) and a portion of human
SRC-1(623710) was resolved at 2.3 Å (21). The crystal structure
showed that each member of the receptor dimer interacts with a single
and different LXXLL motif of the same SRC-1 molecule. The hydrophobic
face of the LXXLL helix packs into a hydrophobic pocket formed by
helices 3, 4, 5, and 13 (H12 in other receptors) of PPAR-
. The
nuclear hormone receptors contain similar LXXLL motifs within their own
AF-2. Surprisingly, the crystal structure of the unliganded PPAR-
homodimer indicates that the AF-2 helix of one receptor can interact
with the LBD of a second receptor (21). This suggests that the
ligand-dependent activation leads to the displacement of the AF-2 helix
from the LBD of the other receptor in favor of the recruitment of an
LXXLL motif of SRC-1. This model was also proposed for the RXR/RAR
heterodimer (22).
SRC-1 is also capable of interacting with both the A/B and D/E regions
of PR and ER through multiple receptor-interaction sites (23, 24).
Furthermore, the binding of SRC-1 to steroid receptors is more
efficient when both AF-1 and AF-2 are present. This could potentially
explain the transcriptional synergy observed between AF-1 and AF-2
(5).
The ligand-dependent interaction between SRC-1 and nuclear receptors is
established, but the way the transcriptional activation signal is
transmitted to the transcriptional machinery remains obscure. One
possibility is the direct binding of SRC-1 to the basal transcription
machinery through TFIIB or TATA-binding protein (TBP) (17).
Alternatively, SRC-1 may be part of a larger coactivator complex.
Hence, upon estrogen binding, ER becomes associated with numerous
proteins, including SRC-1 and p300 together with proteins of 140
(ERAP140), 100, 90, and 30 kDa (25). However, there is no clear
evidence that these proteins are part of the same complex.
Nevertheless, it was not surprising when SRC-1 was shown to interact
directly with a conserved region in the C terminus of p300 and its
homolog CBP (15, 16). Moreover, CBP/p300 is a coactivator that binds to
nuclear hormone receptor in a ligand-dependent manner (26) and enhances
steroid-dependent transcription in synergy with SRC-1 (27). However,
there is increasing evidence indicating that the limiting CBP/p300
factor serves a broader function, i.e. as an integrator of
many different activation pathways (28, 29, 30). Indeed, CBP/p300 has been
shown to interact with an increasing number of other DNA-binding
factors and with components of the basal transcription machinery.
p300/CBP-associated factor (P/CAF) and p300/CBP
cointegrator-associated protein (p/CIP) are two other nuclear
hormone receptor coactivators that can associate with CBP/p300
(31, 32, 33). Both CBP/p300 and p/CIP, together with SRC-1 (NCoA-1), are
required to allow full ligand-activated gene transcription in several
cell lines (32). Finally, p/CIP and SRC-1 can bind P/CAF (34). Despite
all the described potential interactions between all these cofactors,
there is little biochemical evidence of the existence of such a complex
in vivo. Some interactions may be mutually exclusive.
Alternatively, various combinations of subsets of these coactivators
may coexist in the cell, giving rise to a number of possibilities in
term of specificity of regulation. In an attempt to isolate such
complexes, cells were recently subjected to biochemical fractionation
(35). This study indicates that the different cofactors cofractionate
in various stable subcomplexes. These data also suggest that the
liganded progesterone receptor recruits a preformed complex that
contains SRC-1 and TIF2. Although many receptors can bind to a given
coactivator, it is possible that they compete with each other and that
each has a different cofactor affinity (36).
Interestingly, P/CAF, CBP/p300, and SRC-1 present histone
acetyltransferase activity (HAT) (33, 37, 38). Since histone
acetylation correlates with promoter activation (reviewed in Ref. 58),
it may explain how these cofactors increase the transcriptional
activation by nuclear receptors. But are all the different HATs
required for the coactivation or do they have some specificity? It
appears that inactivation of the HAT domains of CBP or SRC-1 has no
influence on the coactivation of RAR (34). However, the HAT domain of
P/CAF is indispensable for nuclear receptor activation. On the other
hand, CREB (CRE-binding protein) function needs CBP-HAT activity
and not P/CAF-HAT. This suggests that there is a selectivity in the
specific HAT activity required for the action of different classes of
transcription factors. In addition, P/CAF acetylates preferentially
nucleosomal histone H3, whereas p300/CBP acetylates all nucleosomal
core histones (SRC-1 and ACTR have a specificity for histones H3 and
H4) (33, 37, 38, 40, 41). The presence of multi-HAT activities within a
given complex may lead to various patterns of histone acetylation that
are specific for a particular transactivator or for a promoter context.
Interestingly, P/CAF and p300/CBP have the property to acetylate
nonhistone proteins such as TFIIEß, TFIIF (RAP74 and RAP30), EKLF,
GATA-1, and p53 (42, 43, 44, 45).
Recently, VDR-interacting protein (DRIP) was isolated and
purified as a new coactivator complex (46, 47). Despite the lack of HAT
activities, DRIP is a potent coactivator of the vitamin D receptor in a
chromatin context. Any chromatin remodeling activity related to DRIP
(directly or not) has not been identified to date. Interestingly, some
DRIP subunits are homologous to components of mediator complex that are
found associated with the RNA polymerase II complex as well. This
finding gives us a clue as to how DRIP may target the RNA polymerase II
to the promoter. Surprisingly, DRIP, and most probably its related TRAP
(48) complex, shares most of the subunits with yet another complex, ARC
(activator-recruited cofactor) (49). The latter, however, is a
coactivator for transcription factors such as SREBP-1a, VP16, and
NF-
B (p65 subunit) within chromatin. It appears likely that there is
a convergence in the coactivation pathways of many transcriptional
activators, the differences residing in the fine composition of
coactivator complexes or subcomplexes.
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OTHER POTENTIAL COACTIVATORS
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According to the definition stated earlier in this review, a
coactivator must interact directly with the activation domain of a
nuclear receptor in an agonist-dependent manner but not in the presence
of an antagonist. Rap46 was shown to interact in vitro with
numerous receptors (ER, AR, GR, PR, TR) independently of the presence
of any ligands, agonist or antagonist (50), but so far, no functional
experiments have been performed. Another protein, RSP5/RPF1,
potentiates hormone-dependent activation of transcription by GR and PR
(51), although no direct interaction with either receptors was ever
documented (M.O. Imhof, personal communication). Interestingly, in one
case, there is ligand-dependent release of a coactivator. The
constitutive androstane receptor ß (CAR-ß) is active in absence of
its ligand. Surprisingly, the addition of androstenol or of androstanol
promotes the dissociation of the steroid receptor coactivor 1 (SRC-1)
and leads to transcriptional repression (52).
Another criterion for belonging to the coactivator family is the
ability to enhance receptor function. This basic requirement is not
observed with TIF1
, which down-regulates transactivation by ER, RAR,
and RXR in Cos-1 cells (53). It is possible, however, that
overexpression of TIF1 titrates out an essential limiting nuclear
protein required for AF-2 activity. Proteins such as SUG1
(suppressor of a mutation in the transcriptional activation domain of
the yeast activator Gal4) and Trip1 (TR-interacting protein 1)
interact with several nuclear hormone receptors in a ligand-dependent
fashion as well as with TBP (54, 55). The fact that SUG1 was proposed
to be a component of the RNA polymerase II holoenzyme reinforced its
classification as a coactivator (56). However, SUG1 is a subunit of the
26S proteasome (57, 58) and Trip1 inhibits transactivation (54).
Therefore, it is likely that these proteins are not coactivators but
rather are involved in receptor degradation.
A third criterion is the requirement for a direct contact between the
cofactor itself and the basal transcription machinery in light of the
bridging model. This aspect is difficult to assess and was not
determined for all potential coactivators. One can also envision that
individual cofactors are part of a larger complex, limiting the need
for a direct interaction with basal transcription factors. Although
RIP140 interacts with several nuclear receptors in vitro and
enhances weakly ER function in vivo, it is not able to
associate with either TFIIB or TBP (59, 60, 61). Does this disqualify it as
a nuclear hormone receptor coactivator ? It is still possible that it
interacts with other basal transcription factors. Moreover, the fact
that RIP140 inhibits transcription upon overexpression argues in favor
of the need for another intermediary factor (60).
Finally, coactivators should not enhance the basal transcriptional
activity on their own, although they contain an autonomous activation
function (12, 13). Indeed, in the absence of a nuclear hormone
receptor, coactivators cannot be recruited to promoters and therefore
cannot coactivate transcription.
The first described nuclear hormone-positive regulators are members of
the SWI/SNF family of proteins. Ligand-dependent transcriptional
enhancement of GR or ER in yeast requires several SWI gene products,
such as SWI1, SWI2, and SWI3 (62), which are part of a large SWI/SNF
chromatin remodeling complex (63, 64). The human homologs of SWI2,
termed SNF2
, SNF2ß, or brahma, were also shown to coactivate ER,
GR, and RAR in mammalian cells (65, 66). It has not been established,
however, whether or not the described interaction between SW3 and GR
(which requires SWI1 and SW2) is direct (62). The finding that SWI1
contains nuclear hormone receptor-binding motifs (LXXLL), present in
many cofactors (18), is puzzling and might suggest that it is
potentially a coactivator (67). However, the importance of these LXXLL
motifs was not tested for SW1.
COACTIVATOR AND LIGAND-INDEPENDENT TRANSACTIVATION
A list of nonsteroid compounds or extracellular signals can
efficiently activate the ER including dopamine (68), EGF (epidermal
growth factor) (69, 70), TGF
(tumor growth factor
) (70),
cAMP (69, 71), insulin-like growth factor I (71), phorbol ester
(tetradecanoylphorbol acetate) (69), and many others. Since all
these molecules induce protein phosphorylation, it is likely that
altered phosphorylation of the receptors (and/or associated proteins)
is a key event in the ligand-independent activation. Moreover, okadaic
acid, an inhibitor of protein phosphatases 1 and 2A, is also able to
activate ER-dependent transcription (69).
Ligand-independent phosphorylation of the steroid hormone receptors has
been known for a long time (reviewed in Refs. 63, 64). The ER is
mainly phosphorylated on serines residues in the A/B domain (74)
although phosphorylation of a tyrosine residue in the E/F domain was
also reported (75, 76). The chain of events linking EGF to ER
phosphorylation has been analyzed more extensively. EGF activates the
Ras-Raf-MAPK cascade through its membrane receptor and leads to
phosphorylation of hER on serine 118 and to enhancement of
transcription (69, 77). However, the functional relationship between a
particular phosphorylation site and transcriptional activation remained
elusive until recently. Effectively, phosphorylation of two ERß
serines residues (Ser 102 and Ser 124 within the AF-1 domain), via the
MAPK cascade, promotes the recruitment of SRC-1 in the absence of
estrogen (Fig. 1
) (78). Similar findings were
made with the orphan nuclear receptor SF-1 (steroidogenic factor 1).
Intriguingly, phosphorylation enhances the recruitment of both a
coactivator [GR-interacting protein 1 (GRIP1)] and a corepressor
[silencing mediator for retinoid and thyroid hormone receptor
(SMRT)] to SF-1 (79). In this particular situation, the
functional importance of phosphorylation in transcriptional
activation appears unclear.

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Figure 1. The ER Can Activate Transcription Through Different
Mechanisms.
A, Ligand-independent recruitment of coactivators by the ER. The
MAPK-dependent phosphorylation of serine residues within the AF-1
domain allows the functional interaction with SRC-1 (left
panel). Alternatively, the need for a ligand is abolished by
the presence of cyclin D1, which acts as a bridging protein between the
ER AF2 domain and SRC-1 and or P/CAF (right panel). In
the latter situation, the described synergism between estradiol and
cyclin D1 might result from their cooperation in the recruitment of
SRC1. The presence of SRC-1 and/or P/CAF suggests that other components
of a coactivation complex might be present as well (dashed
oval). B, Ligand-dependent recruitment of coactivators by the
ER. The presence of the ligand induces a conformational switch in the
ER ligand binding domain that leads to the recruitment of a
coactivation complex (left panel, see also Fig. 2 )
containing protein such as SRC-1, P/CAF, p300/CBP, p/CIP, and possibly
many others (dashed oval). It is possible that
ligand-dependent and -independent mechanisms cooperate to provide
maximal transcriptional competency to the receptor (right
panel).
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Phosphorylation is not the only event that directs
ligand-independent transactivation. Cyclin D1 has the property to
potentiate the activity of the ER in a cyclin-dependent
kinase-independent mechanism (80, 81). Interestingly, cyclin D1
is able to interact with SRC-1 through a region that resembles the
receptor leucine-rich coactivator binding motif (LLxxxL) in AF-2 (Fig. 1
) (82). Cyclin D1 is essential for proper recruitment of coactivators
to unliganded ER and functions as a bridging factor between the
receptor and SRC-1. Similarly, recent experiments have shown that P/CAF
associates functionally with cyclin D1 (83). Thus, cyclin D1 plays a
crucial role in ER activation by recruiting HAT activities in the
absence of any ligand. Altogether, these results indicate that the
activity of a receptor can be modulated in multiple ways. The
combination of various mechanisms could elicit widespread responses to
different cellular stimuli (Fig. 1
).
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NUCLEAR RECEPTOR COREPRESSORS
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Transcriptional activation is mediated by the recruitment of
coactivators by the activated receptor. However, nuclear hormone
receptors can repress transcription under various circumstances
(reviewed in Refs. 9, 74). Repression occurs mostly in the absence
of a ligand or when an antagonist is bound to the receptor. In the
latter situation, the antagonist competes away the natural ligand,
preventing proper activation. Transcriptional repression involves
several mechanisms (85). It may result from the binding of a repressor
directly to DNA, leading either to a competition for the same DNA
element (thus preventing the binding of the activator), to an
interference with the activator function after binding to a
nonoverlapping site (quenching), or to the direct silencing of the
basal transcription machinery irrespective of the presence or absence
of the activator. Alternatively, repression may be achieved after the
recruitment of a limiting corepressor to the promoter by
protein-protein interaction with the activator (Fig. 2
). In this situation, the corepressor is not
able to bind to DNA on its own. We will focus here on the repression
mediated by the recruitment of a corepressor (Table 3
).

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Figure 2. Ligand-Dependent Switch between A Nuclear Hormone
Receptor Associated Either with a Corepression or a Coactivation
Complex
The nuclear hormone receptor (NR) is associated with a corepressor
(N-CoR, SMRT), which in turn recruits a histone deacetylase (HDAC)
through its interaction with Sin3. Deacetylation of histone tails leads
to transcriptional repression. Addition of the ligand disrupts this
repression complex in favor of the association of a coactivation
complex (SRC-1, P/CAF, p300/CBP, pCIP, and others). These proteins
possess a histone acetyltransferase activity that allows chromatin
decompaction through histone modifications. The interaction between the
nuclear hormone receptor AF-2 domain and the coactivation complex
occurs through the LXXLL motif found in many coactivators. The
coactivator and corepressor complexes are represented with
dashed lines since their exact composition in
vivo is not determined.
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A true corepressor must fulfill several criteria. First it has to
interact directly with the unliganded receptor, leading to enhancement
of basal transcription repression. A corepressor should also interact
with components of the basal transcription machinery and possess an
autonomous repression domain.
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DISCOVERY OF COREPRESSORS
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The active repression mediated by some members of the
nuclear receptor superfamily in the absence of ligand has attracted a
lot of interest. The unliganded TR, which is able to bind DNA, is not
only transcriptionally incompetent but acts as a repressor (86, 87, 88, 89, 90).
The finding that TR-mediated repression is reversed by cotransfection
of either the unliganded RAR or the C terminus of the oncogene v-ErbA
(viral TR homologue) revealed that TR corepressors might exist within
the cell (86). Three such corepressors were then identified (Table 3
):
SMRT (91), N-CoR (nuclear receptor copressor) (92, 93), and SUN-CoR
(small ubiquitous nuclear corepressor) (94). These proteins have
the characteristic to interact with the unliganded TR or RAR associated
with their RXR heterodimeric partner on DNA. The C terminus of N-CoR
interacts with TR and RAR in a region encompassing the hinge domain
(region D) and a portion of the ligand-binding domain (92).
Interestingly, this interaction region (CoR box) is significantly
conserved only between TR, v-ErbA, and RAR but not among the receptors
that do not associate naturally with N-CoR such as ER (see below).
Silencing is abolished upon ligand-dependent release of the repressor
from the receptor. Protease resistance assays have suggested that the
release of SMRT from TR is imposed by the conformational switch of the
LBD (helix 12) upon hormone binding (95). Importantly, the
constitutively inactive viral oncogene v-ErbA is associated with SMRT
regardless of the presence or absence of a ligand. The behavior of
v-ErbA argues that the release of SMRT is a prerequisite for proper
transcriptional activation. Interestingly, the point mutant TR160
(Pro160->Arg), which is incapable of silencing but retains its
ligand-dependent transactivation, cannot efficiently recruit SMRT,
indicating that silencing is linked to the recruitment of SMRT (91).
The necessity for a receptor to release a corepressor to activate
transcription is well illustrated with the RAR/RXR heterodimer. It is
well documented that RXR and RAR activate transcription from direct
repeats when spaced by five nucleotides (DR5), but not when spaced by
only one nucleotide (DR1) (96, 97). This differential regulation stems
from the incapacity of all-trans-retinoic acid to dissociate
N-CoR from the RAR/RXR heterodimer on a DR1 DNA element and therefore
to relieve repression (93). It appeared that RXR and RAR occupy the 5'-
and 3'-half-sites of a DR5 element, respectively, whereas the polarity
is inverted on a DR1 element (98). The latter polarity is likely to
impose allosteric constraints on RAR, preventing the release of N-CoR.
However, the occupancy of either a DR1 or DR5 response element by
RAR/RXR has no impact on the ligand-dependent recruitment of
coactivators (93).
It was first reported that ER and PR are unable to interact with
either N-CoR or SMRT, in the absence of any ligand (92). It appeared,
however, that their respective antagonists (tamoxifen and RU486) induce
such an interaction. Interestingly, these antagonists switch into
perfect agonists when the receptor ligand-independent activation
function (AF-1) is activated by the MAPK pathway. This activation is
concomitant to the release of the corepressors and to the recruitment
of components of the coactivator complex (99). This phenomenon may
explain why patients, treated for breast cancer, eventually acquire
resistance to tamoxifen. Intriguingly, a small coactivator (L7 or SPA
for switch protein for antagonist) has been recently identified and
whose coexpression enhances transcription of antagonist- occupied
ER and GR (100). Surprisingly, L7/SPA has no effect on
agonist-dependent transcription by these receptors. In light of these
data, it is possible that the cellular ratio between corepressors and
coactivators such as L7/SPA might determine whether an antagonist-bound
receptor would be active or not.
The above mentioned corepressors interfere directly with
transcriptional activation. Transcriptional inhibition can also be
efficiently achieved by preventing nuclear receptor from accessing DNA.
TRUP and calreticulin are such proteins whose binding either to the
hinge-domain of TR and RAR (TRUP) or to the DNA-binding domain of AR,
GR, and RAR (calreticulin) interferes with their DNA binding
(101, 102, 103). However, these proteins should not be considered as being
real corepressors according to its definition mentioned earlier.
Indeed, TRUP and calreticulin prevent transcriptional activation by
interfering with receptor binding but not by enhancing basal
transcription repression.
The yeast protein Ssn6 was isolated as a negative regulator of the
estrogen and progesterone receptors (104). It appeared to repress the
ligand-independent activity of ER-AF-1. It is not clear whether Ssn6
should qualify as a nuclear hormone corepressor especially because it
affects AF-1 but not AF-2. In addition, there is no study available
that could indicate whether Ssn6 fits all the criteria of the
corepressor family, and since the steroid hormone receptors are not
naturally expressed in yeast, it is unclear whether a similar mechanism
would occur in mammals. Interestingly, Ssn6 is involved in
glucose-mediated gene repression and requires a partner, Tup1, to
achieve full repression (105). Tup1 has been shown to mediate
repression by its ability to interact directly with histones H3 and H4
(106). This suggests that repression involves some chromatin
components.
 |
SMRT AND N-CoR MEDIATE TRANSCRIPTIONAL REPRESSION THROUGH THE
RECRUITMENT OF A HISTONE DEACETYLASE COMPLEX
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Immunoprecipitation experiments have revealed that N-CoR and
SMRT are components of a cellular complex containing the proteins
Sin3A/B and histone deacetylases (107, 108, 109). The N terminus repression
domain (SD-1) of SMRT interacts with Sin3A, which in turn associates
with the histone deacetylase HDAC-1 through one of its two silencing
domains (110). No evidence of a direct interaction between HDAC-1 and
SMRT was observed, suggesting that Sin3 acts as a bridging molecule
between SMRT and the deacetylase complex. These findings argue that at
least part of the silencing mediated by nuclear hormone repressors
involves the deacetylation of histones through the recruitment of a
histone deacetylase complex (Fig. 2
).
The importance of histone deacetylation associated to corepression has
been highlighted recently in human leukemia (111, 112). Two forms of
acute promyelocytic leukemia (APL) are caused by chromosomal
translocations that create oncogenic fusion proteins between RAR and
either PML (promyelocytic leukemia) or PFLZ (promyelocytic leukemia
zinc finger). Both PML-RAR and PFLZ-RAR recruit the
corepressor-deacetylase complex through RAR in a ligand-independent
fashion. These interactions are abolished with high-dose retinoic acid.
However, PFLZ-RAR is also able to associate constitutively and stably
with corepressors and deacetylases through the PFLZ moiety,
irrespective of the presence of the ligand. This explains why PML-RAR
APL patients usually recover after treatment with retinoic acid but not
PFLZ-RAR patients. These data strongly suggest that leukemia induced by
PML-RAR and PFLZ-RAR is derived from aberrant chromatin
deacetylation.
Chromatin modification through acetylation cannot account solely for
the repression of transcription mediated by unliganded receptors.
Silencing is indeed observed in systems that are devoid of proper
chromatin such as transient transfections and in vitro
transcription (86, 87, 89). Therefore, alternative silencing pathways
must exist and function independently of the recruitment of any histone
deacetylase. Early results have suggested that TR silencing is mediated
by its direct interaction with the general transcription factor TFIIB
and that thyroid hormone is able to decrease this interaction (113). In
agreement with these results, TFIIB was recently demonstrated to
interact with the corepressors N-CoR and SMRT as well as with Sin3
(110). It appears that TFIIB binds in vitro to the same
silencing domain (SD-1) of SMRT as does Sin3 (see above). It is not
clear to date whether the binding of TFIIB and Sin3 to SMRT are
mutually exclusive. Interestingly, overexpression of SMRT reduces the
transcriptional activity of TFIIB tethered to a promoter indicating
that their physical interaction is functional. In another study, N-CoR
was shown to make simultaneous and noncompetitive contacts with the
general transcription factors TFIIB, TAFII32, and
TAFII70 (114). In this case the binding of TFIIB
with N-CoR can occur in the presence of Sin3B and HDAC-1. The
sequestration of TFIIB and TAFII32 by N-CoR
inhibits the functional interactions of the two former factors, which
is crucial for transcriptional initiation. SMRT contains two silencing
domains within its amino-terminal region, namely SD-1 and SD-2, but
only SD-1 reportedly interacts with Sin3A or TFIIB (110). Similarly,
Sin3A possesses two silencing domains, one of which interacts only with
the histone deacetylase HDAC-1. Moreover, the histone deacetylase
inhibitor, trichostatin A, has no notable effect on the Sin3A
ability to repress transcription. These results suggest that, in
addition to the recruitment of either TFIIB or HDACs, other
unidentified alternative silencing pathways may exist.
 |
CONCLUDING REMARKS
|
---|
The increasing number of described cofactors adds to the
complexity of the transcriptional regulation mediated by nuclear
hormone receptors. One of the future challenges will be to determine
the specificities of the coregulator family. There is strong evidence
that coregulators do not modulate the activity of all nuclear hormone
receptors. For instance, it is known that neither SMRT nor N-CoR
represses PPAR
activity although they interact in solution (115). In
fact, the PPAR
/RXR
heterodimer fails to recruit these
corepressors once bound to DNA, at least at the acyl CoA oxidase gene
promoter. More interestingly, N-CoR but not SMRT potentiates RevErb
repression indicating that these two corepressors do not possess
redundant functions. Similarly, the recently described "repressor of
estrogen receptor activity" (REA) appears to be selective for the
liganded ER (116). Thus, the first level of specificity might be
achieved by the selective recruitment of a given cofactor. We now know
that some coregulators are part of multisubunit complexes such as DRIP
and P/CAF (47, 49, 117). The presence of various accessory proteins
within these complexes or alternative subcomplexes will likely
influence the specificity of transcription. We have also seen that some
coactivators possess a HAT activity. Finally, posttranslational
modifications of coregulators or of other components within their
complex may as well prove to be important for proper regulation. All
these potential levels of regulation increase not only the complexity
but also the number of possibilities available for a better tuning of
transcriptional control. The active research in the nuclear hormone
receptor during the last decade has dramatically changed the simple
view of the mechanism of receptor action. More surprises are likely to
come in the near future.
 |
FOOTNOTES
|
---|
Address requests for reprints to: Dr. Walter Wahli, Institut de Biologie Animale, Université de Lausanne, Bâtiment de Biologie, CH-1015 Lausanne, Switzerland. E-mail:
walter.wahli{at}iba.unil.ch
1 Present address: Department of Biological Chemistry, Molecular
Biology Institute, University of California, Los Angeles, California
90095. 
Received for publication July 21, 1999.
Revision received September 27, 1999.
Accepted for publication October 6, 1999.
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