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J. Biol. Chem., Vol. 276, Issue 40, 36865-36868, October 5, 2001
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§ and
From the Department and School of Medicine,
Howard Hughes Medical Institute, University of California, San Diego,
La Jolla, California 92095-0648 and ¶ Department of Cellular and
Molecular Medicine, Department and School of Medicine, University of
California, San Diego, La Jolla, California 92093-0651
Members of the nuclear receptor superfamily
directly activate or repress target genes by binding to hormone
response elements (HREs)1 in
promoter or enhancer regions, and by binding to other DNA sequence-specific activators and can inhibit the transcriptional activities of other classes of transcription factors by
transrepression. Hormone response elements provide specificity to
receptor homodimer heterodimer binding (reviewed in Ref. 2).
Nuclear receptor functions are directed by specific activation domains,
referred to as activation function 1 (AF-1), which resides in the N
terminus, and activation function 2 (AF-2), which resides in the
C-terminal ligand binding domain (LBD) (reviewed in Ref. 1). Regulation of gene transcription by nuclear receptors requires the recruitment of
proteins characterized as coregulators, with
ligand-dependent exchange of corepressors for coactivators
serving as the basic mechanism for switching gene repression to
activation. In this review, we discuss biochemical and genetic studies
suggesting that coregulatory complexes are differentially utilized in
both a cell- and promoter-specific fashion to activate or repress gene transcription. These coregulatory components, themselves targets of
diverse intracellular signaling pathways, provide a combinatorial code
for tissue- and gene-specific responses, utilizing both enzymatic and
platform assembly functions to mediate the actions of nuclear receptor
genetic programs critical for developmental and homeostatic processes
in metazoan organisms.
A diverse group of proteins have emerged as potential coactivators
for nuclear receptors. Ligand-dependent recruitment of coactivators is dependent on AF-2, which consists of a short conserved helical sequence within the C terminus of the LBD (2). Biochemical and
expression cloning approaches have been used to identify a large number
of factors that interact with nuclear receptors in either a
ligand-independent or a ligand-dependent manner and are often components of large multiprotein complexes. Many of these factors
are capable of potentiating nuclear receptor activity in transient
cotransfection assays. In addition, a distinct set of coactivators is
associated with the AF-1 domain. As the number of potential
coregulators clearly exceeds the capacity for direct interaction by a
single receptor, the most plausible hypothesis is that transcriptional
activation by nuclear receptors involves the actions of multiple
factors. These factors act in a sequential and/or combinatorial manner
to reorganize chromatin templates and to modify and recruit basal
factors and RNA polymerase II (3, 4).
As chromatinized transcription units are "repressed" compared
with naked DNA, a critical aspect of gene activation involves nucleosomal remodeling (reviewed in Refs. 3-5). Two general classes of
chromatin remodeling factors that appear to play critical roles in
transcriptional activation by nuclear receptors have been identified. These are ATP-dependent nucleosome remodeling complexes and
factors that contain histone acetyltransferase activity. The yeast
SWI·SNF complex facilitates the binding of sequence-specific
transcription factors to nucleosomal DNA and can cause local changes in
chromatin structure in an ATP-dependent manner (3-12).
Mammalian homologues of Drosophila SWI2/SNF2 such as
BRG1/hBrm function as components of large multiprotein complexes.
Transfection of ATPase-defective alleles of either Brg1 or
hBrm into several mammalian cell lines leads to a
significant decrease in the ability of several nuclear receptors to
activate transcription (3-6). Remodeling complexes containing ISWI
(imitation SWI) may also be involved in nuclear receptor function
(7-11).
Rates of gene transcription roughly correlate with the degree of
histone acetylation, with hyperacetylated regions of the genome
appearing to be more actively transcribed than hypoacetylated regions
(reviewed in Ref. 7). The specific recruitment of a complex with
histone acetyltransferase activity to a promoter may play a critical
role in overcoming repressive effects of chromatin structure on
transcription (4-7). This concept was further supported by the
subsequent finding that the mammalian Gcn5 orthologues, including
p/CAF, CREB-binding protein (CBP), adenovirus E1A-binding protein p300,
and TAFII250, each possess intrinsic histone
acetyltransferase (HAT) activity (7-11). Conversely, the discovery
that a mammalian histone deacetylase (HDAC) was a homologue of the
yeast corepressor, RPD3 (13), gave rise to the hypothesis that
regulated activation events might involve the exchange of complexes
containing histone deacetylase functions with those containing histone
acetyltransferase activity (Fig. 1). It
appears that in most cases the acetyltransferases are not directly
recruited to nuclear receptors but associate with other coactivators
that exhibit higher affinity for the liganded receptor. The
acetyltransferase functions of factors such as CBP/p300 are
directly required for enhanced transcription on chromatinized templates (14).
A large number of proteins that are recruited in a
ligand-dependent fashion have the capacity to enhance
transcriptional activation by transient transfection. Several insights
into the mechanisms by which coactivator complexes are recruited to
nuclear receptors in a ligand-dependent manner have been
provided by the initial identification of the p160 family of nuclear
receptor coactivators, referred to as SRC-1/NCOA1, TIF2/GRIP1, and
p/CIP/A1B1/ACTR/RAC/TRAM-1 (reviewed in Ref. 15). The p160 factors
consist of three members that exhibit a common domain structure,
illustrated in Fig. 1. The central conserved domain mediates
ligand-dependent interactions with the nuclear receptor
LBD, whereas the conserved C-terminal transcriptional activation
domains mediate interactions with either CBP/p300 or protein-arginine
methyltransferase (16, 17). Based on the presence of three regulatory
domains, members of the p160 family have been suggested to function as
coactivators, at least in part, by serving as adapter molecules that
recruit CBP and/or p300 complexes to promoter-bound nuclear receptors
in a ligand-dependent manner (18, 19). Biochemical studies
have also demonstrated strong ligand-dependent
interactions between nuclear receptors and p140 factors,
probably representing the coregulator RIP140, which results
in a reproductive defect in female mice on gene deletion (20).
Analysis of the nuclear receptor interaction domain of the p160 family
led to the identification of three repeated motifs with a consensus
sequence LXXLL in which L represents leucine and
X represents any amino acid. The LXXLL motif has
been found to be necessary and sufficient for
ligand-dependent interactions with the nuclear receptor
ligand binding domain (19, 21-25). Structural studies of the PPAR Many additional factors have been demonstrated to enhance nuclear
receptor activity in functional assays, suggesting that they may serve
as nuclear receptor coregulators (reviewed in Ref. 1). Biochemical
studies and protein-protein interaction screens suggest that many of
these proteins function as components of large multiprotein complexes
and that additional enzymatic activities may be important for their
function. For example, the p160 protein GRIP1 can associate with
arginine methyltransferase 1 (CARM1), which potentiates
ligand-dependent transcription by several nuclear receptors
(16). PRMTI, a second arginine methyltransferase related to CARM1, also
functions independently as a nuclear receptor coactivator (17). The
CBP/p300 coactivators can recruit additional factors with HAT activity,
such as the p/CAF·Gcn5L complexes (11, 18). The content and
conformation of the recruited complexes may explain why distinct
acetyltransferases are required by different DNA-bound transcription
factors on specific gene targets (28).
In addition to coactivator complexes that harbor nucleosome
remodeling or histone acetyltransferase activities, other coactivator complexes have been identified. The best characterized of these is the
TRAP·DRIP·ARC complex, which enhances the transcriptional activities of nuclear receptors and other signal-dependent
transcription factors in vitro (29-31). The
TRAP·DRIP·ARC complex is recruited to nuclear receptors in a
ligand-dependent manner via a 220-kDa component referred to
as PBP/TRAP220/DRIP205, which contains two alternatively utilized
LXXLL nuclear receptor interaction motifs (32, 33).
Disruption of the TRAP220/PRIP205/PBP gene in the mouse results in
embryonic lethality at embryonic day 11.5, and initial studies in
myocyte enhancer factors have suggested a defect in
ligand-dependent thyroid hormone and PPAR As more than 30 additional putative coactivators have been identified,
including proteins with protease activity and an RNA that appears to
function as a coactivator (reviewed in Ref. 15), it is likely that
different protein complexes can act either sequentially, combinatorially, or in parallel, particularly in light of the evidence
of rapid turnover of DNA-receptor interactions (36, 37). One potential
scenario for a division of labor among coactivators would be for
Brg-1·Brm-like complexes to carry out chromatin remodeling while
ligand-dependent recruitment of the so called p160 factors, in concert with other factors such as CBP, p300, and p/CAF, bring required acetyltransferase activities. Finally,
recruitment of complexes such as the TRAP·DRIP·ARC
complex may function to enhance RNA polymerase II recruitment
to the promoter.
In addition, a number of factors have been isolated that can act
in a promoter-specific fashion, potentially adding important enzymatic
activities or protein-protein interactions and acting synergistically
or antagonistically with other complexes. For example, a coactivator
ASC2/Rap250/NRC/PRIP/TRBP interacts both with nuclear receptors and
CBP/p300 p160 factors or a TRAP component (DRIP130/CRSP130/Sur2) via a
C-terminal domain and possibly also contacts factors in the basal
transcription complex (38, 39).
Genetic evidence has revealed alternative promoter-specific redundancy
in cofactor requirements or absolute dependence on specific
coregulators. Both CBP and p300 are functionally limiting, exhibiting
haploinsufficiency phenotypes (40, 41), and transfection studies in
p300( The alternative requirements for diverse coactivators reflect, in part,
their tissue-specific distributions and covalent modifications of
different coactivators, exemplified by the variations in CBP in
specific cell types (47). However, a major conceptual problem is that
the number of potential coregulators clearly exceeds the capacity for
direct interaction by a single receptor. Using chromatin immunoprecipitation assays, CBP/p300·p160 complexes and
TRAP·DRIP·ARC complexes are found to be "simultaneously" bound
to estrogen receptor target genes in response to hormones (37). Whether
these complexes indeed simultaneously contact each estrogen receptor
cannot be established by this technique, especially in light of the
evidence of rapid turnover of DNA-bound receptors (36). A very rapid turnover of receptors, on the glucocorticoid response elements of
hormonally induced gene, was established by determining the turnover of
fluorescent labeled glucocorticoid receptors in a cell line containing
a multimerized contig of mouse mammary tumor virus
promoter/transcription units (36). One might speculate that there is a
correspondingly rapid exchange of receptors associated with different
coactivator, which could then combinatorially mediate a series of
essential and nonredundant steps required for transcriptional activation.
A striking example of a promoter-specific coactivator requirement has
been provided by identification of the cold-inducible coactivator PGC-1
(48, 49). PGC-1 is induced in brown fat cells by thermal stimulation
and acts as a coactivator, along with CBP and p160 factors, for
PPAR Several members of the nuclear receptor family appear to exert
critical physiologic roles by actively repressing gene transcription, alternatively functioning as a ligand-independent repressor on some
target genes or a ligand-dependent repressor on other
transcription units (Fig. 1). A search for interacting proteins
mediating these effects led to the cloning of the nuclear receptor
corepressors N-CoR and SMRT (50-52). These factors harbor
multi-independent repressor domains that can interact with mammalian
homologues of proteins that have been defined genetically in yeast to
mediate transcriptional repression, including Sin3 and histone
deacetylases (53, 54). Thyroid hormone resistance syndromes can be
correlated with mutations in the ligand binding domain of thyroid
hormone receptor Genetic evidence has permitted linkage between N-CoR and repression, as
deletion of the murine N-CoR locus relieves nuclear receptor-mediated
repression of specific genes (56). Altered patterns of transcription in
cells derived from N-CoR gene-deleted mice and the resulting block at
specific points in erythrocyte, thymocyte, and neural development
indicate that N-CoR is a required component of short term active
repression by nuclear receptors and other factors. In addition, N-CoR
also appears to be required for a subset of long term repression
events. Thus, available data suggest that specific combinations of
corepressor and histone deacetylases mediate the gene-specific actions
of DNA-bound repressors on the development of multiple organ systems.
N-CoR and SMRT appear to be components of several distinct corepressor
complexes. Although both proteins were initially suggested to interact
with complexes containing Sin3 and specific HDACs based on
coimmunoprecipitation experiments (53, 54), Sin3 complexes isolated
under stringent biochemical conditions did not contain N-CoR or SMRT.
However, purification of N-CoR from Xenopus laevis oocytes
resulted in recovery of three distinct complexes (57). One complex
contained Sin3, HDAC1, and RbAp48; the second contained a
Sin3-independent histone deacetylase; and the third complex lacked HDAC
activity. Purification of N-CoR complexes from HeLa cells has also
resulted in the recovery of at least three complexes (58-61). One
complex contains HDAC1, HDAC2, and several other components found in
the Sin3A·HDAC complex, consistent with the original
immunoprecipitation studies (58). The second complex contains several
additional components, including BRG-1, BAF170, BAF155, BAF47/INO1, and
KAP-1, a corepressor that has been linked to heterochromatin silencing
(53). What appears to be a third complex, identified through
purification of either SMRT or N-CoR, contains transducin Two sequences in the C-terminal regions of N-CoR and SMRT appear
to function cooperatively to mediate interactions with DNA-bound thyroid hormone receptor/RXR heterodimers, each containing a conserved consensus sequence LXXXIXXX(I/L) that mediate
interactions with unliganded thyroid and retinoic acid receptors
(63-65). This motif is predicted to form an extended Emerging evidence indicates that coactivators and corepressors are
themselves targets of multiple signal transduction pathways, examples
of which are illustrated in Fig. 2. Regulation of coactivator and corepressor function potentially
provides a means for integration of responses to specific
signals across families of sequence-specific transcription
factors. For example, the histone acetyltransferase activity of CBP has
been suggested to be regulated by cyclin-dependent kinases,
which presumably alter its coactivator activities during the cell cycle
(68). The ability of CBP to serve as a coactivator of CREB is enhanced
in response to calcium signaling via a mechanism involving calmodulin
kinase IV (69). The p160 nuclear receptors can be phosphorylated in
response to different signaling events, causing redistribution of p/CIP
from the cytoplasm to the nucleus (46). Further
CBP-dependent acetylation of lysine residues adjacent to
LXXLL motifs may facilitate the disassociation from
DNA-bound receptors. Similarly, corepressors are apparent targets of
signal transduction pathways, with activation of MAP kinase cascades correlating with a redistribution of SMRT from a predominantly nuclear
location to a predominantly perinuclear or cytoplasmic compartment (69,
70). The N terminus of N-CoR has been shown to interact with
mSiah2, the mammalian homologue of Drosophila Seven in
absentia (71), implicated in regulating proteosomal degradation of
proteins. Based on cotransfection assays mSiah2 can mediate a dramatic
decrease of N-CoR protein levels, blocked by a proteosome inhibitor.
The association of N-CoR/SMRT with nuclear receptors is modulated by
cell signaling events that can regulate the association and activity of
N-CoR/SMRT. Thus, activation of signaling pathways that stimulate the
MAP kinase pathway decreased association of N-CoR with estrogen
receptors in the presence of the antagonist tamoxifen, based on the
phosphorylation of the ER N terminus (67). In addition, treatment with
forskolin or epidermal growth factor resulting in serine
phosphorylation of TR Nuclear receptors can serve as repressors or activators,
apparently dependent upon the regulated exchange of binding of factors and complexes, characterized by distinct enzymatic and platform functions. In addition to a ligand-dependent switch,
various signal transduction pathways can modulate interactions of
specific coregulators with nuclear receptors or mediate their
activity or distribution between nuclear or cytoplasmic compartments.
The potential for rapid exchange of nuclear receptors and cofactors has
intriguing implications for the functional significance of ever
expanding multiple receptors of coregulatory complexes.
INTRODUCTION
Nuclear Receptor Coactivators
ATP-dependent Chromatin Remodeling Complexes
Acetyltransferases
View larger version (27K):
[in a new window]
Fig. 1.
Alternative activation and repression
functions of nuclear receptors regulated by ligand (or signaling
pathway) control of recruitment of either coactivators
or corepressors. These include complexes (Brg-1·Brm, CBP·p300,
p/CAF·Gcn5L), TRAP·DRIP·ARC, and the p160 factors (SRC-1, GRIP1,
p/CIP), which in turn can associate with an arginine
methyltransferase, CARM1. The corepressors N-CoR and
SMRT can recruit different complexes, some containing HDACs; components
of the Brg-1·Brm complex appear to be involved in repression
events.
Nuclear Receptor-interacting Coactivators
,
ER, and T3R ligand binding domains complexed to fragments
of the p160 nuclear receptor interaction domains revealed that these
motifs form short 
helices (22-25), with multiple LXXLL
motifs within a single coactivator mediating cooperative interactions
with nuclear receptor dimers or heterodimers. The LXXLL
helix is oriented and positioned at each end by a "charge-clamp" consisting of a conserved lysine in helix 3 of the ligand binding domain and a conserved glutamate in the AF-2 helix. These residues grip
the LXXLL helix so that the internal leucine residues can pack into a hydrophobic pocket in the receptor C terminus. Most nuclear
receptor coactivators have proved to contain functionally important LXXLL helices, with additional residues
contributing to binding specificity (e.g. Refs. 26 and 27).
Furthermore, these contacts are sensitive to conformational
changes induced by structurally distinct ligands.
The TRAP·DRIP·ARC Complex
receptor
function (31, 32). Intriguingly other classes of transcription factors remain competent to activate transcription in these cells. The TRAP·DRIP·ARC complex consists of more than a dozen polypeptides, a
subset of which appears to constitute modules that are components of
other activator complexes, including CRSP, NAT, SMCC, and mouse mediator, and have no known enzymatic functions (29, 31, 34). These
factors may thus function to recruit RNA polymerase II holoenzyme to
ligand-bound nuclear receptors. The TRAP·DRIP·ARC complex is not
stably associated with RNA polymerase II but can be
coimmunoprecipitated in the presence of ligand-activated vitamin D
receptor (35), suggesting a conformational change or recruitment of
additional components that allow stable interactions with RNA
polymerase II complexes.
Combinatorial Control of Receptor Function
/) embryonic fibroblasts suggest impairment in retinoic acid
receptor signaling, supporting the idea from biochemical studies that
correct regulation of transcription requires precise levels of
p300 and CBP (42). While mice lacking each of the p160 factors are
viable, subtle defects are suggested in specific receptor functions
(43-46); for example, p/CIP/SRC-3 exerts effects on somatic growth,
modulating cell-autonomous cell cycle events (45, 46).
- and T3R-mediated transcriptional activation. These
observations raise the intriguing question of why specific combinations
of coactivators are required for only some promoters regulated by the
same nuclear receptor.
Nuclear Receptor Corepressors
that enhance ligand-independent interactions with
N-CoR/SMRT (55). N-CoR also exerts repressive roles in the actions of
other classes of transcription factors (reviewed in Ref. 1).
-like
protein 1 (TBL-1), a protein with structural and functional
similarities to the WD40-containing Tup1 and Groucho corepressors (60).
HDAC3 is also a component of the N-CoR·TBL-1 complex (60, 61),
raising intriguing issues as to the specific functions of various HDACs
in N-CoR action. A specific conserved corepressor domain of N-CoR and
SMRT has also been shown to be capable of direct interaction with HDACs 4 and 5 (62, 63). In concert, these findings suggest that N-CoR
associations with specific corepressor complexes are dynamically regulated and will exhibit promoter and cell-type specificity.
Determination of N-CoR/SMRT, Receptor Interactors
helix, one
helical turn longer than the LXXLL recognition motif present
in nuclear receptor coactivators. Biochemical findings indicate that
the LXXXIXXX(I/L) motif in N-CoR and SMRT and the
LXXLL motif in coactivators utilize overlapping surfaces for
interactions, with inability of the corepressor helix to fit in the
charge clamp. However, a clever phage display screen suggests that a
second type of corepressor can be recruited to receptors, such as
estrogen receptor in the presence of antagonist (66), although N-CoR
also appears to be a required component (56, 67). Crystal structures of
the estrogen receptor bound to tamoxifen or raloxifene indicate
displacement of the AF-2 helix (e.g. Ref. 25), facilitating
corepressor binding.
Coactivators and Corepressors as Targets of Signal Transduction
Pathways
1 and dissociation of SMRT with MAP
kinase-extracellular signal-regulated kinase 1 directly inhibits
interactions between SMRT and nuclear receptors or PLZF (72).
Conclusions
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ACKNOWLEDGEMENTS |
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We apologize to our colleagues whose contributions could not be cited based on the limitation on references in this format, which also precluded detailed discussions of receptor structure. We thank our colleagues for helpful discussions.
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FOOTNOTES |
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* This minireview will be reprinted in the 2001 Minireview Compendium, which will be available in December, 2001. This is the first article of five in the "Nuclear Receptor Minireview Series." This work was supported by the National Institutes of Health, CaPCURE, and CRP.
§ Investigator of the Howard Hughes Medical Institute. To whom correspondence should be addressed. Tel.: 858-534-5858; Fax: 858-534-8180; E-mail: mrosenfeld@ucsd.edu.
Published, JBC Papers in Press, July 17, 2001, DOI 10.1074/jbc.R100041200
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ABBREVIATIONS |
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The abbreviations used are:
HRE, hormone
response element;
PPAR, peroxisome proliferator-activated receptor;
T3R, thyroid hormone receptor;
ER, estrogen receptor;
LBD, ligand binding domain;
N-CoR, nuclear receptor corepressor;
SMRT, silencing mediator of retinoic acid and thyroid hormone receptor;
ISWI, imitation SWI;
CREB, cAMP response element-binding protein;
CBP, CREB-binding protein;
HAT, histone acetyltransferase;
MAP, mitogen-activated protein;
HDAC, histone deacetylase;
SRC, steroid
receptor coactivator;
RIP, RAR interacting protein;
GRIP, glucocorticoid receptor interacting protein;
TRAP, T3R
receptor associated protein;
DRIP, vitamin receptor D interacting
protein.
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TOP
INTRODUCTION
Nuclear Receptor Coactivators