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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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 TOP INTRODUCTION DESCRIPTION OF THE NUCLEAR...NUCLEAR RECEPTOR COACTIVATORSCOACTIVATORS, A GROWING FAMILYSRC-1/CBP/p300/pCAF: A...OTHER POTENTIAL COACTIVATORSNUCLEAR RECEPTOR COREPRESSORSDISCOVERY OF COREPRESSORSSMRT AND N-CoR MEDIATE...CONCLUDING REMARKSREFERENCES |
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DESCRIPTION OF THE NUCLEAR HORMONE RECEPTORS |
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TOPINTRODUCTIONDESCRIPTION OF THE NUCLEAR...NUCLEAR RECEPTOR COACTIVATORSCOACTIVATORS, A GROWING FAMILYSRC-1/CBP/p300/pCAF: A...OTHER POTENTIAL COACTIVATORSNUCLEAR RECEPTOR COREPRESSORSDISCOVERY OF COREPRESSORSSMRT AND N-CoR MEDIATE...CONCLUDING REMARKSREFERENCES |
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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)].
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NUCLEAR RECEPTOR COACTIVATORS |
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TOPINTRODUCTIONDESCRIPTION OF THE NUCLEAR...NUCLEAR RECEPTOR COACTIVATORSCOACTIVATORS, A GROWING FAMILYSRC-1/CBP/p300/pCAF: A...OTHER POTENTIAL COACTIVATORSNUCLEAR RECEPTOR COREPRESSORSDISCOVERY OF COREPRESSORSSMRT AND N-CoR MEDIATE...CONCLUDING REMARKSREFERENCES |
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).
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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TOPINTRODUCTIONDESCRIPTION OF THE NUCLEAR...NUCLEAR RECEPTOR COACTIVATORSCOACTIVATORS, A GROWING FAMILYSRC-1/CBP/p300/pCAF: A...OTHER POTENTIAL COACTIVATORSNUCLEAR RECEPTOR COREPRESSORSDISCOVERY OF COREPRESSORSSMRT AND N-CoR MEDIATE...CONCLUDING REMARKSREFERENCES |
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), 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. |
SRC-1/CBP/p300/pCAF: A COACTIVATION COMPLEX? |
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TOPINTRODUCTIONDESCRIPTION OF THE NUCLEAR...NUCLEAR RECEPTOR COACTIVATORSCOACTIVATORS, A GROWING FAMILYSRC-1/CBP/p300/pCAF: A...OTHER POTENTIAL COACTIVATORSNUCLEAR RECEPTOR COREPRESSORSDISCOVERY OF COREPRESSORSSMRT AND N-CoR MEDIATE...CONCLUDING REMARKSREFERENCES |
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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(623–710) 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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TOPINTRODUCTIONDESCRIPTION OF THE NUCLEAR...NUCLEAR RECEPTOR COACTIVATORSCOACTIVATORS, A GROWING FAMILYSRC-1/CBP/p300/pCAF: A...OTHER POTENTIAL COACTIVATORSNUCLEAR RECEPTOR COREPRESSORSDISCOVERY OF COREPRESSORSSMRT AND N-CoR MEDIATE...CONCLUDING REMARKSREFERENCES |
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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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) (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). |
NUCLEAR RECEPTOR COREPRESSORS |
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TOPINTRODUCTIONDESCRIPTION OF THE NUCLEAR...NUCLEAR RECEPTOR COACTIVATORSCOACTIVATORS, A GROWING FAMILYSRC-1/CBP/p300/pCAF: A...OTHER POTENTIAL COACTIVATORSNUCLEAR RECEPTOR COREPRESSORSDISCOVERY OF COREPRESSORSSMRT AND N-CoR MEDIATE...CONCLUDING REMARKSREFERENCES |
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). 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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DISCOVERY OF COREPRESSORS |
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TOPINTRODUCTIONDESCRIPTION OF THE NUCLEAR...NUCLEAR RECEPTOR COACTIVATORSCOACTIVATORS, A GROWING FAMILYSRC-1/CBP/p300/pCAF: A...OTHER POTENTIAL COACTIVATORSNUCLEAR RECEPTOR COREPRESSORSDISCOVERY OF COREPRESSORSSMRT AND N-CoR MEDIATE...CONCLUDING REMARKSREFERENCES |
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):
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.
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SMRT AND N-CoR MEDIATE TRANSCRIPTIONAL REPRESSION THROUGH THE RECRUITMENT OF A HISTONE DEACETYLASE COMPLEX |
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TOPINTRODUCTIONDESCRIPTION OF THE NUCLEAR...NUCLEAR RECEPTOR COACTIVATORSCOACTIVATORS, A GROWING FAMILYSRC-1/CBP/p300/pCAF: A...OTHER POTENTIAL COACTIVATORSNUCLEAR RECEPTOR COREPRESSORSDISCOVERY OF COREPRESSORSSMRT AND N-CoR MEDIATE...CONCLUDING REMARKSREFERENCES |
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). 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.
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CONCLUDING REMARKS |
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TOPINTRODUCTIONDESCRIPTION OF THE NUCLEAR...NUCLEAR RECEPTOR COACTIVATORSCOACTIVATORS, A GROWING FAMILYSRC-1/CBP/p300/pCAF: A...OTHER POTENTIAL COACTIVATORSNUCLEAR RECEPTOR COREPRESSORSDISCOVERY OF COREPRESSORSSMRT AND N-CoR MEDIATE...CONCLUDING REMARKSREFERENCES |
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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.
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FOOTNOTES |
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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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REFERENCES |
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TOPINTRODUCTIONDESCRIPTION OF THE NUCLEAR...NUCLEAR RECEPTOR COACTIVATORSCOACTIVATORS, A GROWING FAMILYSRC-1/CBP/p300/pCAF: A...OTHER POTENTIAL COACTIVATORSNUCLEAR RECEPTOR COREPRESSORSDISCOVERY OF COREPRESSORSSMRT AND N-CoR MEDIATE...CONCLUDING REMARKSREFERENCES |
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. Nature 395:137–143[CrossRef][Medline]
recruit histone deacetylase in promyelocytic
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. EMBO J 18:3676–3687[CrossRef][Medline]
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C.-d. Geng, J. R. Schwartz, and W. V. Vedeckis A Conserved Molecular Mechanism Is Responsible for the Auto-Up-Regulation of Glucocorticoid Receptor Gene Promoters Mol. Endocrinol., December 1, 2008; 22(12): 2624 - 2642. [Abstract] [Full Text] [PDF]
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J. Cheng, D. V. Yu, J.-H. Zhou, and D. J. Shapiro Tamoxifen Induction of CCAAT Enhancer-binding Protein {alpha} Is Required for Tamoxifen-induced Apoptosis J. Biol. Chem., October 19, 2007; 282(42): 30535 - 30543. [Abstract] [Full Text] [PDF]
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D. Li, Q. Kang, and D.-M. Wang Constitutive Coactivator of Peroxisome Proliferator-Activated Receptor (PPAR{gamma}), a Novel Coactivator of PPAR{gamma} that Promotes Adipogenesis Mol. Endocrinol., October 1, 2007; 21(10): 2320 - 2333. [Abstract] [Full Text] [PDF]
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T. Suzuki and K. Nohara Regulatory Factors Involved in Species-specific Modulation of Arylhydrocarbon Receptor (AhR)-dependent Gene Expression in Humans and Mice J. Biochem., October 1, 2007; 142(4): 443 - 452. [Abstract] [Full Text] [PDF]
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N. K. Mukhopadhyay, B. Cinar, L. Mukhopadhyay, M. Lutchman, A. S. Ferdinand, J. Kim, L. W. K. Chung, R. M. Adam, S. K. Ray, A. B. Leiter, et al. The Zinc Finger Protein Ras-Responsive Element Binding Protein-1 Is a Coregulator of the Androgen Receptor: Implications for the Role of the Ras Pathway in Enhancing Androgenic Signaling in Prostate Cancer Mol. Endocrinol., September 1, 2007; 21(9): 2056 - 2070. [Abstract] [Full Text] [PDF]
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K. P. Madauss, E. T. Grygielko, S.-J. Deng, A. C. Sulpizio, T. B. Stanley, C. Wu, S. A. Short, S. K. Thompson, E. L. Stewart, N. J. Laping, et al. A Structural and in Vitro Characterization of Asoprisnil: A Selective Progesterone Receptor Modulator Mol. Endocrinol., May 1, 2007; 21(5): 1066 - 1081. [Abstract] [Full Text] [PDF]
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C. Tudor, J. N. Feige, H. Pingali, V. B. Lohray, W. Wahli, B. Desvergne, Y. Engelborghs, and L. Gelman Association with Coregulators Is the Major Determinant Governing Peroxisome Proliferator-activated Receptor Mobility in Living Cells J. Biol. Chem., February 16, 2007; 282(7): 4417 - 4426. [Abstract] [Full Text] [PDF]
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L. Michalik, J. N. Feige, L. Gelman, T. Pedrazzini, H. Keller, B. Desvergne, and W. Wahli Selective Expression of a Dominant-Negative Form of Peroxisome Proliferator-Activated Receptor in Keratinocytes Leads to Impaired Epidermal Healing Mol. Endocrinol., September 1, 2005; 19(9): 2335 - 2348. [Abstract] [Full Text] [PDF]
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D. Wang and S. S. Simons Jr. Corepressor Binding to Progesterone and Glucocorticoid Receptors Involves the Activation Function-1 Domain and Is Inhibited by Molybdate Mol. Endocrinol., June 1, 2005; 19(6): 1483 - 1500. [Abstract] [Full Text] [PDF]
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J. N. Feige, L. Gelman, C. Tudor, Y. Engelborghs, W. Wahli, and B. Desvergne Fluorescence Imaging Reveals the Nuclear Behavior of Peroxisome Proliferator-activated Receptor/Retinoid X Receptor Heterodimers in the Absence and Presence of Ligand J. Biol. Chem., May 6, 2005; 280(18): 17880 - 17890. [Abstract] [Full Text] [PDF]
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N. Yoshikawa, K. Yamamoto, N. Shimizu, S. Yamada, C. Morimoto, and H. Tanaka The Distinct Agonistic Properties of the Phenylpyrazolosteroid Cortivazol Reveal Interdomain Communication within the Glucocorticoid Receptor Mol. Endocrinol., May 1, 2005; 19(5): 1110 - 1124. [Abstract] [Full Text] [PDF]
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J. E. Lee, K. Kim, J. C. Sacchettini, C. V. Smith, and S. Safe DRIP150 Coactivation of Estrogen Receptor {alpha} in ZR-75 Breast Cancer Cells Is Independent of LXXLL Motifs J. Biol. Chem., March 11, 2005; 280(10): 8819 - 8830. [Abstract] [Full Text] [PDF]
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L. A. Tintignac, J. Lagirand, S. Batonnet, V. Sirri, M. P. Leibovitch, and S. A. Leibovitch Degradation of MyoD Mediated by the SCF (MAFbx) Ubiquitin Ligase J. Biol. Chem., January 28, 2005; 280(4): 2847 - 2856. [Abstract] [Full Text] [PDF]
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M. S. Ozers, K. M. Ervin, C. L. Steffen, J. A. Fronczak, C. S. Lebakken, K. A. Carnahan, R. G. Lowery, and T. J. Burke Analysis of Ligand-Dependent Recruitment of Coactivator Peptides to Estrogen Receptor Using Fluorescence Polarization Mol. Endocrinol., January 1, 2005; 19(1): 25 - 34. [Abstract] [Full Text] [PDF]
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K. C. Park, K.-H. Song, H. K. Chung, H. Kim, D. W. Kim, J. H. Song, E. S. Hwang, H. S. Jung, S.-H. Park, I. Bae, et al. CR6-Interacting Factor 1 Interacts with Orphan Nuclear Receptor Nur77 and Inhibits Its Transactivation Mol. Endocrinol., January 1, 2005; 19(1): 12 - 24. [Abstract] [Full Text] [PDF]
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M. Ananthanarayanan, S. Li, N. Balasubramaniyan, F. J. Suchy, and M. J. Walsh Ligand-dependent Activation of the Farnesoid X-receptor Directs Arginine Methylation of Histone H3 by CARM1 J. Biol. Chem., December 24, 2004; 279(52): 54348 - 54357. [Abstract] [Full Text] [PDF]
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J. Ruegg, F. Holsboer, C. Turck, and T. Rein Cofilin 1 Is Revealed as an Inhibitor of Glucocorticoid Receptor by Analysis of Hormone-Resistant Cells Mol. Cell. Biol., November 1, 2004; 24(21): 9371 - 9382. [Abstract] [Full Text] [PDF]
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K. Stokes, B. Alston-Mills, and C. Teng Estrogen response element and the promoter context of the human and mouse lactoferrin genes influence estrogen receptor {alpha}-mediated transactivation activity in mammary gland cells J. Mol. Endocrinol., October 1, 2004; 33(2): 315 - 334. [Abstract] [Full Text] [PDF]
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V. Bourdeau, J. Deschenes, R. Metivier, Y. Nagai, D. Nguyen, N. Bretschneider, F. Gannon, J. H. White, and S. Mader Genome-Wide Identification of High-Affinity Estrogen Response Elements in Human and Mouse Mol. Endocrinol., June 1, 2004; 18(6): 1411 - 1427. [Abstract] [Full Text] [PDF]
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Q. Wang, J. A. Blackford Jr., L.-N. Song, Y. Huang, S. Cho, and S. S. Simons Jr. Equilibrium Interactions of Corepressors and Coactivators with Agonist and Antagonist Complexes of Glucocorticoid Receptors Mol. Endocrinol., June 1, 2004; 18(6): 1376 - 1395. [Abstract] [Full Text] [PDF]
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Y. Liu, B. O. Kim, C. Kao, C. Jung, J. T. Dalton, and J. J. He Tip110, the Human Immunodeficiency Virus Type 1 (HIV-1) Tat-interacting Protein of 110 kDa as a Negative Regulator of Androgen Receptor (AR) Transcriptional Activation J. Biol. Chem., May 21, 2004; 279(21): 21766 - 21773. [Abstract] [Full Text] [PDF]
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S. Burgdorf, P. Leister, and K. H. Scheidtmann TSG101 Interacts with Apoptosis-antagonizing Transcription Factor and Enhances Androgen Receptor-mediated Transcription by Promoting Its Monoubiquitination J. Biol. Chem., April 23, 2004; 279(17): 17524 - 17534. [Abstract] [Full Text] [PDF]
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M.-B. Debril, L. Gelman, E. Fayard, J.-S. Annicotte, S. Rocchi, and J. Auwerx Transcription Factors and Nuclear Receptors Interact with the SWI/SNF Complex through the BAF60c Subunit J. Biol. Chem., April 16, 2004; 279(16): 16677 - 16686. [Abstract] [Full Text] [PDF]
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V. S. Likhite, E. I. Cass, S. D. Anderson, J. R. Yates, and A. M. Nardulli Interaction of Estrogen Receptor {alpha} with 3-Methyladenine DNA Glycosylase Modulates Transcription and DNA Repair J. Biol. Chem., April 16, 2004; 279(16): 16875 - 16882. [Abstract] [Full Text] [PDF]
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C. L. Smith and B. W. O'Malley Coregulator Function: A Key to Understanding Tissue Specificity of Selective Receptor Modulators Endocr. Rev., February 1, 2004; 25(1): 45 - 71. [Abstract] [Full Text] [PDF]
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D. Bauer, N. Wolfram, G. F. Kahl, and K. I. Hirsch-Ernst Transcriptional Regulation of CYP2B1 Induction in Primary Rat Hepatocyte Cultures: Repression by Epidermal Growth Factor Is Mediated via a Distal Enhancer Region Mol. Pharmacol., January 1, 2004; 65(1): 172 - 180. [Abstract] [Full Text] [PDF]
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S. Benko, J. D. Love, M. Beladi, J. W. R. Schwabe, and L. Nagy Molecular Determinants of the Balance between Co-repressor and Co-activator Recruitment to the Retinoic Acid Receptor J. Biol. Chem., October 31, 2003; 278(44): 43797 - 43806. [Abstract] [Full Text] [PDF]
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Y.-W. Liu, W. Gao, H.-L. Teh, J.-H. Tan, and W.-K. Chan Prox1 Is a Novel Coregulator of Ff1b and Is Involved in the Embryonic Development of the Zebra Fish Interrenal Primordium Mol. Cell. Biol., October 15, 2003; 23(20): 7243 - 7255. [Abstract] [Full Text] [PDF]
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D. Chen, M. J. Lucey, F. Phoenix, J. Lopez-Garcia, S. M. Hart, R. Losson, L. Buluwela, R. C. Coombes, P. Chambon, P. Schar, et al. T:G Mismatch-specific Thymine-DNA Glycosylase Potentiates Transcription of Estrogen-regulated Genes through Direct Interaction with Estrogen Receptor {alpha} J. Biol. Chem., October 3, 2003; 278(40): 38586 - 38592. [Abstract] [Full Text] [PDF]
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V. Marsaud, A. Gougelet, S. Maillard, and J.-M. Renoir Various Phosphorylation Pathways, Depending on Agonist and Antagonist Binding to Endogenous Estrogen Receptor {alpha} (ER{alpha}), Differentially Affect ER{alpha} Extractability, Proteasome-Mediated Stability, and Transcriptional Activity in Human Breast Cancer Cells Mol. Endocrinol., October 1, 2003; 17(10): 2013 - 2027. [Abstract] [Full Text] [PDF]
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L. Ding, J. Yan, J. Zhu, H. Zhong, Q. Lu, Z. Wang, C. Huang, and Q. Ye Ligand-independent activation of estrogen receptor {alpha} by XBP-1 Nucleic Acids Res., September 15, 2003; 31(18): 5266 - 5274. [Abstract] [Full Text] [PDF]
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L. Amazit, Y. Alj, R. K. Tyagi, A. Chauchereau, H. Loosfelt, C. Pichon, J. Pantel, E. Foulon-Guinchard, P. Leclerc, E. Milgrom, et al. Subcellular Localization and Mechanisms of Nucleocytoplasmic Trafficking of Steroid Receptor Coactivator-1 J. Biol. Chem., August 22, 2003; 278(34): 32195 - 32203. [Abstract] [Full Text] [PDF]
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K. De Bosscher, W. Vanden Berghe, and G. Haegeman The Interplay between the Glucocorticoid Receptor and Nuclear Factor-{kappa}B or Activator Protein-1: Molecular Mechanisms for Gene Repression Endocr. Rev., August 1, 2003; 24(4): 488 - 522. [Abstract] [Full Text] [PDF]
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J. M. Maglich, J. A. Caravella, M. H. Lambert, T. M. Willson, J. T. Moore, and L. Ramamurthy The first completed genome sequence from a teleost fish (Fugu rubripes) adds significant diversity to the nuclear receptor superfamily Nucleic Acids Res., July 15, 2003; 31(14): 4051 - 4058. [Abstract] [Full Text] [PDF]
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F. Yan, X. Gao, D. M. Lonard, and Z. Nawaz Specific Ubiquitin-Conjugating Enzymes Promote Degradation of Specific Nuclear Receptor Coactivators Mol. Endocrinol., July 1, 2003; 17(7): 1315 - 1331. [Abstract] [Full Text] [PDF]
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S. S. Auerbach, R. Ramsden, M. A. Stoner, C. Verlinde, C. Hassett, and C. J. Omiecinski Alternatively spliced isoforms of the human constitutive androstane receptor Nucleic Acids Res., June 15, 2003; 31(12): 3194 - 3207. [Abstract] [Full Text] [PDF]
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N. Sakai, T. Maruyama, R. Sakurai, H. Masuda, Y. Yamamoto, A. Shimizu, I. Kishi, H. Asada, S. Yamagoe, and Y. Yoshimura Involvement of Histone Acetylation in Ovarian Steroid-induced Decidualization of Human Endometrial Stromal Cells J. Biol. Chem., May 2, 2003; 278(19): 16675 - 16682. [Abstract] [Full Text] [PDF]
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K. Kim, N. Thu, B. Saville, and S. Safe Domains of Estrogen Receptor {alpha} (ER{alpha}) Required for ER{alpha}/Sp1-Mediated Activation of GC-Rich Promoters by Estrogens and Antiestrogens in Breast Cancer Cells Mol. Endocrinol., May 1, 2003; 17(5): 804 - 817. [Abstract] [Full Text] [PDF]
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D.-Y. Lin, M.-Z. Lai, D. K. Ann, and H.-M. Shih Promyelocytic Leukemia Protein (PML) Functions as a Glucocorticoid Receptor Co-activator by Sequestering Daxx to the PML Oncogenic Domains (PODs) to Enhance Its Transactivation Potential J. Biol. Chem., April 25, 2003; 278(18): 15958 - 15965. [Abstract] [Full Text] [PDF]
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X. Hu, L. Cherbas, and P. Cherbas Transcription Activation by the Ecdysone Receptor (EcR/USP): Identification of Activation Functions Mol. Endocrinol., April 1, 2003; 17(4): 716 - 731. [Abstract] [Full Text] [PDF]
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M. Maira, C. Martens, E. Batsche, Y. Gauthier, and J. Drouin Dimer-Specific Potentiation of NGFI-B (Nur77) Transcriptional Activity by the Protein Kinase A Pathway and AF-1-Dependent Coactivator Recruitment Mol. Cell. Biol., February 1, 2003; 23(3): 763 - 776. [Abstract] [Full Text]
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A. Hoffmann, E. Ciani, J. Boeckardt, F. Holsboer, L. Journot, and D. Spengler Transcriptional Activities of the Zinc Finger Protein Zac Are Differentially Controlled by DNA Binding Mol. Cell. Biol., February 1, 2003; 23(3): 988 - 1003. [Abstract] [Full Text]
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R. Kumar and E. B. Thompson Transactivation Functions of the N-Terminal Domains of Nuclear Hormone Receptors: Protein Folding and Coactivator Interactions Mol. Endocrinol., January 1, 2003; 17(1): 1 - 10. [Abstract] [Full Text] [PDF]
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Y. He, D. Szapary, and S. S. Simons Jr. Modulation of Induction Properties of Glucocorticoid Receptor-Agonist and -Antagonist Complexes by Coactivators Involves Binding to Receptors but Is Independent of Ability of Coactivators to Augment Transactivation J. Biol. Chem., December 13, 2002; 277(51): 49256 - 49266. [Abstract] [Full Text] [PDF]
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N. B. Dillner and M. M. Sanders Upstream Stimulatory Factor (USF) Is Recruited into a Steroid Hormone-triggered Regulatory Circuit by the Estrogen-inducible Transcription Factor delta EF1 J. Biol. Chem., September 6, 2002; 277(37): 33890 - 33894. [Abstract] [Full Text] [PDF]
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G. Min, H. Kim, Y. Bae, L. Petz, and J. K. Kemper Inhibitory Cross-talk between Estrogen Receptor (ER) and Constitutively Activated Androstane Receptor (CAR). CAR INHIBITS ER-MEDIATED SIGNALING PATHWAY BY SQUELCHING p160 COACTIVATORS J. Biol. Chem., September 6, 2002; 277(37): 34626 - 34633. [Abstract] [Full Text] [PDF]
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H. Lim and S. K. Dey Minireview: A Novel Pathway of Prostacyclin Signaling--Hanging Out with Nuclear Receptors Endocrinology, September 1, 2002; 143(9): 3207 - 3210. [Abstract] [Full Text] [PDF]
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M. Gehin, M. Mark, C. Dennefeld, A. Dierich, H. Gronemeyer, and P. Chambon The Function of TIF2/GRIP1 in Mouse Reproduction Is Distinct from Those of SRC-1 and p/CIP Mol. Cell. Biol., August 15, 2002; 22(16): 5923 - 5937. [Abstract] [Full Text] [PDF]
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C. Lethimonier, G. Flouriot, O. Kah, and B. Ducouret The Glucocorticoid Receptor Represses the Positive Autoregulation of the Trout Estrogen Receptor Gene by Preventing the Enhancer Effect of a C/EBP{beta}-Like Protein Endocrinology, August 1, 2002; 143(8): 2961 - 2974. [Abstract] [Full Text] [PDF]
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H. Guissouma, S. M. Dupre, N. Becker, E. Jeannin, I. Seugnet, B. Desvergne, and B. A. Demeneix Feedback on Hypothalamic TRH Transcription Is Dependent on Thyroid Hormone Receptor N Terminus Mol. Endocrinol., July 1, 2002; 16(7): 1652 - 1666. [Abstract] [Full Text] [PDF]
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J. Chen, S. Kaul, and S. S. Simons Jr. Structure/Activity Elements of the Multifunctional Protein, GMEB-1. CHARACTERIZATION OF DOMAINS RELEVANT FOR THE MODULATION OF GLUCOCORTICOID RECEPTOR TRANSACTIVATION PROPERTIES J. Biol. Chem., June 7, 2002; 277(24): 22053 - 22062. [Abstract] [Full Text] [PDF]
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C. A. Heinlein and C. Chang Androgen Receptor (AR) Coregulators: An Overview Endocr. Rev., April 1, 2002; 23(2): 175 - 200. [Abstract] [Full Text] [PDF]
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C.-Y. Chang and D. P. McDonnell Evaluation of Ligand-Dependent Changes in AR Structure Using Peptide Probes Mol. Endocrinol., April 1, 2002; 16(4): 647 - 660. [Abstract] [Full Text] [PDF]
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T. E. Akiyama, C. T. Baumann, S. Sakai, G. L. Hager, and F. J. Gonzalez Selective Intranuclear Redistribution of PPAR Isoforms by RXR{alpha} Mol. Endocrinol., April 1, 2002; 16(4): 707 - 721. [Abstract] [Full Text] [PDF]
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J. D. Norris, D. Fan, A. Sherk, and D. P. McDonnell A Negative Coregulator for the Human ER Mol. Endocrinol., March 1, 2002; 16(3): 459 - 468. [Abstract] [Full Text] [PDF]
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H. A. Molenda, A. L. Griffin, A. P. Auger, M. M. McCarthy, and M. J. Tetel Nuclear Receptor Coactivators Modulate Hormone-Dependent Gene Expression in Brain and Female Reproductive Behavior in Rats Endocrinology, February 1, 2002; 143(2): 436 - 444. [Abstract] [Full Text] [PDF]
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C. L. Smith, D. G. DeVera, D. J. Lamb, Z. Nawaz, Y.-H. Jiang, A. L. Beaudet, and B. W. O'Malley Genetic Ablation of the Steroid Receptor Coactivator-Ubiquitin Ligase, E6-AP, Results in Tissue-Selective Steroid Hormone Resistance and Defects in Reproduction Mol. Cell. Biol., January 15, 2002; 22(2): 525 - 535. [Abstract] [Full Text] [PDF]
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N. Becker, I. Seugnet, H. Guissouma, S. M. Dupre, and B. A. Demeneix Nuclear Corepressor and Silencing Mediator of Retinoic and Thyroid Hormone Receptors Corepressor Expression Is Incompatible with T3-Dependent TRH Regulation Endocrinology, December 1, 2001; 142(12): 5321 - 5331. [Abstract] [Full Text] [PDF]
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V. Vivat-Hannah, D. You, C. Rizzo, J.-P. Daris, P. Lapointe, F. C. Zusi, A. Marinier, M. V. Lorenzi, and M. M. Gottardis Synergistic Cytotoxicity Exhibited by Combination Treatment of Selective Retinoid Ligands with Taxol (Paclitaxel) Cancer Res., December 1, 2001; 61(24): 8703 - 8711. [Abstract] [Full Text] [PDF]
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S. C. Nagel, J. L. Hagelbarger, and D. P. McDonnell Development of an ER Action Indicator Mouse for the Study of Estrogens, Selective ER Modulators (SERMs), and Xenobiotics Endocrinology, November 1, 2001; 142(11): 4721 - 4728. [Abstract] [Full Text] [PDF]
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 M. E. Taplin and S.-M. Ho The Endocrinology of Prostate Cancer J. Clin. Endocrinol. Metab., August 1, 2001; 86(8): 3467 - 3477. [Full Text] [PDF]
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I. A. Hughes Minireview: Sex Differentiation Endocrinology, August 1, 2001; 142(8): 3281 - 3287. [Abstract] [Full Text] [PDF]
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D. Knutti, D. Kressler, and A. Kralli Regulation of the transcriptional coactivator PGC-1 via MAPK-sensitive interaction with a repressor PNAS, July 24, 2001; (2001) 171184698. [Abstract] [Full Text] [PDF]
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M. R. Yudt and J. A. Cidlowski Molecular Identification and Characterization of A and B Forms of the Glucocorticoid Receptor Mol. Endocrinol., July 1, 2001; 15(7): 1093 - 1103. [Abstract] [Full Text] [PDF]
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J. R. Wood, V. S. Likhite, M. A. Loven, and A. M. Nardulli Allosteric Modulation of Estrogen Receptor Conformation by Different Estrogen Response Elements Mol. Endocrinol., July 1, 2001; 15(7): 1114 - 1126. [Abstract] [Full Text] [PDF]
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A. Aranda and A. Pascual Nuclear Hormone Receptors and Gene Expression Physiol Rev, July 1, 2001; 81(3): 1269 - 1304. [Abstract] [Full Text] [PDF]
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C. Pasqualini, D. Guivarc'h, J.-V. Barnier, B. Guibert, J.-D. Vincent, and P. Vernier Differential Subcellular Distribution and Transcriptional Activity of {{Sigma}}E3, {{Sigma}}E4, and {{Sigma}}E3-4 Isoforms of the Rat Estrogen Receptor-{{alpha}} Mol. Endocrinol., June 1, 2001; 15(6): 894 - 908. [Abstract] [Full Text] [PDF]
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K. W. Cheng, B. K. C. Chow, and P. C. K. Leung Functional Mapping of a Placenta-Specific Upstream Promoter for Human Gonadotropin-Releasing Hormone Receptor Gene Endocrinology, April 1, 2001; 142(4): 1506 - 1516. [Abstract] [Full Text]
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F. D. Urnov and A. P. Wolffe A Necessary Good: Nuclear Hormone Receptors and Their Chromatin Templates Mol. Endocrinol., January 1, 2001; 15(1): 1 - 16. [Full Text]
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 I. A. Hughes A Novel Explanation for Resistance to Androgens N. Engl. J. Med., September 21, 2000; 343(12): 880 - 882. [Full Text]
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D. K. Lee, H. O. Duan, and C. Chang Androgen Receptor Interacts with the Positive Elongation Factor P-TEFb and Enhances the Efficiency of Transcriptional Elongation J. Biol. Chem., March 23, 2001; 276(13): 9978 - 9984. [Abstract] [Full Text] [PDF]
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L. F. Su, R. Knoblauch, and M. J. Garabedian Rho GTPases as Modulators of the Estrogen Receptor Transcriptional Response J. Biol. Chem., January 26, 2001; 276(5): 3231 - 3237. [Abstract] [Full Text] [PDF]
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F. D. Urnov and A. P. Wolffe An Array of Positioned Nucleosomes Potentiates Thyroid Hormone Receptor Action in Vivo J. Biol. Chem., June 1, 2001; 276(23): 19753 - 19761. [Abstract] [Full Text] [PDF]
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C. Teyssier, K. Belguise, F. Galtier, and D. Chalbos Characterization of the Physical Interaction between Estrogen Receptor alpha and JUN Proteins J. Biol. Chem., September 21, 2001; 276(39): 36361 - 36369. [Abstract] [Full Text] [PDF]
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