1 Howard Hughes Medical Institute, Division of Nucleic Acids Enzymology, Robert
Wood Johnson Medical School, Piscataway, NJ 08854, USA
2 Department of Biochemistry, Division of Nucleic Acids Enzymology, Robert Wood
Johnson Medical School, Piscataway, NJ 08854, USA
* Author for correspondence (e-mail: reinbedf{at}umdnj.edu)
![]() |
Summary |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
Key words: Transcription regulation, Mediator, Coactivator
![]() |
Introduction |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
Other coactivators are broadly defined by their histone acetyltransferase
(HAT) activities. These include the GCN5-containing HATs and the nuclear
hormone receptor (or related) HATs
(Belotserkovskaya and Berger,
1999). As their name suggests, these coactivators acetylate
nucleosomes and other transcription factors, thereby permitting additional
access of the transcriptional machinery to the promoter as well as
facilitating protein-protein interactions. A third class of coactivator
includes the various chromatin-remodeling complexes
(Vignali et al., 2000
). These
factors alter the structure of chromatin and, in common with the HATs, permit
access of the transcriptional machinery to the DNA. The fourth complex,
mediator, links the activator directly to the core promoter and the general
transcriptional machinery (GTFs). This large multiprotein complex is brought
to the promoter by DNA-bound activators, is necessary for transcription in
vivo, and stimulates high levels of activator-dependent transcription in
vitro. There are several previous detailed reviews of mediator function and
subunit composition (Boube et al.,
2002
; Carlson,
1997
; Hampsey and Reinberg,
1999
; Lee and Young,
2000
; Lemon and Tjian,
2000
; Malik and Roeder,
2000
; Naar et al.,
2001
; Rachez and Freedman,
2001
). Here, we describe the major findings that support a role
for mediator as a coactivator and discuss more recent work in the field,
proposing a functional role for the mediator complex.
![]() |
Isolation of yeast and human mediator complexes |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
|
Human mediator complexes were purified using in vitro activator-dependent
assays, immunopurification assays based on the various human Srb/Med
homologues or an activator affinity purification step. These disparate
purification procedures identified two complexes: a larger 2 MDa complex
variously designated TRAP, DRIP, ARC, SMCC or NAT
(Boyer et al., 1999;
Fondell et al., 1996
;
Fondell et al., 1999
;
Ito et al., 1999
;
Naar et al., 1999
;
Rachez et al., 1999
;
Rachez et al., 1998
;
Sun et al., 1998
) and a
smaller 500-700 kDa complex termed PC2/CRSP
(Malik et al., 2000
;
Ryu et al., 1999
)
(Table 1). Both complexes were
shown to mediate activator-dependent transcription in vitro. Additionally, the
NAT and SMCC complexes were shown to repress activator-dependent
transcription, as well as basal transcription, but apparently through
different pathways (Akoulitchev et al.,
2000
; Gu et al.,
1999
; Sun et al.,
1998
).
|
The differences between the various purification schemes are potentially
significant. Tjian's group demonstrated that both the GST-VP16 and
SREBP-1 (sterol-responsive enhancer binding protein) activator affinity
purifications produce not one, as was originally thought, but two different
mediator complexes (Taatjes et al.,
2002
). The larger, 2 MDa complex, denoted ARC-L, appears to be
identical to the previously identified TRAP/DRIP/ARC/SMCC/NAT complexes. The
smaller complex is the 500 kDa CRSP complex. Affinity purification of CRSP
from the mixture, using a CRSP-specific antibody, separates CRSP from the
ARC-L complex. Interestingly, the ARC-L complex does not mediate activation on
the SREBP-responsive promoter in vitro, whereas CRSP does.
Results obtained with ARC-L are consistent with those obtained from the
isolation of the NAT complex, which was purified by affinity purification
using antibodies to CDK8 (the human homolog of the yeast Srb10) and shown to
inhibit transcription (Sun et al.,
1998). Indeed, the larger 2 MDa mediator complexes contain the
cyclin-C-CDK8 pair, MED230 and MED240, as does the ARC-L complex. These
proteins are the homologues of four yeast proteins: Srb8 and Srb9 are MED230
and MED240 (Borggrefe et al.,
2002
; Boube et al.,
2002
), whereas Srb10 and Srb11 are CDK8 and cyclin C
(Liao et al., 1995
). Genetic
studies in yeast suggest that these proteins are involved in the repression of
certain genes (reviewed by Carlson,
1997
). Moreover, they exist as a distinct complex that can be
isolated from yeast (Borggrefe et al.,
2002
). One additional point is that CRSP70 is present only in the
CRSP complex, suggesting that it may have a positive role in CRSP function
(Taatjes et al., 2002
).
Tjian and co-workers suggest that the larger complex is transcriptionally
inert, and the smaller CRSP complex is the active species on the promoter
(Taatjes et al., 2002), but
these interpretations are based on in vitro assays and may not reflect
mediator-promoter mechanisms in vivo. For example, the 2 MDa complex may still
be recruited to promoters by activators and subsequent unknown events may
alleviate its repressive effects (e.g. dissociation of the MED230, MED240,
CDK8 or cyclin C subunits). Nevertheless, these data suggest that, contrary to
expectations, the smaller CRSP complex is actually the `active' complex,
whereas, at least under the conditions assayed, the larger complex does not
respond to an activator. It is, however, not clear whether ARC-L or CRSP
mediates nuclear-receptor-dependent transcription.
![]() |
Recruitment of mediator to the promoter |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
Several recent studies show that mediator can be recruited to a promoter at
different times. Some of these results run counter to our perception that
mediator is recruited by an activator and that transcription is initiated by
the immediate recruitment of RNA polymerase II. Chromatin immunoprecipitation
experiments (ChiP) demonstrate that the arrival of MED220 only slightly
precedes that of RNA polymerase II when transcription is induced by estrogen
from an estrogen receptor-responsive promoter
(Shang et al., 2000). A
thyroid-receptor-dependent promoter acts similarly: transcription begins
roughly 1 hour after ligand addition, and MED220 recruitment peaks at
transcription initiation (Sharma and
Fondell, 2002
). The temporal association of MED220 with the
enterocyte-specific
-antitrypsin promoter is quite different, however.
Expression is induced at day 6 after stimulation of enterocyte
differentiation, but the activator HNF1
, subunits of the TFIID complex
(TAFII250 and TAFII30), mediator proteins MED220 and
MED100, and RNA polymerase II are present by day 2
(Soutoglou and Talianidis,
2002
). These data suggest that the recruitment of mediator and RNA
polymerase II is not sufficient for the initiation of transcription and,
secondly, that there is not necessarily a correlation between initiation and
mediator recruitment.
Other data show disparity in recruitment and resultant transcription
initiation. Kim and colleagues used the Drosophila hsp70 promoter (a
heat shock promoter) to study mediator recruitment during heat shock
induction. In situ and ChiP assays show that the mediator is recruited to the
hsp70 and hsp26 promoters upon heat shock induction
(Park et al., 2001b). RNA
polymerase II is present before heat shock, and transcription initiation
correlates with the recruitment of mediator and the activator HSF, which
interacts with dMED78 (Park et al.,
2001b
).
An additional permutation is seen in the regulation of the yeast
HO promoter. The binding of the Swi5 activator to the URS1 binding
site is the first step in the events leading to the activation of HO
transcription (Cosma et al.,
1999). Mediator and Swi5 are concomitantly brought to the URS1
site early. Fifteen minutes later, mediator binds both URS1- and URS2-binding
sites. This does not recruit RNA polymerase II, however, which arrives at the
TATA region of the promoter only immediately before transcription starts.
However, in the case of other promoters, such as PIR1, mediator and
RNA polymerase II are recruited concomitantly with the activator Swi5
(Bhoite et al., 2001
).
Clearly one may suggest from these studies that activators have temporal
functions in transcription defined by promoter context. Each would have a
temporally defined role in recruitment of particular coactivators to the
promoter at specific times. These coactivators do not necessarily play a role
in controlling the rate of transcription initiation itself. For example, the
HAT coactivator SRC-1, possibly playing a role in chromatin remodeling, is
recruited to promoters by thyroid receptor but much earlier than
MED220/mediator. Its transient association with the promoter peaks at 15
minutes after ligand addition and then disappears. Meanwhile, the presence of
MED220 correlates with transcription initiation at 60 minutes after ligand
addition (Sharma and Fondell,
2002). The Swi5 data (discussed above, in the context of the HO
and PIR1 promoters) suggest a second alternative: it is not the activator but
the promoter context that dictates the timing of mediator recruitment. These
distinctions can be resolved only once experiments that compare the same
activator in different promoter contexts are performed. Note that promoter
specificity could be due to the core promoter, various combinations of
activators, or both of these parameters.
These recruitment data can be summarized and interpreted in another way. They suggest that three (and possibly more) activator-dependent pathways exist and are reflected by the temporal order of recruitment of mediator and RNA polymerase II. The first is the initial recruitment of mediator followed by the arrival of RNA polymerase II and the concomitant initiation of transcription. The second is the corecruitment of mediator and RNA polymerase II; transcription is initiated later. The third is the recruitment of RNA polymerase II and the later arrival of mediator, concomitantly with transcription initiation. These different temporal patterns of recruitment of mediator and RNA polymerase II may be necessary for the appropriate regulation of transcription of a particular gene, and reflect either the existence of multiple types of preinitiation complexes, or the recruitment of alternative mediator complexes (ARC-L or CRSP) and their subsequent conversion into transcriptionally active complexes.
Recruitment of mediator has also been analyzed in vitro to determine the
role that mediator plays in preinitiation complex (PIC) formation in yeast.
Using immobilized DNA templates bound to a support, the sequential assembly of
the GTFs into the PIC can be monitored. Mutations in yeast Srb2, Srb4, and
Srb5, and a CTD truncation all severely compromise transcription at the level
of PIC formation: of all the GTFs, only TFIIA and TFIID were recruited to the
promoter (Ranish et al.,
1999). Importantly, the mediator mutants cannot support multiple
rounds of transcription, which suggests that mediator functions in the
reinitation step of the transcription cycle. In fact, a reinitiation
intermediate/scaffold that contains TFIIA, TFIID, TFIIH, TFIIE, and mediator
can be isolated. This intermediate supports transcription after a brief
incubation to supply the missing factors released through the process of
transcription initiation (Yudkovsky et
al., 2000
). Lastly, mutation of members of the Sin4 module (Sin4
and Pgd1; see next section) also produces defects in transcription and PIC
formation. Despite both components residing in the Sin4 module, only Pdg1
plays a role in the formation of a functional scaffold/reinitiation
intermediate: in contrast to a Sin4 deletion, a Pgd1 deletion is unable to
reinitiate transcription in vitro (Reeves
and Hahn, 2003
). Importantly, this scaffold was not observed in
initial studies using immobilized template to analyze recycling of GTFs in the
absence of mediator and activator (Zawel
et al., 1993
). Those studies demonstrated that the only factors
that remain bound at the promoter after the first round of transcription are
TFIID (TBP) and TFIIA.
![]() |
Mediator modules |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
Analysis of several mediator proteins has revealed physical and genetic
interactions between certain mediator subunits. Specifically, a mutation in a
particular mediator protein causes the loss of groups of other subunits. For
example, mutations in Gal11 module components (Gal11, Rgr1, Sin4, Med2, and
Pgd1) produce similar phenotypes (Jiang et
al., 1995; Jiang and Stillman,
1995
) and Rgr1 truncations result in loss of Gal11, Sin4 and Pgd1
(Myers et al., 1998
).
Additionally, a gal11 mutant lacks other members of the module and is
activation defective (Lee et al.,
1999b
; Park et al.,
2000
). Structural studies of a Sin4-deletion mutant (see below)
are also consistent with this notion: the entire tail domain is missing,
leading the authors to conclude that the Sin4 module comprises the tail domain
(Dotson et al., 2000
) (see
next section below and Fig. 1).
Gal11 and Pgd1 bind to several activators in vitro, which suggests that the
Gal11 module is a major recognition unit for activators
(Bhoite et al., 2001
;
Han et al., 1999
;
Lee et al., 1999b
;
Myers et al., 1999
).
The existence of an Srb4 module is supported by genetic and biochemical
data. The Srb4 module can be reconstituted de novo
(Koh et al., 1998); its
assembly is consistent with genetic data showing that Srb5-null extracts
require Srb2 and Srb5 to rescue in vitro activity
(Thompson et al., 1993
) and
that suppressors of an Srb4 mutant are Med6 and Srb6
(Lee et al., 1998
).
Biochemically, the Srb4 module remains together during urea washes of
immobilized mediator complexes (Lee and
Kim, 1998
). It is suggested to play a more general role in
regulating transcription by modulating RNA polymerase II activity through the
CTD (Lee and Kim, 1998
), or
perhaps by serving as a conduit for transferring activator `information' from
the Gal11/Sin4 module to RNA polymerase II.
The existence of the Med9/Med10 module is suggested by its de novo
reconstitution from recombinant proteins. Assays of the reconstituted modules
for interactions with the general transcriptional machinery revealed that the
Med9/Med10 and Srb4 modules interact with the CTD of RNA polymerase II. TBP
and TFIIB interact with both modules, whereas TFIIE interacts with Med9/Med10
(Kang et al., 2001). The
interaction between the Srb4 module and TBP is possibly through Srb2
(Koleske et al., 1992
).
Finally, in vitro data indicate that the Srb10-Srb11 pair interacts with the
Med9/Med10 module (Kang et al.,
2001
).
Srb8-Srb11 may also constitute a distinct module. Borggrefe et al. isolated
Srb8-Srb11 as a separate entity from yeast extracts
(Borggrefe et al., 2002), and
its components have repressive functions in yeast
(Carlson, 1997
;
Hengartner et al., 1998
).
Likewise, the human Srb10-Srb11 pair (CDK8-cyclin-C) represses
activator-dependent transcription in vitro
(Akoulitchev et al., 2000
;
Sun et al., 1998
), and the
large, transcriptionally inactive human ARC-L complex contains MED230, MED240,
CDK8, and cyclin C (Taatjes et al.,
2002
) (Table 1).
Thus, there is evidence in yeast and humans that these subunits are physically
and functionally coupled (Kang et al.,
2002
).
![]() |
In vivo analysis of human mediator |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
MED220-null mice die by embryonic day 8.5, have heart and neural defects,
and MED220-null cell lines grow slower than their wild-type counterparts
(Ito et al., 2000;
Zhu et al., 2000
).
Interestingly, these cells exhibit defective transcription stimulated by the
thyroid receptor but not RAR, VP16 or p53 activators
(Ito et al., 2000
).
MED220-null cells also exhibit defective adipogenesis and
PPAR
-dependent activation, which can be rescued by ectopic MED220
expression (Ge et al., 2002
).
These results are consistent with others that showed that the
adipocyte-specific nuclear receptor PPAR
physically interacts with
MED220 (Yuan et al., 1998
;
Zhu et al., 1997
).
Furthermore, mediator isolated from MED220-null cells does not interact with
PPAR
in vitro (Ge et al.,
2002
). Interestingly, the null cells can still differentiate into
myofibers, which suggests that the MED220 defects are not global
(Ge et al., 2002
). There are
several additional examples of mediator components that are necessary for
developmentally specific events in Drosophila, C. elegans, and
Xenopus (Boube et al.,
2000
; Kato et al.,
2002
; Kwon et al.,
2001
; Kwon and Lee,
2001
; Kwon et al.,
1999
; Shim et al.,
2002
; Treisman,
2001
).
Targeted ablation of MED100 produces results that contrast with MED220
ablation. Although the MED100-null mutation is embryonic lethal as well,
studies of MED100-/- MEFs revealed that multiple
activator-dependent and metal-induction pathways are defective in these mice
(Ito et al., 2002). This
suggests that the loss of MED100 has pleiotropic effects, seriously
debilitating the response to activators. This is easily explained if the
MED220-/- defects are restricted to a subset of activators, whereas
the MED100 pleiotropic defects evident in the MED100-/- animals are
the manifestation of the loss of multiple mediator functions and possibly its
physical integrity (Ito et al.,
2002
).
Boyer et al. isolated human MED130 on the basis of its ability to interact
with the viral E1A activator and stimulate E1A-dependent transcription in
vitro and showed that it was part of the human mediator complex
(Boyer et al., 1999).
Immunoprecipitation of CDK8 from human MED130-/- cells revealed
that, in addition to the lack of MED130, the CDK8 complex in these cells
contains reduced amounts of MED100 and MED95, suggesting that MED130 is
necessary for the incorporation of MED100 and MED95 into the complex.
Transient expression assays indicated that E1A activation is defective in the
absence of MED130, which is consistent with earlier work. In contrast, VP16
activation is similar in both wild-type and mutant cells
(Stevens et al., 2002
). This
result is expected since VP16 does not interact with MED130 but, instead, the
MED78 subunit; thus, mediator can still be recruited by VP16 to the promoter
(Ito et al., 1999
).
These in vivo experiments indicate that different mediator proteins seem to
have activator-specific roles. This activator specificity is similar to that
described for yeast mediator. For example, the yeast CUP1 activator is Srb4
independent, but Rgr1 dependent (Lee et
al., 1999a). Mutations in Med2, Pgd1 and Sin4 all generate cells
in which VP16 activation is defective but only a Sin4 mutant is GCN4
defective (Han et al., 1999
).
Additionally, some mediator ablations in mice result in loss of other subunits
of mediator and the crippling of multiple activator-dependent pathways. Again,
this is similar to the yeast complex, in which Rgr1 and Gal11 mutations cause
loss of other members of the module (Lee
et al., 1999b
; Myers et al.,
1998
; Park et al.,
2000
). Although the data do not necessarily prove the existence of
modules in the murine mediator complex, they do point to certain subunits
maintaining the structural integrity of the complex through interactions with
other subunits.
![]() |
The structure of mediator |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
Additional studies showed that the yeast mediator tail domain corresponds
to the Gal11/Sin4 module (Sin4, Gal11, Med2 and Pgd1) and suggested that this
domain is linked to the middle domain through Rgr1. The head domain is
postulated to contain the Srb4 module
(Dotson et al., 2000)
(Fig. 1). Asturias and
colleagues suggest that one mediator-RNA-polymerase-II interaction (in
addition to the CTD interaction) is centered on the Rpb3-Rpb11 heterodimer
(Davis et al., 2002
). This
finding fits nicely with genetic studies demonstrating that mutations that
result in defects in activator-dependent, but not basal, transcription map to
Rpb3 (Tan et al., 2000
).
The studies of the mammalian mediator complexes revealed a similar overall
structure to that of yeast mediator. The smaller CRSP complex was purified on
either CTD-containing or VP16 activator affinity resins. EM structures of the
two preparations obtained are virtually identical but, importantly,
conformational differences specific for a particular activator are evident
(Fig. 2). The ARC structure of
Taatjes et al. (Taatjes et al.,
2002) clearly resembles that of the yeast mediator and the human
TRAP complex (Dotson et al.,
2000
), with similar head, middle, and tail domains, whereas the
smaller CRSP complex lacks the head domain as well as some protein density in
the tail (Fig. 2). Lastly, the
structure of the murine mediator closely resembles the yeast mediator
structure (Asturias et al.,
1999
). Clearly, despite the evolutionary distances, the mediator
structure is conserved between yeast and humans at least at the 30-40 Å
resolution of these studies.
|
![]() |
Conclusions and perspectives |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
The mouse in vivo ablation experiments support conclusions from yeast that
some mediator subunits are activator specific and that mutations in one
subunit do not necessarily affect other activator pathways. However, it is
premature to conclude that the majority of activators operate through a
mediator-dependent mechanism. Only a small number of activators have been
assayed. In addition, there are several examples of activators that do not, at
least physically, interact with mediator
(Naar et al., 1999;
Park et al., 2001a
). This may
not be a concern if one considers that the composite nature of the promoter,
both in terms of its core promoter elements and activator sites, may allow the
binding of mediator that is undetectable under more artificial experimental
conditions. Nevertheless, since high levels of transcription appear to require
mediator, one must ask whether there is a mediator interaction with a
particular activator or whether it is possible to resurrect TFIID as a
coactivator in some cases. Several reports suggest that TFIID (as opposed to
the TATA-binding protein, TBP, which is a component of the TFIID complex) is
required, in addition to mediator, for maximal levels of transcription
(Baek et al., 2002
;
Johnson et al., 2002
). Perhaps
then, in the end, a unification of mediator and TFIID as coactivators is
necessary. It is also entirely possible that other activator-dependent
mechanisms of transcription initiation await discovery.
The in vivo and in vitro recruitment experiments suggest varying roles of mediator in transcription initiation and preinitiation complex (PIC) formation. This should be a particularly interesting and illuminating area of research. Does mediator play a different role depending on when it is recruited? Is there a difference between PICs on different promoters, as suggested by the in vivo recruitment experiments? Does promoter structure influence the role mediator plays in transcription? Can we define genes in terms of the timing with which they recruit mediator (or another GTF for that matter)?
The following model of mediator function takes some of these considerations
into account. In part, mediator is recruited to the promoter in a manner
defined by the promoter architecture (the composition and arrangement of its
core promoter elements and activator binding sites). One function of mediator
is to provide a scaffold for multiple rounds of transcription
(Yudkovsky et al., 2000).
Thus, the timing of its recruitment may be irrelevant for post-initiation
events, although the in vivo recruitment studies suggest an important role of
the timing of mediator recruitment in preinitiation events. After all, what is
important in vivo is the number of RNA polymerase II molecules that can enter
the transcription cycle in a defined period of time. The time required for the
formation of the transcription initiation complex might change on different
promoters, but after formation of the complex, the rate at which RNA
polymerase II molecules gain access to the preformed `scaffold' becomes the
rate-limiting step. Depending on the composition of the activators at the
promoter, mediator may adopt different configurations at the promoter and this
may regulate RNA polymerase II access (Fig.
3). This would be a novel mechanism by which the combination of
promoter elements and the activators present regulate the rate of
transcription. This would not involve the translocation of a polymerase
molecule along the DNA at different rates, but instead changes in the number
of RNA polymerase II molecules capable of loading onto the promoter and
initiating transcription within a defined period of time. Our model also
offers an explanation for why mediator adopts different conformations in the
presence of different activators (and, by extension, binds multiple activators
simultaneously). These different conformations have differing intrinsic
affinities for RNA polymerase II (or otherwise affect the rate of formation of
a functional preinitation complex). This would then affect the magnitude of
transcription at the level of PIC formation itself, the inititation of
transcription, or subsequent re-entry of RNA polymerase II onto the preformed
scaffold. Consequently, we suggest that the regulation and magnitude of
transcription is a function of the promoter architecture and the activator's
influence on mediator conformation. All of these are intimately related to
each other, each influencing the timing and magnitude of transcription.
|
The idea that mediator is organized into distinct physical and functional modules concisely combines a variety of genetic and biochemical observations. Yet, the assignment of specific functions is arguably incomplete and a more definitive assessment awaits mechanistic studies of mediator function. However, the EM structural data thus far has elegantly provided confirmation of some mediator module identities and the existence of significant structural alterations of mediator upon binding of RNA polymerase II, the CTD itself, or activators. These structural differences suggest that, mechanistically, activators force mediator into a unique structure that has implications for transcription. Further structural analysis using a variety of yeast mediator mutants, human and yeast activators, the addition of basal factors, and an increased resolution should provide a more detailed mechanistic model of mediator-dependent transcription.
The discovery and characterization of mediator has been a significant contribution to our understanding of transcriptional activation. Mediator has survived numerous tests of its function as a coactivator, and the identification of mediator has solved, at least partially, the problem of activator-dependent transcription. The continued study of this fascinating complex should further illuminate our understanding of the mechanism of transcriptional activation.
![]() |
Acknowledgments |
---|
![]() |
References |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
Akoulitchev, S., Chuikov, S. and Reinberg, D. (2000). TFIIH is negatively regulated by cdk8-containing mediator complexes. Nature 407, 102-106.[CrossRef][Medline]
Albright, S. R. and Tjian, R. (2000). TAFs revisited: more data reveal new twists and confirm old ideas. Gene 242, 1-13.[CrossRef][Medline]
Asturias, F. J., Jiang, Y. W., Myers, L. C., Gustafsson, C. M.
and Kornberg, R. D. (1999). Conserved structures of mediator
and RNA polymerase II holoenzyme. Science
283,
985-987.
Baek, H. J., Malik, S., Qin, J. and Roeder, R. G.
(2002). Requirement of TRAP/mediator for both
activator-independent and activator-dependent transcription in conjunction
with TFIID-associated TAF(II)s. Mol. Cell Biol.
22,
2842-2852.
Belotserkovskaya, R. and Berger, S. L. (1999). Interplay between chromatin modifying and remodeling complexes in transcriptional regulation. Crit. Rev. Euk. Gene Exp. 9, 221-230.[Medline]
Bhoite, L. T., Yu, Y. and Stillman, D. J.
(2001). The Swi5 activator recruits the Mediator complex to the
HO promoter without RNA polymerase II. Genes Dev.
15,
2457-2469.
Borggrefe, T., Davis, R., Erdjument-Bromage, H., Tempst, P. and
Kornberg, R. D. (2002). A complex of the Srb8, -9, -10, and
-11 transcriptional regulatory proteins from yeast. J. Biol.
Chem. 277,
44202-44207.
Boube, M., Faucher, C., Joulia, L., Cribbs, D. L. and Bourbon,
H. M. (2000). Drosophila homologs of transcriptional mediator
complex subunits are required for adult cell and segment identity
specification. Genes Dev.
14,
2906-2917.
Boube, M., Joulia, L., Cribbs, D. L. and Bourbon, H. M. (2002). Evidence for a mediator of RNA polymerase II transcriptional regulation conserved from yeast to man. Cell 110, 143-151.[Medline]
Boyer, T. G., Martin, M. E., Lees, E., Ricciardi, R. P. and Berk, A. J. (1999). Mammalian Srb/Mediator complex is targeted by adenovirus E1A protein. Nature 399, 276-279.[CrossRef][Medline]
Carlson, M. (1997). Genetics of transcriptional regulation in yeast: connections to the RNA polymerase II CTD. Annu. Rev. Cell Dev. Biol. 13, 1-23.[CrossRef][Medline]
Cosma, M. P., Tanaka, T. and Nasmyth, K. (1999). Ordered recruitment of transcription and chromatin remodeling factors to a cell cycle- and developmentally regulated promoter. Cell 97, 299-311.[Medline]
Davis, J. A., Takagi, Y., Kornberg, R. D. and Asturias, F. A. (2002). Structure of the yeast RNA polymerase II holoenzyme: Mediator conformation and polymerase interaction. Mol. Cell 10, 409-415.[Medline]
Dotson, M. R., Yuan, C. X., Roeder, R. G., Myers, L. C.,
Gustafsson, C. M., Jiang, Y. W., Li, Y., Kornberg, R. D. and Asturias, F.
J. (2000). Structural organization of yeast and mammalian
mediator complexes. Proc. Natl. Acad. Sci. USA
97,
14307-14310.
Fondell, J. D., Ge, H. and Roeder, R. G.
(1996). Ligand induction of a transcriptionally active thyroid
hormone receptor coactivator complex. Proc. Natl. Acad. Sci.
USA 93,
8329-8333.
Fondell, J. D., Guermah, M., Malik, S. and Roeder, R. G.
(1999). Thyroid hormone receptor-associated proteins and general
positive cofactors mediate thyroid hormone receptor function in the absence of
the TATA box-binding protein-associated factors of TFIID. Proc.
Natl. Acad. Sci. USA 96,
1959-1964.
Ge, K., Guermah, M., Yuan, C. X., Ito, M., Wallberg, A. E., Spiegelman, B. M. and Roeder, R. G. (2002). Transcription coactivator TRAP220 is required for PPARgamma2-stimulated adipogenesis. Nature 417, 563-567.[CrossRef][Medline]
Gu, W., Malik, S., Ito, M., Yuan, C. X., Fondell, J. D., Zhang, X., Martinez, E., Qin, J. and Roeder, R. G. (1999). A novel human SRB/MED-containing cofactor complex, SMCC, involved in transcription regulation. Mol. Cell 3, 97-108.[Medline]
Gustafsson, C. M., Myers, L. C., Li, Y., Redd, M. J., Lui, M.,
Erdjument-Bromage, H., Tempst, P. and Kornberg, R. D. (1997).
Identification of Rox3 as a component of mediator and RNA polymerase II
holoenzyme. J. Biol. Chem.
272, 48-50.
Gustafsson, C. M., Myers, L. C., Beve, J., Spahr, H., Lui, M.,
Erdjument-Bromage, H., Tempst, P. and Kornberg, R. D. (1998).
Identification of new mediator subunits in the RNA polymerase II holoenzyme
from Saccharomyces cerevisiae. J. Biol. Chem.
273,
30851-30854.
Hampsey, M. and Reinberg, D. (1999). RNA polymerase II as a control panel for multiple coactivator complexes. Curr. Opin. Genet. Dev. 9, 132-139.[CrossRef][Medline]
Han, S. J., Lee, Y. C., Gim, B. S., Ryu, G. H., Park, S. J.,
Lane, W. S. and Kim, Y. J. (1999). Activator-specific
requirement of yeast mediator proteins for RNA polymerase II transcriptional
activation. Mol. Cell. Biol.
19,
979-988.
Hengartner, C. J., Thompson, C. M., Zhang, J., Chao, D. M., Liao, S. M., Koleske, A. J., Okamura, S. and Young, R. A. (1995). Association of an activator with an RNA polymerase II holoenzyme. Genes Dev. 9, 897-910.[Abstract]
Hengartner, C. J., Myer, V. E., Liao, S. M., Wilson, C. J., Koh, S. S. and Young, R. A. (1998). Temporal regulation of RNA polymerase II by Srb10 and Kin28 cyclin-dependent kinases. Mol. Cell 2, 43-53.[Medline]
Hittelman, A. B., Burakov, D., Iniguez-Lluhi, J. A., Freedman,
L. P. and Garabedian, M. J. (1999). Differential regulation
of glucocorticoid receptor transcriptional activation via AF-1-associated
proteins. EMBO J. 18,
5380-5388.
Ito, M., Yuan, C. X., Malik, S., Gu, W., Fondell, J. D., Yamamura, S., Fu, Z. Y., Zhang, X., Qin, J. and Roeder, R. G. (1999). Identity between TRAP and SMCC complexes indicates novel pathways for the function of nuclear receptors and diverse mammalian activators. Mol. Cell 3, 361-370.[Medline]
Ito, M., Yuan, C. X., Okano, H. J., Darnell, R. B. and Roeder, R. G. (2000). Involvement of the TRAP220 component of the TRAP/SMCC coactivator complex in embryonic development and thyroid hormone action. Mol. Cell 5, 683-693.[Medline]
Ito, M., Okano, H. J., Darnell, R. B. and Roeder, R. G.
(2002). The TRAP100 component of the TRAP/Mediator complex is
essential in broad transcriptional events and development. EMBO
J. 21,
3464-3475.
Jiang, Y. W. and Stillman, D. J. (1995).
Regulation of HIS4 expression by the Saccharomyces cerevisiae SIN4
transcriptional regulator. Genetics
140,
103-114.
Jiang, Y. W., Dohrmann, P. R. and Stillman, D. J.
(1995). Genetic and physical interactions between yeast RGR1 and
SIN4 in chromatin organization and transcriptional regulation.
Genetics 140,
47-54.
Johnson, K. M., Wang, J., Smallwood, A., Arayata, C. and Carey,
M. (2002). TFIID and human mediator coactivator complexes
assemble cooperatively on promoter DNA. Genes Dev.
16,
1852-1863.
Kang, J. S., Kim, S. H., Hwang, M. S., Han, S. J., Lee, Y. C.
and Kim, Y. J. (2001). The structural and functional
organization of the yeast mediator complex. J. Biol.
Chem. 276,
42003-42010.
Kang, Y. K., Guermah, M., Yuan, C. X. and Roeder, R. G.
(2002). The TRAP/Mediator coactivator complex interacts directly
with estrogen receptors alpha and beta through the TRAP220 subunit and
directly enhances estrogen receptor function in vitro. Proc. Natl.
Acad. Sci. USA 99,
2642-2647.
Kato, Y., Habas, R., Katsuyama, Y., Naar, A. M. and He, X. (2002). A component of the ARC/Mediator complex required for TGF beta/Nodal signalling. Nature 418, 641-646.[CrossRef][Medline]
Kim, Y. J., Bjorklund, S., Li, Y., Sayre, M. H. and Kornberg, R. D. (1994). A multiprotein mediator of transcriptional activation and its interaction with the C-terminal repeat domain of RNA polymerase II. Cell 77, 599-608.[Medline]
Koh, S. S., Ansari, A. Z., Ptashne, M. and Young, R. A. (1998). An activator target in the RNA polymerase II holoenzyme. Mol. Cell 1, 895-904.[Medline]
Koleske, A. J. and Young, R. A. (1994). An RNA polymerase II holoenzyme responsive to activators. Nature 368, 466-469.[CrossRef][Medline]
Koleske, A. J., Buratowski, S., Nonet, M. and Young, R. A. (1992). A novel transcription factor reveals a functional link between the RNA polymerase II CTD and TFIID. Cell 69, 883-894.[Medline]
Kwon, J. Y. and Lee, J. (2001). Biological significance of a universally conserved transcription mediator in metazoan developmental signaling pathways. Development 128, 3095-3104.[Medline]
Kwon, J. Y., Park, J. M., Gim, B. S., Han, S. J., Lee, J. and
Kim, Y. J. (1999). Caenorhabditis elegans mediator complexes
are required for developmental-specific transcriptional activation.
Proc. Natl. Acad. Sci. USA
96,
14990-14995.
Kwon, J. Y., Kim-Ha, J., Lee, B. J. and Lee, J. (2001). The MED-7 transcriptional mediator encoded by let-49 is required for gonad and germ cell development in Caenorhabditis elegans. FEBS Lett. 508, 305-308.[CrossRef][Medline]
Lee, T. I. and Young, R. A. (2000). Transcription of eukaryotic protein-coding genes. Annu. Rev. Genet. 34, 77-137.[CrossRef][Medline]
Lee, Y. C. and Kim, Y. J. (1998). Requirement
for a functional interaction between mediator components Med6 and Srb4 in RNA
polymerase II transcription. Mol. Cell. Biol.
18,
5364-5370.
Lee, T. I., Wyrick, J. J., Koh, S. S., Jennings, E. G., Gadbois,
E. L. and Young, R. A. (1998). Interplay of positive and
negative regulators in transcription initiation by RNA polymerase II
holoenzyme. Mol. Cell. Biol.
18,
4455-4462.
Lee, D. K., Kim, S. and Lis, J. T. (1999a).
Different upstream transcriptional activators have distinct coactivator
requirements. Genes Dev.
13,
2934-2939.
Lee, Y. C., Park, J. M., Min, S., Han, S. J. and Kim, Y. J.
(1999b). An activator binding module of yeast RNA polymerase II
holoenzyme. Mol. Cell. Biol.
19,
2967-2976.
Lefstin, J. A. and Yamamoto, K. R. (1998). Allosteric effects of DNA on transcriptional regulators. Nature 392, 885-888.[CrossRef][Medline]
Lemon, B. and Tjian, R. (2000). Orchestrated
response: a symphony of transcription factors for gene control.
Genes Dev. 14,
2551-2569.
Liao, S. M., Zhang, J., Jeffery, D. A., Koleske, A. J., Thompson, C. M., Chao, D. M., Viljoen, M., van Vuuren, H. J. and Young, R. A. (1995). A kinase-cyclin pair in the RNA polymerase II holoenzyme. Nature 374, 193-196.[CrossRef][Medline]
Malik, S. and Roeder, R. G. (2000). Transcriptional regulation through Mediator-like coactivators in yeast and metazoan cells. Trends Biochem. Sci. 25, 277-283.[CrossRef][Medline]
Malik, S., Gu, W., Wu, W., Qin, J. and Roeder, R. G. (2000). The USA-derived transcriptional coactivator PC2 is a submodule of TRAP/SMCC and acts synergistically with other PCs. Mol. Cell 5, 753-760.[Medline]
Myers, L. C., Gustafsson, C. M., Bushnell, D. A., Lui, M.,
Erdjument-Bromage, H., Tempst, P. and Kornberg, R. D. (1998).
The Med proteins of yeast and their function through the RNA polymerase II
carboxy-terminal domain. Genes Dev.
12, 45-54.
Myers, L. C., Gustafsson, C. M., Hayashibara, K. C., Brown, P.
O. and Kornberg, R. D. (1999). Mediator protein mutations
that selectively abolish activated transcription. Proc. Natl. Acad.
Sci. USA 96,
67-72.
Naar, A. M., Beaurang, P. A., Zhou, S., Abraham, S., Solomon, W. and Tjian, R. (1999). Composite co-activator ARC mediates chromatin-directed transcriptional activation. Nature 398, 828-832.[CrossRef][Medline]
Naar, A. M., Lemon, B. D. and Tjian, R. (2001). Transcriptional coactivator complexes. Annu. Rev. Biochem. 70, 475-501.[CrossRef][Medline]
Naar, A. M., Taatjes, D. J., Zhai, W., Nogales, E. and Tjian,
R. (2002). Human CRSP interacts with RNA polymerase II CTD
and adopts a specific CTD-bound conformation. Genes
Dev. 16,
1339-1344.
Park, J. M., Kim, H. S., Han, S. J., Hwang, M. S., Lee, Y. C.
and Kim, Y. J. (2000). In vivo requirement of
activator-specific binding targets of mediator. Mol. Cell.
Biol. 20,
8709-8719.
Park, J. M., Gim, B. S., Kim, J. M., Yoon, J. H., Kim, H. S.,
Kang, J. G. and Kim, Y. J. (2001a). Drosophila Mediator
complex is broadly utilized by diverse gene-specific transcription factors at
different types of core promoters. Mol. Cell. Biol.
21,
2312-2323.
Park, J. M., Werner, J., Kim, J. M., Lis, J. T. and Kim, Y. J. (2001b). Mediator, not holoenzyme, is directly recruited to the heat shock promoter by HSF upon heat shock. Mol. Cell 8, 9-19.[Medline]
Rachez, C. and Freedman, L. P. (2001). Mediator complexes and transcription. Curr. Opin. Cell Biol. 13, 274-280.[CrossRef][Medline]
Rachez, C., Suldan, Z., Ward, J., Chang, C. P., Burakov, D.,
Erdjument-Bromage, H., Tempst, P. and Freedman, L. P. (1998).
A novel protein complex that interacts with the vitamin D3 receptor in a
ligand-dependent manner and enhances VDR transactivation in a cell-free
system. Genes Dev. 12,
1787-1800.
Rachez, C., Lemon, B. D., Suldan, Z., Bromleigh, V., Gamble, M., Naar, A. M., Erdjument-Bromage, H., Tempst, P. and Freedman, L. P. (1999). Ligand-dependent transcription activation by nuclear receptors requires the DRIP complex. Nature 398, 824-828.[CrossRef][Medline]
Ranish, J. A., Yudkovsky, N. and Hahn, S.
(1999). Intermediates in formation and activity of the RNA
polymerase II preinitiation complex: holoenzyme recruitment and a
postrecruitment role for the TATA box and TFIIB. Genes
Dev. 13,
49-63.
Reeves, W. M. and Hahn, S. (2003).
Activator-independent functions of the yeast mediator sin4 complex in
preinitiation complex formation and transcription reinitiation.
Mol. Cell Biol. 23,
349-358.
Ren, Y., Behre, E., Ren, Z., Zhang, J., Wang, Q. and Fondell, J.
D. (2000). Specific structural motifs determine TRAP220
interactions with nuclear hormone receptors. Mol. Cell
Biol. 20,
5433-5446.
Ryu, S., Zhou, S., Ladurner, A. G. and Tjian, R. (1999). The transcriptional cofactor complex CRSP is required for activity of the enhancer-binding protein Sp1. Nature 397, 446-450.[CrossRef][Medline]
Shang, Y., Hu, X., DiRenzo, J., Lazar, M. A. and Brown, M. (2000). Cofactor dynamics and sufficiency in estrogen receptor-regulated transcription. Cell 103, 843-852.[Medline]
Sharma, D. and Fondell, J. D. (2002). Ordered
recruitment of histone acetyltransferases and the TRAP/Mediator complex to
thyroid hormone-responsive promoters in vivo. Proc. Natl. Acad.
Sci. USA 99,
7934-7939.
Shim, E. Y., Walker, A. K. and Blackwell, T. K.
(2002). Broad requirement for the mediator subunit RGR-1 for
transcription in the Caenorhabditis elegans embryo. J. Biol.
Chem. 277,
30413-30416.
Soutoglou, E. and Talianidis, I. (2002).
Coordination of PIC assembly and chromatin remodeling during
differentiation-induced gene activation. Science
295,
1901-1904.
Stevens, J. L., Cantin, G. T., Wang, G., Shevchenko, A. and
Berk, A. J. (2002). Transcription control by E1A and MAP
kinase pathway via Sur2 mediator subunit. Science
296,
755-758.
Sun, X., Zhang, Y., Cho, H., Rickert, P., Lees, E., Lane, W. and Reinberg, D. (1998). NAT, a human complex containing Srb polypeptides that functions as a negative regulator of activated transcription. Mol. Cell 2, 213-222.[Medline]
Taatjes, D. J., Naar, A. M., Andel, F., 3rd, Nogales, E. and
Tjian, R. (2002). Structure, function, and activator-induced
conformations of the CRSP coactivator. Science
295,
1058-1062.
Tan, Q., Linask, K. L., Ebright, R. H. and Woychik, N. A.
(2000). Activation mutants in yeast RNA polymerase II subunit
RPB3 provide evidence for a structurally conserved surface required for
activation in eukaryotes and bacteria. Genes Dev.
14,
339-348.
Thompson, C. M., Koleske, A. J., Chao, D. M. and Young, R. A. (1993). A multisubunit complex associated with the RNA polymerase II CTD and TATA-binding protein in yeast. Cell 73, 1361-1375.[Medline]
Treisman, J. (2001). Drosophila homologues of
the transcriptional coactivation complex subunits TRAP240 and TRAP230 are
required for identical processes in eye-antennal disc development.
Development 128,
603-615.
Treuter, E., Johansson, L., Thomsen, J. S., Warnmark, A., Leers,
J., Pelto-Huikko, M., Sjoberg, M., Wright, A. P., Spyrou, G. and Gustafsson,
J. A. (1999). Competition between thyroid hormone
receptor-associated protein (TRAP) 220 and transcriptional intermediary factor
(TIF) 2 for binding to nuclear receptors. Implications for the recruitment of
TRAP and p160 coactivator complexes. J. Biol. Chem.
274,
6667-6677.
Vignali, M., Hassan, A. H., Neely, K. E. and Workman, J. L.
(2000). ATP-dependent chromatin-remodeling complexes.
Mol. Cell. Biol. 20,
1899-1910.
Wang, Q., Sharma, D., Ren, Y. and Fondell, J. D.
(2002). A coregulatory role for the TRAP-mediator complex in
androgen receptor-mediated gene expression. J. Biol.
Chem. 277,
42852-42858.
Yuan, C. X., Ito, M., Fondell, J. D., Fu, Z. Y. and Roeder, R.
G. (1998). The TRAP220 component of a thyroid hormone
receptor-associated protein (TRAP) coactivator complex interacts directly with
nuclear receptors in a ligand-dependent fashion. Proc. Natl. Acad.
Sci. USA 95,
7939-7944.
Yudkovsky, N., Ranish, J. A. and Hahn, S. (2000). A transcription reinitiation intermediate that is stabilized by activator. Nature 408, 225-229.[CrossRef][Medline]
Zawel, L., Lu, H., Cisek, L. J., Corden, J. L. and Reinberg, D. (1993). The cycling of RNA polymerase II during transcription. Cold Spring Harb. Symp. Quant. Biol. 58, 187-198.[Medline]
Zhu, Y., Qi, C., Jain, S., Rao, M. S. and Reddy, J. K.
(1997). Isolation and characterization of PBP, a protein that
interacts with peroxisome proliferator-activated receptor. J. Biol.
Chem. 272,
25500-25506.
Zhu, Y., Qi, C., Jia, Y., Nye, J. S., Rao, M. S. and Reddy, J.
K. (2000). Deletion of PBP/PPARBP, the gene for nuclear
receptor coactivator peroxisome proliferator-activated receptor-binding
protein, results in embryonic lethality. J. Biol.
Chem. 275,
14779-14782.
Related articles in JCS: