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Molecular and Cellular Biology, December 2000, p. 8933-8943, Vol. 20, No. 23
Division of Biochemistry and Molecular
Biology, University of Glasgow, Glasgow G12 8QQ, United
Kingdom
Received 13 June 2000/Returned for modification 15 July
2000/Accepted 5 September 2000
The p300/CREB-binding protein (CBP) family of proteins consists of
coactivators that influence the activity of a wide variety of
transcription factors. Although the mechanisms that allow p300/CBP proteins to achieve transcriptional control are not clear, it is
believed that the regulation of chromatin is an important aspect of the
process. Here, we describe a new level of p300-dependent control
mediated through the functional interaction between p300/CBP and
members of the family of nucleosome assembly proteins (NAP), which
includes NAP1, NAP2, and TAF1. We find that NAP proteins, which have
previously been implicated in the regulation of transcription factor
binding to chromatin, augment the activity of different p300 targets,
including p53 and E2F, through a process that is likely to involve the
physical interaction between p300 and NAP. NAP proteins can form
oligomers, and the results show that NAP proteins can bind to both core
histones and p300 coactivator proteins, perhaps in a multicomponent
ternary complex. We also provide data in support of the idea that
histones can influence the interaction between p300 and NAP protein.
These results argue that NAP is a functionally important component of
the p300 coactivator complex and suggest that NAP may serve as a point
of integration between transcriptional coactivators and chromatin.
Transcription of the eukaryotic
genome is a dynamic process in which genes are constantly being
switched on and off. Mammalian genomic DNA exists as chromatin, which
is subject to the action of sequence-specific transcription factors and
their associated coactivator complexes that regulate the transcription
of target genes. The p300/CREB-binding protein (CBP) family is a group
of coactivator proteins that act to nucleate the assembly of diverse cofactors into a coactivator complex (13, 14, 28, 48, 62).
Furthermore, p300/CBP proteins have been implicated in regulating a
variety of sequence-specific transcription factors, including the p53
tumor suppressor protein and the cell cycle-regulating transcription
factor E2F (4, 21, 37, 38, 54). Although the molecular
complexity of the p300/CBP coactivator complex has yet to be resolved,
cofactors that have been found to associate with p300/CBP include
P/CAF, P/CIP (ACTR or AIB1), SRC1, and JMY (2, 12, 29, 47, 53, 60,
61).
The gene-regulating properties of chromatin can be influenced by
posttranslational modification, such as acetylation, and a role for
transcriptional coactivator complexes in mediating and regulating the
acetylation of chromatin has been suggested (7, 19, 52, 57,
58). For example, p300/CBP proteins together with P/CAF, P/CIP,
and SRC1 possess an intrinsic histone acetyltransferase activity (HAT)
that can acetylate histones (5, 12, 43, 50, 61).
Moreover, p300/CBP and P/CAF are capable of acetylating nonhistone
proteins, including p53, which may be required to augment p53 activity
in vivo (6, 20, 24, 46). Taken together, these observations
suggest that sequence-specific transcription factors recruit p300/CBP
coactivator complexes to target genes and that the acetylation of the
local chromatin environment facilitates its accessibility to
transcription factors and other protein components required to
stimulate transcription.
The most basic repeating unit of chromatin is the nucleosome, which is
composed of an octamer of core histones (an H3-H4 tetramer bound to two
H2A-H2B dimers) wrapped around about 146 bp of DNA. Chromatin is
generally inhibitory to transcription and can impede the binding of
certain transcription factors (32, 33, 51). In the cell, the
need to regulate the influence of chromatin appears to be
achieved in part through utilizing multicomponent remodeling activities, such as ACF, CHRAC, SWI-SNF, RSC, and NURF, which possess
the common property of perturbing chromatin in an ATP-dependent fashion
(3, 10, 27, 31). The transcriptional activation of a target
gene in a chromatin environment is therefore most likely to involve the
coordinated interplay between transcription factors, coactivator
complexes, and multicomponent chromatin remodeling activities.
The nucleosome assembly protein/template activating factor (NAP/TAF)
family (from now on referred to as NAP) is a group of histone
chaperone-like proteins which have been credited with playing a variety
of roles related to transcriptional control and possibly DNA
replication. For example, the TAF1 member of the family was identified
on the basis of its ability to stimulate adenovirus replication of a
viral chromatin template (42). Furthermore, the TAF1 gene
(also called set) is the subject of a chromosomal aberration
in myeloid leukemogenesis (56), implying that deregulated NAP activity may play a role in oncogenesis. Another member of the
family, yeast NAP1, was shown to possess chromatin assembly and histone
binding capability (16), while similar activities have been
established for the other NAP proteins (42, 45), and NAP1
can augment the binding of transcription factors to a nucleosome-containing binding site (59). The stimulation of transcription factor binding and nucleosome displacement occurs in a
manner similar to the action of nucleoplasmin and through a process
that requires nucleosome disassembly (59).
Drosophila NAP1 was further shown to exist as a complex of
H2A and H2B (9, 26), similar results having been observed in
HeLa cells (11), suggesting that NAP1 may act as a histone
chaperone. NAP proteins may also function in the assembly of regularly
spaced nucleosomal arrays, since the ability of ACF to assemble
nucleosomal arrays requires core histones, ATP, DNA, and
NAP1 or CAF1 (27). In addition, NAP proteins have been
shown to be associated not only with core histones in cytosolic
extracts (11, 25) but also with cyclin B within an
independent complex (30) and undergo nucleocytoplasmic
shuttling during cell cycle progression (25). Overall,
therefore, the NAP family comprises a group of multifunctional proteins
that can participate in different aspects of chromatin-related activities.
Here, we report that p300/CBP proteins functionally interact with
members of the NAP family of proteins. By studying the effect of NAP on
p300/CBP-dependent transcription factors, such as p53 and E2F, we find
that NAP augments p300/CBP-dependent transcription. Moreover, we find
that NAP proteins can form both homomers and heteromers and that all
members of the NAP family analyzed can bind directly to both core
histones and p300 coactivator proteins. Most importantly, the
data suggest that NAP proteins can form a ternary complex
involving p300 and histones. These results argue that NAP proteins are
likely to function as important components of p300/CBP-dependent
effects and suggest that NAP proteins serve as a point of
integration between coactivators and chromatin.
Isolation of p300-interacting proteins.
For the isolation of
p300-interacting proteins, the yeast strain CTY10.5 containing the
LexA- Immunoprecipitation.
For immunoprecipitation, U2OS cells
were transfected with pG4-p300611-2283 (30 µg), pG4 (30 µg), or pCMV-HA-NAP2 (30 µg) and after 48 h harvested in a
solution containing 50 mM Tris-HCl (pH 7.4), 120 mM NaCl, 5 mM EDTA,
0.5% NP-40, 50 mM NaF, 1 mM dithiothreitol (DTT), 1 mM
phenylmethylsulfonyl fluoride (PMSF), 0.2 mM sodium orthovanadate,
leupeptin (0.5 µg/ml), trypsin inhibitor (0.5 µg/ml), aprotinin
(0.5 µg/ml), and bestatin (40 µg/ml) and incubated on ice for 30 min. The cell extract was precleared by incubation with protein
A-agarose for 1 h at 4°C, and the supernatant was incubated with
a mouse anti-Gal4 monoclonal antibody (Santa Cruz) for a further 1 h at 4°C. Samples were incubated with protein A agarose for another
1 h, collected, and washed three times in extraction buffer.
Immunocomplexes were resolved by sodium dodecyl sulfate-polyacrylamide
gel electrophoresis (SDS-PAGE) and thereafter immunoblotted with a
mouse antihemagglutinin (anti-HA) monoclonal antibody (Boehringer Mannheim).
0270-7306/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.
Functional Interaction between Nucleosome Assembly
Proteins and p300/CREB-Binding Protein Family Coactivators
ABSTRACT
Top
Abstract
Introduction
Materials and Methods
Results
Discussion
References
INTRODUCTION
Top
Abstract
Introduction
Materials and Methods
Results
Discussion
References
MATERIALS AND METHODS
Top
Abstract
Introduction
Materials and Methods
Results
Discussion
References
-galactosidase reporter vector pLex (HIS) and
pLex-p300611-2283 were as described previously (8,
47). Screening a 10.5-day-postcoitum mouse embryo random-primed
cDNA library fused to the VP16 trans activation domain
(55) yielded two positive clones containing NAP2 and
one containing the NAP1 sequence. Full-length NAP2 clones were isolated
through screening cDNA libraries prepared from F9 EC (18).
Expression vectors.
The NAP2 1-123, 98-386, 1-279,
234-386, 98-386, 
110-230, and 110-230 derivatives were prepared
by PCR using the appropriate primers, and the resulting fragments were
isolated and cloned into the pCDNA3 (Invitrogen) backbone at the
BamHI/XhoI site. For the glutathione
S-transferase (GST)-p300 constructs, the appropriate fragments were removed by a restriction enzyme digest from Gal4-p300 (37) and cloned directly into the pGEX-3KG vector
(Pharmacia). pCBP HAT was as previously described (40), and
expression vectors for p53 and E2F-1, together with pBax-luc, were as
previously described (37). pG4-p30019-567 was
prepared by subcloning the relevant fragment from Gal4-p300 into pCDNA3.
NAP and p300 binding assays. For the in vitro binding assay, the indicated NAP2 proteins were in vitro translated by using a TNT-coupled reticulocyte lysate system (Promega) in the presence of [35S]methionine-cysteine (Amersham) and incubated with GST beads loaded with the fusion protein in TNN buffer (50 mm Tris [pH 8.0], 150 mM NaCl, 0.5% NP-40, 1 mM EDTA, and protease inhibitor cocktail [Calbiochem]). After 1 h of incubation at 4°C, the beads were washed three times with 1 ml of TNN buffer. Protein bound to the beads was eluted directly into SDS loading buffer. Flag epitope-tagged p300 protein (residues 1135 to 2414) and wild-type p300 protein (43) were expressed in Sf9 cells in the baculovirus system and bound to M2-anti-Flag antibody-agarose (Sigma). For the control, the M2 beads were treated with cell extract from uninfected Sf9 cells. NAP2 protein in pET28 (Novagen) was expressed and purified using nickel beads according to the manufacturer's instructions (Pharmacia). The eluted NAP2 protein was dialyzed against 50 mM Tris (pH 7.5)-100 mM KCl-20% glycerol-0.2 mM PMSF-0.1 mM DTT. NAP2 protein was incubated with either p300 coupled or control beads with or without histones at 4°C for 2 h in buffer containing 50 mM Tris (pH 7.5), 1.5 mM MgCl, 0.2 mM EDTA, 0.5% NP-40, 10% glycerol, protease inhibitor cocktail (Calbiochem), 0.1 mM DTT, 0.1 mM PMSF, and 0.5 mg of bovine serum albumin per ml. The protein complex on the beads was washed three times in TNN buffer and subjected to SDS-PAGE, followed by a Western blot with anti-NAP2 antiserum. Alternatively, in vitro-translated [35S]methionine-labeled NAP2 and mutant derivatives were used in the binding reaction, and binding efficiency was assessed after SDS-PAGE.
Mammalian two-hybrid assays. For the mammalian two-hybrid assay, 0.5 µg of pG4-p300611-2283, -p300611-1257, -p3001302-1572, -p3001572-2283, or -p3001572-1906 (37) was transfected with 0.5 µg of pVP16 or pVP16-NAP2 into U2OS cells. The Gal4 reporters pG5-luc and pG4-AdML-luc have been described previously (37).
Transfection. Transfection of SAOS2 and U2OS cells was carried out as previously described (47, 49). Immunoblotting of transfected cell extracts was performed as previously described using anti-p53 (DO1; Santa Cruz), anti-p21 (C19; Santa Cruz), and anti-NAP2 peptide antiserum.
Anti-NAP2 peptide antibody. The anti-NAP2 peptide antibody was raised in rabbits against the peptide taken from the C-terminal region of NAP2 containing residues GDEEGEDEDDDDDDADVNPKK.
Core histone octamer preparation. Core histone octamers were prepared from chicken blood as described previously (22). The composition was checked by SDS-PAGE and verified to contain H2A, H2B, H3, and H4.
Histone binding assays. Glutathione beads containing Drosophila GST histone tails (17) derived from H2A, H3, H2B, and H4 (2 µg of each) and in vitro-translated NAP were incubated in the binding buffer (10 mM Tris-HCl [pH 8], 1 mM EDTA, 150 mM NaCl, 0.1% Triton X-100, 0.5 mM PMSF, 1 mM DTT) for 1 h at 4°C. Beads were collected by centrifugation, washed twice with the same buffer, and resuspended in SDS sample buffer. [35S]methionine-radiolabeled NAP was resolved on a 7.5% gel.
Sucrose gradient analysis. NAP2 and p300 (residues 1135 to 2414) proteins were purified as described above, and core histones were obtained from Sigma. For the in vitro analysis, protein complexes were formed in 50 mM Tris [pH 7.5], 1.5 mM MgCl2, 0.4 mM EDTA, 10% glycerol, and 0.25 mg of bovine serum albumin per ml at 4°C for 30 min. A 20 to 50% sucrose gradient was sedimented at 47,000 rpm for 17 h in an SW55 rotor (Beckman). Fractions were collected from the bottom of the gradient. Typically, about 25 fractions of about 200 µl each were collected and analyzed by immunoblotting with either the anti-NAP2 peptide antibody, anti-p300 (NM11; Calbiochem), or anti-histone H2A-H2B (Santa Cruz), as described above. Each gradient analysis was repeated several times. Standard molecular mass proteins (Amersham Pharmacia Biotech) included in the gradient analysis were aldolase (158 kDa), catalase (232 kDa), and ferritin (440 kDa).
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RESULTS |
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Top
Abstract
Introduction
Materials and Methods
Results
Discussion
References
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NAP proteins bind to p300.
To investigate the mechanisms
through which p300/CBP coactivators regulate transcription, we screened
for proteins capable of interacting with p300 in the yeast
two-hybrid assay. Using LexA-p300611-2283 as the bait,
a 10.5-day-postcoitum mouse embryo activation domain-tagged library was screened from which we isolated a previously identified protein, known as NAP1, together with another less well characterized and more recently identified member of the family, referred to as
NAP2 (23, 45). A comparison of NAP1 and NAP2 indicated that both proteins are of similar size (391 to 386 amino acid residues,
respectively) and in certain regions possess striking similarity (Fig.
1a). The NAP family of proteins also
includes TAF1, which is closely related to both NAP1 and NAP2 (Fig. 1a) and exists as two alternatively spliced variants, known as 
and (42). In the following study, we present data
derived mostly from assays performed with NAP2, although it
should be noted that unless otherwise stated, the properties of all
three NAP proteins (NAP1, NAP2, and TAF1) were similar in the
study reported here.
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) (lane 2) of homologous peptide followed by
immunoblotting with either anti-NAP2 (top) or anti-p300 (bottom). Lane
1 shows the input extract, and NAP2 and p300 are indicated. Note that
the NAP2 polypeptide is absent in the presence of the competing NAP2
peptide (+) (top) and that p300 in the immunoprecipitate correlates
with the presence of NAP2 (bottom).
was coexpressed (Fig. 1b),
supporting the idea that each of these three NAP family proteins can
interact with p300. The stimulation in activity was specific for
G4-p300611-2283, since VP16-NAP had little effect
on the Gal4 DNA binding domain (Fig. 1b). Further evidence for an
interaction between NAP and p300 was provided by the introduction
of expression vectors for G4-p300611-2283 and
HA-NAP2 into U2OS cells, followed by immunoprecipitation with
anti-Gal4 and immunoblotting with anti-HA, where NAP2 was found to be
specifically coimmunoprecipitated with p300 (Fig. 1c). Importantly,
similar observations were made when the immunoprecipitation was
performed on endogenous proteins from nontransfected murine A31 cells,
where p300 was found to coimmunoprecipitate with endogenous NAP2. Thus,
by using an anti-NAP2 peptide antibody that recognized murine NAP2, we
found that when the immunoprecipitation was performed with anti-NAP2 in
the presence or absence of a competing NAP2 peptide, p300 was detected
only in the presence of the control peptide (Fig. 1d, panel ii). In
summary, therefore, these results provide considerable support for
the idea that p300 can physically interact with members of the NAP
family of proteins and further that this interaction occurs under
physiological conditions.
Binding domains in p300 and NAP2.
To resolve which region in
p300 is responsible for the interaction with NAP2, we used the
mammalian two-hybrid assay together with a panel of G4-p300
hybrids which were studied in the presence of coexpressed VP16-NAP2. An
interaction was apparent between VP16-NAP2 and the C-terminal region of
p300, encompassed within residues 1572 to 2283, which was further
resolved to the region between amino acid residue 1572 and 1906 (Fig.
2a). These results were further confirmed
through a biochemical binding assay in which different regions of p300
were expressed as GST fusion proteins and incubated with in
vitro-translated NAP2. In agreement with the two-hybrid results, we
found that GST-p3001572-1906 bound
efficiently to NAP2, whereas the overlapping fusion proteins GST-p3001302-1737 and
GST-p3001818-2080 failed to do so (Fig. 2b and d).
Moreover, using in vitro-translated luciferase as a negative control,
we could not detect any binding between luciferase and p300 (Fig. 2c).
Overall, these results indicate that p300 and NAP2 are likely to
directly interact in mammalian cells, and the results identify a
C-terminal region in p300, encompassing the CH3 region, as a likely
binding domain that can interact with NAP2.
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NAP proteins augment p300-dependent transcription.
To
investigate the functional consequence of NAP2 on the activity of p300,
we studied the effect of NAP2 on two p300-dependent transcription
factors, p53 and E2F-1 (4, 21, 37, 38, 54). The
transcriptional activity of p53 was assayed on different p53-responsive
promoters, and we present data derived from the bax
promoter, which is a p53-responsive gene that encodes a protein involved with inducing apoptosis (41). As expected, the
bax promoter was efficiently activated in the presence of
p53, and a titratable increase in p53-dependent transcription was
apparent as the level of NAP2 was increased, with a marginal but
significant enhancement evident upon the coexpression of p300 (Fig.
4a). The stimulation of transcription by
NAP2 and p300 was dependent upon the integrity of the N-terminal
activation domain, since a p53 derivative containing an inactive
trans activation domain, p5322/23
(39), failed to respond to NAP2 and p300 (Fig. 4a). We also found that both NAP1 and TAF1 could similarly induce p53 activity (data not shown).
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/ and Rb/)
together with NAP2 and p300, either alone or together, and monitored the levels of endogenous p21. As expected, we found that p53 could stimulate p21 expression as the level of p53 was increased (Fig. 4d).
At a subsaturating amount of p53, we introduced NAP2 and p300.
Whereas neither NAP2 nor p300 had a profound effect on the p53-dependent induction of p21, when both NAP2 and p300 were introduced together a greater level of p21 was apparent, usually exhibiting about
a threefold induction (Fig. 4d). These results therefore further
strengthen the idea that NAP2 and p300 can functionally interact in the
induction of genes within a chromatin environment.
NAP binds to core histone tails.
In the next series
of experiments, we explored the biochemical properties of NAP
proteins and thereafter established a likely relevance of
the association between p300 and NAP. Previous studies have indicated that NAP1 copurifies with the core histones H2A and H2B,
an interaction that may facilitate the assembly of nucleosomes onto a
DNA template (9, 11, 16). We extended these observations by
determining if NAP2 showed binding activity for N-terminal tails and
thereafter whether there was any specificity for the N-terminal tail
region of core histones. In an assay using GST tail proteins derived
from Drosophila H2A, H2B, H3, and H4 (17), we
found that NAP2 could bind to isolated histone tails and reproducibly exhibited stronger binding activity for the H2A and H3 tail regions, although it was able to bind specifically to H2B and H4 (Fig. 5a). Similar results were observed on the
tail binding specificity of NAP1 and TAF1, which also exhibited
preferential binding activity for the H2A and H3 tail regions (Fig.
5a). It is important to note that this binding specificity did not
appear to reflect the conservation of protein sequence between the
Drosophila and murine tail regions, which were all greater
than 90% identical in sequence across the N-terminal 50 residues.
Thus, these results suggest that NAP proteins can directly interact
with the tail region of core histones and further imply that a level of
specificity may exist that allows NAP proteins to bind more efficiently
to certain core histone tails.
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p300 efficiently binds to NAP in the presence of core
histones.
Having gained evidence that a ternary complex between
p300, NAP2, and core histones may occur, we investigated the effect that core histones had on the interaction between p300 and NAP2. To
pursue this question, we identified binding conditions in which subsaturating levels of NAP2 bound specifically to
p3001135-2414 (Fig. 6a,
compare lanes 2 and 4). We reasoned that under these conditions,
histones may play a role in facilitating the interaction between NAP2
and p3001135-2414. We therefore assessed the effect of
core histones and found that the addition of core histones caused
a notable and specific increase in the efficiency of the
interaction between p3001135-2414 and NAP2 (Fig. 6a,
compare lanes 2 and 3), suggesting that the presence of core histones
could act to enhance the interaction between p300 and NAP2. It should
be noted that this effect was unlikely to be caused by the charged
nature of histones, since polyanions, such as spermidine, failed to
cause a similar effect (data not shown).
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110-230 (Fig. 6b, compare lanes 1, 2, and 3). For both of these
NAP2 mutants, we assessed the effect on the interaction with p300 of
adding core histones, which we found enhanced the interaction to a far
lesser extent than that observed for wild-type NAP2 binding to
wild-type p300, which was, as previously noted, significantly enhanced
by core histones (Fig. 6b, compare lanes 5, 6, and 7). The effects were
specific to the interaction between NAP2 and p300, since similar
effects were not observed on the binding of NAP2 to Flag-tagged control beads (Fig. 6b and c, compare lanes 5, 6, and 7). In contrast to
results for the other two NAP2 mutants, the binding of the internal
region of NAP2, 110 to 230, to p300 was enhanced by the presence of
core histones (Fig. 6b), suggesting that this region of NAP2 possesses
a domain that is influenced by the presence of core histones. Overall,
these results suggest that the presence of core histones may influence
the interaction between p300 and NAP.
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DISCUSSION |
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Top
Abstract
Introduction
Materials and Methods
Results
Discussion
References
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NAP proteins functionally interact with p300/CBP coactivators. The NAP proteins are an evolutionarily conserved family of chaperone-like proteins, to which the functions of both transcription and DNA replication-related mechanisms have been ascribed (1, 25, 26, 27, 42). For example, NAP proteins can act to facilitate the binding of sequence-specific transcription factors to a nucleosomal template (59) and further may play a role in nucleosome assembly by interacting with ACF (27). Other reports are consistent with NAP proteins taking part in the intracellular transport of histones (26), and a separate interaction with cyclin B has also been documented for yeast (30).
In this study, we have identified a hitherto unexpected role for NAP proteins in contributing to the activity of p300/CBP coactivators. The results strongly suggest that NAP proteins can physically associate with p300 and imply that this interaction allows NAP to augment p300 activity and thus p300-responsive transcription factors, such as p53 and E2F-1. Moreover, although NAP can form a complex with p300, we also found that NAP possesses the intrinsic capacity for binding to histone tails. Most interestingly, we acquired some evidence to suggest that NAP, p300, and core histones may interact to form a ternary complex and further that core histones may influence the interaction between NAP and p300. It seems likely, therefore, that certain aspects of p300 activity will entail a functional interaction with NAP proteins.NAP proteins augment p300 activity. Although it has previously been shown that NAP proteins can augment the binding of sequence-specific transcription factors to a nucleosomal template (59), the data described here define a new level of control through which NAP can regulate transcription. In this respect, it is interesting that we gained evidence to support the idea that the ability of NAP to bind to p300 may be influenced by the presence of core histones (Fig. 6), thus providing a plausible mechanism that could account for certain aspects of transcriptional control through NAP. Perhaps such a mechanism is important in maintaining the association of coactivator complexes with areas of chromatin that are destined to become, or already have become, transcriptionally active. In addition, another relevant consideration relates to the ability of NAP to influence nucleosome assembly in conjunction with ACF (27). It is possible that such an activity may favor the recruitment and stable association of p300 complexes with newly replicated DNA, which could be an important step in regulating the transcriptional activity of newly replicated genes. A role for the NAP-p300 interaction in a DNA replication-related context cannot therefore be excluded.
Transcriptional control by NAP. Although the results reported here generally support the NAP-p300 interaction in transcriptional activation, the stage or stages at which this interaction is required in the activation process have yet to be determined. However, it has become clear that chromatin can provide a substantial barrier to transcription, mostly through the inability of sequence-specific transcription factors to penetrate to DNA in a chromatin environment, and that a variety of ATP-dependent chromatin-remodeling activities can act to overcome this barrier (3, 10, 31). One potential model suggests that chromatin-remodeling activities create a fluid chromatin environment by regulating the rate of interconversion between different chromatin states and that activating transcription complexes lock chromatin in an active state, whereas repressing complexes fix chromatin in an inactive state. In the context of this model, it is likely that the interaction between NAP and p300 functions as an activating complex which, in collaboration with a remodeling activity, locks transcription into the on state. Thus, another role for the interaction between p300 and NAP may be relevant to a later stage of a multistep activation process, once chromatin-remodeling activities have been targeted and chromatin has been modified. In this respect, it is noteworthy that our results show that NAP proteins can bind to histone tail regions. While the copurification of NAP1 with H2A and H2B has been previously noted to occur (9, 11, 26), the data presented here suggest in addition that NAP proteins can bind to the tail region of core histones. Furthermore, within this tail binding activity we obtained evidence that specificity resides for certain core histones. It will be most interesting to establish the relevance of this tail binding activity to NAP function in vivo.
The results presented in this study raise a number of important questions. For example, while we find that the activities of p53 and E2F-1 are likely to be influenced by NAP and p300, we have yet to determine whether this process represents a general feature of p300-dependent transcriptional activation. Furthermore, the p300 HAT activity appears to be important in allowing p300 to activate some transcription factors (34, 35, 36, 40, 44), although the results presented here suggest that NAP does not directly influence the isolated HAT domain (Fig. 4d). It is possible, though it has yet to be proven, that other HATs in p300 complexes are responsible for augmenting transcription when NAP assembles with p300 or, alternatively, that NAP augments p300 activity through a process that does not involve HAT.A model for NAP-dependent transcriptional activation through p300
coactivators.
The ability of NAP to interact with both p300 and
core histones, combined with the fact that the presence of core
histones appears to regulate the interaction between p300 and NAP,
implies a plausible model that may account for the capacity of NAP to stimulate p300-dependent transcription (Fig.
7). We suggest that the stable
association of p300 coactivators with transcriptional activation
domains and the subsequent p300 binding to NAP may result in an overall
stabilizing influence which acts to strengthen the association of
coactivator complexes with chromatin. According to the results
presented here, the interaction between p300 and NAP may be augmented
by the histone, perhaps nucleosomal, environment of a chromatin
template. We suggest that this is a useful mechanistic feature that is
a desirable property of transcriptional coactivators, since it provides
a process that is destined to aid transcriptional activation. Moreover,
we would also anticipate, based on the results in previous reports
(59), that the presence of NAP in close proximity to a
transcription factor binding site positioned within a nucleosome will
favor DNA binding activity, which we imagine is an equally important
event that will contribute to enhanced transcriptional activity.
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ACKNOWLEDGMENTS |
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We thank Marie Caldwell for help in preparing the manuscript, T. Owen-Hughes and C. Peterson for discussion and technical advice, Y. Nakatani for p300 constructs, K. Nagata for TAF plasmids, and C. Wu for the GST-tail constructs.
We thank the Medical Research Council, the European Molecular Biology Organisation, and the Cancer Research Campaign for supporting this research. H.M.C. was supported by the Wellcome Trust.
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FOOTNOTES |
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* Corresponding author. Mailing address: Division of Biochemistry and Molecular Biology, Davidson Building, University of Glasgow, Glasgow G12 8QQ, United Kingdom. Phone: 44 141 330 5514. Fax: 44 141 330 5859. E-mail: nlathangue{at}bio.gla.ac.uk.
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REFERENCES |
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Top
Abstract
Introduction
Materials and Methods
Results
Discussion
References
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