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THE JOURNAL OF BIOLOGICAL CHEMISTRY VOL. 280, NO. 38, pp. 32565–32568, September 23, 2005
© 2005 by The American Society for Biochemistry and Molecular Biology, Inc. Printed in the U.S.A.

Dynamic Combinatorial nated, and sequential manner. These findings challenged the conventional
view of stable, NR-based, template-bound complexes and suggested a dynamic
Networks in Nuclear Receptor- and multistep model involving rapid and carefully orchestrated series of
exchanges between NRs, coregulators, and the promoter. In this review, we
mediated Transcription* will focus on the dynamics of the interactions between NRs and their coregu-
lators and on their fine tuning by a variety of post-translational modifications
Published, JBC Papers in Press, August 1, 2005, DOI 10.1074/jbc.R500008200
or degradation processes that occur in response to the ligand or to other
Cécile Rochette-Egly1 cellular signalings, so that, in the end, the correct proteins are present with the
From the Department of Cell Biology and Signal Transduction, Institut de right activity, at the right place, and at the right time.
Génétique et de Biologie Moléculaire et Cellulaire, CNRS/INSERM/Université
Louis Pasteur, Unité Mixte de Recherche 7104, BP 10142, Orderly Recruitment of NRs and Their Coregulators at
67404 Illkirch Cedex, France a Target Promoter
Following the hormone signal, NRs bound at HREs initiate an ordered and
The nuclear hormone receptor (NR)2 superfamily describes a diverse array coordinated recruitment of a series of coactivator complexes. Five major
of transcription activators working in a ligand-dependent manner and exerting classes of coactivators have been identified: (i) members of the p160 subfamily

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action by regulating the expression of specific subsets of genes (1, 2). The (exemplified by SRC-1/N-CoA1, SRC-2/GRIP-2/TIF-2, and SRC-3/ACTR/
receptors for steroid hormones, which include the estrogen (ER), androgen AIB1/p/CIP/RAC3/TRAM-1) (10), which serve mainly as adapters recruiting
(AR), progesterone (PR), and glucocorticoid (GR) receptors, are held in the other complexes, (ii) histone acetyltransferases (HATs) such as CBP/p300 and
cytoplasm, in association with chaperone complexes. Ligand binding acts as an p/CAF (11), (iii) histone arginine methyltransferases (HMTs) such as CARM1
on-switch, inducing their release from the chaperone molecules, their dimer- or PRMT1 (12), (iv) nucleosome remodeling complexes such as SWI/SNF (7,
ization, their entrance into the nucleus, and their binding to hormone response 13), and finally (v) the multisubunit mediator complex (14, 15) that acts as a
elements (HREs) within the regulatory regions of target genes. In contrast, the “bridge” between NRs and the basal transcriptional machinery.
receptors for non-steroidal hormones such as the vitamin D (VDR), retinoic The orderly and sequential recruitment of these coactivators with different
acid (RARs), and peroxisome proliferator-activated (PPAR) receptors are enzymatic activities has been recognized only recently. In chromatin immu-
found primarily in the nucleus and bound at HREs as heterodimers with the noprecipitation (ChIP) assays, Metivier et al. (16) defined the concept of a
retinoid X receptor (RXR). They are associated with histone deacetylase-con- “transcriptional clock” directing this orderly “procession.” ER and the SRC
taining complexes tethered through corepressors (N-CoR and SMRT), result- family of coactivators are the first to be recruited to the estrogen-responsive
ing in chromatin compaction and gene silencing. Upon ligand binding, the pS2 promoter, followed by the HATs and HMTs, in agreement with their
corepressor-binding interface of NRs is destabilized, leading to the dissocia- essential role in the construction of the complexes involved in chromatin
tion of corepressors (3). remodeling. Then the mediator is recruited, facilitating the arrival of RNA
The basic mechanism for switching on gene transcription by liganded NRs PolII and GTFs. However, the temporal order of recruitment of these com-
(either steroid or non-steroid) relies on a complex and ever growing network of plexes may differ from one target gene to the other (17), indicating that a given
interactions with coregulatory proteins. For most NRs, this network is directed NR can employ multiple programs for gene activation depending on promoter
by a specific domain, the activation function 2 (AF-2) domain, located in the context. As an example, a recent study demonstrated that both the mediator
C-terminal ligand-binding domain (LBD) (Fig. 1A). The LBD is composed of and RNA PolII can be recruited at the promoter of the RAR␤ gene even when
12 ␣ helices organized as an antiparallel sandwich (Fig. 1B). Upon ligand bind- it is in the inactive state. Transcription is initiated by a gene-specific cofactor
ing, the AF-2 domain undergoes major structural rearrangements (4, 5), cre- PARP-1, which converts the mediator to an active form through triggering the
ating a new binding surface for coactivators (Fig. 1B). The AF-2 domain coop- release of the Cdk8 module and the recruitment of TFIIH (18).
erates with a second activation domain residing in the N terminus, the AF-1
domain (4), to recruit multiple complexes to alter the chromatin structure The Ubiquitin-Proteasome Pathway: a Central Regulator of the
surrounding the promoter of target genes (6 – 8). In the end these events pave Dynamics through Proteolysis
the way for the recruitment of the transcription machinery, including RNA After the notion of clock, further work revealed the notion of dynamism
polymerase II (RNA PolII) and the general transcription factors (GTFs) (9). controlling the chronological sequence of the association/dissociation of NRs
A concept that has developed over the last several years is that NRs and their and their coregulators at a promoter. Indeed, once recruited, each coactivator
coregulators are subjected to rapid modifications (phosphorylation, ubiquiti- paves the way for the next one and then dissociates rapidly. Moreover, a new
nation, acetylation, methylation) and proteasomal degradation. Therefore it aspect that has been demonstrated in studies using ChIPs and fluorescence
emerged that they exert transcriptional control in a combinatorial, coordi- recovery after photobleaching is that steroid receptors, together with their
coactivators, cycle on and off the promoter many times, interacting only briefly
with response elements (16, 19 –21). This raised the idea that cyclic interaction
* This minireview will be reprinted in the 2005 Minireview Compendium, which will be with transcription complexes would be a common feature of promoters acti-
available in January, 2006. The studies mentioned in text were supported by funds vated by NRs. It has been proposed that this cyclic recruitment of NRs and
from CNRS, INSERM, the Hôpital Universitaire de Strasbourg, and the Association pour
la Recherche sur le Cancer. their cofactors on a target promoter might be directed by cyclic changes in
1
To whom correspondence should be addressed. Tel.: 33-3-88-65-34-59; Fax: 33-3-88- chromatin structure and in the acetylation/methylation/phosphorylation sta-
65-32-01; E-mail: cegly@igbmc.u-strasbg.fr. tus of histones, NRs, and their cofactors. It might also rely on allosteric changes
2
The abbreviations used are: NR, nuclear receptor; ER, estrogen receptor; AR, androgen induced within partner proteins of the transcription apparatus during their
receptor; PR, progesterone receptor; VDR, vitamin D receptor; RAR, retinoic acid physical interaction (19, 22, 23). However, recent evidence argues that this
receptor; RXR, retinoic X receptor; PPAR, peroxisome proliferator activated receptor;
HRE, hormone response element; N-CoR, nuclear receptor corepressor; SMRT, silenc-
process is likely driven by the ubiquitin-proteasome pathway.
ing mediator of retinoid and thyroid receptors; AF, activation function; LBD, ligand- Classically, the ubiquitin-proteasome pathway targets regulatory proteins
binding domain; RNA PolII, RNA polymerase II; GTF, general transcription factor; SRC, for proteolysis (24, 25) and is broken up in two parts: 1) the ubiquitination
steroid receptor coactivator; HAT, histone acetyltransferase; HMT, histone methyl- machinery, which consists of an E1 ubiquitin-activating enzyme, several E2
transferase; CARM1, coactivator-associated arginine methyltransferase-1; PRMT1, ubiquitin-conjugating enzymes, and multiple E3 ubiquitin ligases directing
protein arginine methyltransferase-1; CBP, cyclic AMP response element-binding
ubiquitin to target proteins and 2) the 26 S proteasome itself, which comprises
protein (CREB)-binding protein; p/CAF, p300/CBP-associated factor; SWI/SNF, switch
defective/sucrose nonfermenter; Cdk, cyclin-dependent kinase; ChIP, chromatin a 20 S core complex and a 19 S complex that recognizes the ubiquitinated
immunoprecipitation; PARP-1, poly(ADP-ribosylation) protein-1; UbcH7, ubiquitin- proteins and prepares them for entry into the 20 S core.
conjugating enzyme 7; E6-AP, papillomavirus E6-associated protein; TBL1, transducin Several laboratories have demonstrated that NRs, as well as coactivators,
␤-like protein 1; TBLR1, TBL1-related protein; P-TEFb, positive transcription elonga- corepressors, and components of the GTF machinery are ubiquitinated and
tion factor; SUG-1 suppressor of Gal4D lesions 1; MAPK, mitogen-activated protein degraded by the 26 S proteasome in response to the ligand (26 –29). A radical
kinase; Erk, extracellular signal-regulated kinase; JNK, c-Jun N-terminal kinase; CAK,
Cdk-activating kinase; XP, xeroderma pigmentosum; pin1, peptidyl-prolyl cis/trans hypothesis first suggested that the functional role of this pathway is to provide
isomerase; E1, ubiquitin-activating enzyme; E2, ubiquitin carrier protein; E3, ubiq- an efficient suicide mechanism for attenuation of the transcriptional signal
uitin-protein isopeptide ligase. (30, 31).

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MINIREVIEW: New Networks in NR-mediated Transcription

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FIGURE 1. A, schematic representation of the func-
tional domains and the major phosphorylation
sites of some nuclear hormone receptors. B, com-
parison of the crystal structures of unliganded
RXR␣ (Protein Data Bank entry 1LBD) and liganded
RAR␥ (Protein Data Bank entry 2LBD) (52).

However, in a perhaps more unexpected twist on the ubiquitin-proteasome plexity. Indeed, recent evidence points out that the ubiquitin-proteasome sys-
theme, it emerged recently that proteasomal degradation is inextricably linked tem can also function in transcriptional activation independently of proteolysis
to transcription. Then the question was how? It has been proposed that deg- (36, 37). In line with this, E3 ubiquitin ligases are integral components of the
radation by the ubiquitin-proteasome pathway might provide an efficient coactivator complexes and of the RNA PolII transcription machinery (37) and
mechanism for regulating the cyclic interaction of NRs with the promoter (19, could participate in NR-mediated transcription without signaling degradation.
23). However, the most plausible mechanism would be to clear out corepres- In the same order of ideas, evidence suggests that ubiquitination may facilitate
sors and/or coactivators so that other coregulators can subsequently bind (29). transcription elongation by controlling the recruitment of the elongation fac-
In line with this theme, E2 ubiquitin-conjugating enzymes (UbcH7) and E3 tor P-TEF-b by transcription activators (38). Another striking example is the
ubiquitin ligases (E6-AP) have been shown to interact with NRs and their proteasome itself. Indeed, SUG-1, which is one of the six ATPases of the 19 S
coactivators and to be implicated in NR-dependent transcription as well as in regulatory complex of the proteasome (also known as APIS), interacts with
the degradation of the transcriptional machinery (29). Moreover, Perissi et al. NRs, the general transcription factor TFIIH, and RNA PolII and is recruited to
(32) demonstrated that TBL1 and TBLR1, which are components of E3 ubiq- transcriptionally active genes (39, 40). It has been suggested that the 19 S
uitin ligase complexes, function as adaptor molecules for the recruitment of complex could facilitate both transcription and elongation by remodeling pro-
the proteasome and the degradation of the N-CoR/SMRT corepressors. Such tein complexes and/or chromatin through its ATP-dependent chaperone
a process could mediate the exchange of corepressor for coactivator com- activity (41– 43). This role of the 19 S complex would be to prevent the inter-
plexes. Proteasomal degradation of NRs and their coregulators could also pro- actions from stalling and therefore to maintain the dynamics of the complexes.
mote disassembly of the initiation complex, facilitating the transition to a Finally, an alternative mechanism has also been suggested from the observa-
productive elongation complex (33, 34). Finally, it has been demonstrated that tion that histones are ubiquitinated (44). In agreement with the histone code
the 26 S proteasome associates with elongating polymerase complexes and that hypothesis, ubiquitination could create new platforms for binding additional
its proteolytic activity is important for resolving stalled complexes at termina- chromatin modifiers and thereby influence other modifications such as acety-
tion sites (35). Altogether, these models are consistent with the idea that tran- lation and methylation (45). It is also probable that histone ubiquitination plays
scription is a dynamic process with continual exchange and turnover of NRs, a structural role by recruiting the 19 S proteasome (46).
coactivators, and other components of the transcriptional machinery. From all these examples, it is clear that components of the ubiquitin-pro-
teasome pathway could function to orchestrate the dynamics of NR-mediated
New Roles for Ubiquitin and Proteasomal Subunits transcription in several diverse ways, ranging from the regulation of chromatin
without Proteolysis to the degradation of the transcriptional complexes. However, due to the
Today, the interconnectivity of transcription and the ubiquitin-proteasome growing number of proteins with double duties in the transcription and pro-
system is clearly established, but the emerging picture is increasing in com- teasome pathways, we can expect many new regulatory strategies in the future.

32566 JOURNAL OF BIOLOGICAL CHEMISTRY VOLUME 280 • NUMBER 38 • SEPTEMBER 23, 2005
MINIREVIEW: New Networks in NR-mediated Transcription

MAP Kinases Signaling to NRs and Their Coregulators:


a Coordination of the Dynamics
Another emerging level of transcription regulation by NRs involves phos-
phorylation processes (47). A number of studies demonstrated that steroid and
non-steroid hormones are able to cross-talk with several signaling pathways
through the rapid activation of kinase cascades. As an example, estradiol and
retinoic acid signaling leads to the rapid activation of MAPKs (Erks and p38
MAPK), which can enter the nucleus and then phosphorylate the N-terminal
AF-1 domains of ER␣ and RAR␥ (40, 47, 48) (Fig. 1A).
It is becoming increasingly clear that MAPKs play a key role in the dynamics
of NR-mediated transcription (49). In particular, phosphorylation of the AF-1
domain of NRs influences the recruitment of p160 coactivators, thereby help-
ing the reorganization of chromatin (47). It also triggers the dissociation of
repressor proteins. In line with this, Bour et al. (50) demonstrated recently that
phosphorylation of the AF-1 domain of the RAR␥ isotype induces the dissoci-
ation of vinexin ␤, a repressor of RAR␥-mediated transcription. Whether such
a dissociation process is followed by the recruitment of other complexes, in

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order to achieve maximal transcription efficiency, remains to be determined.
Phosphorylation by MAPKs also signals the ubiquitination and the degra-
dation of some NRs such as RAR␥ (40) and PR (51). As the transcription and
ubiquitin-proteasome systems are intimately linked (see above), it has been FIGURE 2. Recapitulation of the dynamic assembly of NRs and their cofactors during
proposed that phosphorylation signals recruitment of ubiquitin ligase com- transcription activation. In step 1, the hormone activates NRs and induces their phos-
plexes, which on the one hand could control transcription by bridging NRs to phorylation by MAPKs. Phosphorylation cooperates with the ligand for dissociation and
proteolysis of the histone deacetylase corepressor complexes. The p160 family of coac-
the transcription machinery and, on the other hand, could trigger NR degra-
tivators is also phosphorylated and recruited as well as HAT, HMT, and E3 ubiquitin ligase
dation via ubiquitin-dependent proteolysis (36, 37, 52). It remains to be deter- complexes. Histones are phosphorylated, methylated, acetylated, and ubiquitinated,
mined, however, whether the phosphorylated AF-1 domains of NRs recruit and these modifications cooperate for the recruitment of additional transcriptional com-
complexes with ubiquitin ligase activity as suggested by this model. plexes such as ATP-dependent nucleosome remodeling complexes. In step 2, after mod-
Further complexity came with the finding that corepressors and coactiva- ifying their targets, the coactivators are ubiquitinated by the E3 ubiquitin ligases to
tors are also phosphorylated by MAPKs in response to steroidal and non- signal their destruction by the proteasome. This process continues many times with the
purpose of recruiting all the coactivators with an essential function in chromatin remod-
steroidal hormones (53–55). In agreement with the transcription clock eling, leading to the displacement of impeding nucleosomes within the proximal pro-
hypothesis, it has been suggested that phosphorylation of the N-CoR/SMRT moter region and thus facilitating the arrival of RNA PolII and GTFs. At this step, TFIIH
corepressors might represent a mark for their ubiquitylation and degradation becomes able to interact with NRs, and the Cdk7 kinase subunit phosphorylates their
to allow the recruitment of coactivators (32). The p160 coactivators are also AF-1 domain. This phosphorylation process participates in the assembly of the transcrip-
phosphorylated. The best example is SRC-3/AIB1, which becomes phospho- tional preinitiation complex (PIC). In step 3, the preinitiation complex disassembles and
RNA PolII escapes from the promoter with its own set of E3 ubiquitin ligases and chro-
rylated at several residues by p38 MAPK in response to estrogens (55) and matin remodelers, facilitating transition to elongation. Then, in step 4, NRs are degraded
retinoic acid.3 O’Malley and colleagues (55) proposed that phosphorylation by the ubiquitin-proteasome system. According to this model, on-going transcription
would provide the basis for a combinatorial code determining the ability of would entail continuous reloading of newly synthesized NRs. However, upon cessation
SRCs to distinguish among various NRs. However, our group demonstrated of the signal, histone deacetylase-containing complexes are recruited and chromatin is
that phosphorylation also represents a mark for proteasomal degradation. recompacted.
Finally, histones were also found to be phosphorylated by MAPKs (49, 56).
According to the histone code hypothesis, a combinatorial and coordinated
proline-rich motif within the N-terminal AF-1 domain of NRs (Fig. 1A). In an
dynamic model has been suggested whereby phosphorylation participates with
unexpected twist on the molecular communication between TFIIH and NRs,
acetylation, methylation, and ubiquitination to provide motifs for the recruit-
Drané et al. (64) recently demonstrated that in the absence of a functional AF-1
ment of other chromatin modifying or remodeling complexes.
domain, as observed for VDR, a second transcriptional activator can be phospho-
Thus, it is becoming increasingly evident that MAPK-mediated phospho-
rylated by TFIIH, upon interaction with VDR, thereby filling up the role of an AF-1
rylation processes also orchestrate the dynamics of NR-mediated transcription
domain. However, for other NRs such as RAR␥, the serine residue phosphorylated
through influencing the rapid exchange and turnover of NRs and their coregu-
by Cdk7 is adjacent to the MAPK phosphorylation site (Fig. 1A) so that in the end,
lators within transcriptional complexes.
both Cdk7 and MAPKs cooperate for the activation of target genes, highlighting
General Transcription Factor TFIIH: Another New Central a new level of combinatorial regulation through coordinated phosphorylation
Regulator of NR Phosphorylation and Transcriptional Activity processes (52).
It has been suggested that NR phosphorylation by TFIIH would define a “code”
A fascinating new concept that has developed over the last several years is
specifying the recruitment of partners participating in formation of the preinitia-
that NRs are phosphorylated by the Cdk7/cyclin H/MAT1 (CAK) subcomplex
tion complex. However, one cannot exclude the possibility that it promotes disas-
of TFIIH, which is a general transcription factor composed of 10 subunits (57).
sembly of the preinitiation complex, facilitating transition to elongation, according
This phosphorylation process has been studied extensively by our group in the
to a model very similar to that proposed for phosphorylation of the RNA PolII
case of RARs (58, 59), but other NRs including ER␣ (60), AR (61), and PPARs
CTD by the same Cdk7 kinase within TFIIH (9). Such a code might also include
(62), have also been reported to be phosphorylated by Cdk7. The importance of
cis-trans isomerization of the proline residues that follow the phosphorylated
TFIIH-mediated phosphorylation has been highlighted in recent studies using
serines (66). In line with this the proline isomerase pin1/Ess1 has been recently
cells from patients bearing mutations in the XPD subunit of TFIIH. These
shown to bind the phosphorylated form of RAR␣ (67). It would be interesting to
mutations result in incorrect positioning of the Cdk7 kinase relative to its determine whether phosphorylation changes the equilibria between the cis and
substrate. Indeed, in these cells, NRs are hypophosphorylated, and the ligand- trans forms of the (Ser(P)/Thr)-Pro motifs, as each state is potentially a specific
dependent response is decreased (62– 64). Similarly, expression of RAR␥ recognition state for an interacting factor (66).
mutated at its phosphorylation sites in a RAR␥-null background affected dra-
matically the differentiation of mouse embryocarcinoma cells (F9 cells) and NR Phosphorylation in Response to Other Cellular Signaling
activation of target genes in response to retinoic acid (65). Pathways: a Mechanism to Switch Off the Ligand Response
TFIIH is recruited to the promoter in concomitance with the transcriptional
Today, new roles for phosphorylation in regulation of NR-mediated transcrip-
machinery and thus after the coactivators and the chromatin modifying/remod-
tion are being discovered at an accelerated pace. Several extracellular signals such
eling complexes (16, 18). Binding to the promoter makes TFIIH able to dock NRs
as growth factors, insulin, stress, cytokines, or other signals, activate cytosolic ser-
bound at their cognate HRE, through specific subunits (59, 60), thereby allowing
ine kinase cascade pathways, ending at different kinases, including MAPKs (Erks,
the recognition by the Cdk7 kinase subunit of the phosphorylation site located in a
JNKs, p38 MAPK), protein kinase C, or cyclic AMP-dependent protein kinase,
which can enter the nucleus and phosphorylate NRs. In fact, phosphorylation in
3
M. Gianni and C. Rochette-Egly, submitted for publication. response to such signalings rather inactivates NR-mediated transcription. An

SEPTEMBER 23, 2005 • VOLUME 280 • NUMBER 38 JOURNAL OF BIOLOGICAL CHEMISTRY 32567
MINIREVIEW: New Networks in NR-mediated Transcription

interesting example is that of PPAR␥, the transcriptional activity of which is 48366 – 48371
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Nathalie Bruck, and Sébastien Lalevée for enthusiastic discussions and con- 51. Shen, T., Horwitz, K. B., and Lange, C. A. (2001) Mol. Cell. Biol. 21, 6122– 6131
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53. Hermanson, O., Glass, C. K., and Rosenfeld, M. G. (2002) Trends Endocrinol. Metab.
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