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Review article
CREB-binding protein and p300: molecular integrators
of hematopoietic transcription
Gerd A. Blobel
Introduction
Differentiation of pluripotent hematopoietic stem cells into mature
circulating blood cells is coordinated by a complex series of transcriptional events. During the last decade, numerous transcription
factors have been identified whose expression is highly lineagerestricted within the hematopoietic system. These include the GATA
family of transcription factors, NF-E2, EKLF, the C/EBP family
of proteins, EKLF, and AML-1.1,2 However, tissue-specific and
developmentally correct expression of a given gene is not achieved
by a single transcription factor. Rather, unique combinations of
cell-type specific and widely expressed nuclear factors account for
the enormous specificity and diversity in gene expression profiles.
Recently, 2 highly related and widely expressed molecules, CREBbinding protein (CBP) and p300, have emerged as important cofactors
for a broad number of transcription factors both within and outside
the hematopoietic system. Haploinsufficiency of CBP results in Rubinstein-Taybi Syndrome (RTS) in humans, a disease characterized by
mental retardation, craniofacial abnormalities, broad toes and thumbs,
and an increased propensity for malignancies, including those
derived from the hematopoietic system.3 Mice heterozygous for a
disrupted CBP gene display a phenotype similar to RTS,4 and have
an increased incidence of leukemias and histiocytic sarcomas.5
Mice lacking both CBP alleles die during embryonic development
and display severe defects in primitive and definitive hematopoiesis, and in vasculo-angiogenesis.6 Chromosomal translocations
involving the CBP and p300 genes are associated with certain
forms of leukemia, underscoring the importance of these genes in
the regulation of hematopoietic cell differentiation and proliferation.
A series of recent reviews 7-9 serve as excellent guides through
the large number of factors interacting with CBP and p300. This
review will focus on the role of CBP and p300 in the transcriptional
control of hematopoietic cell differentiation.
After a general overview of CBP and p300, the hematopoietic
transcription factors regulated by CBP and p300 are described in a
systematic fashion. Subsequently, human diseases involving the CBP
and p300 genes and animal models related to these diseases are described. This is followed by an attempt to conceptualize our knowledge by discussing mechanistic aspects of CBP and p300 function.
Overview
CBP was originally discovered based on its ability to interact with
the cAMP response element-binding protein (CREB),10 whereas
From the Division of Hematology, Children’s Hospital of Philadelphia, and the
University of Pennsylvania School of Medicine, Philadelphia, PA.
Submitted April 21, 1999; accepted September 30, 1999.
Reprints: Gerd A. Blobel, MD, PhD, Abramson Pediatric Research Center
#316, Children’s Hospital of Philadelphia, 34th St and Civic Center Blvd,
BLOOD, 1 FEBRUARY 2000 • VOLUME 95, NUMBER 3
p300 was isolated as a cellular target of the adenoviral oncoprotein
E1A.11 Although E1A binds to various cellular proteins, including
the Rb family of tumor suppressor proteins, its ability to block cell
differentiation and to induce cell cycle progression in many cell
types depends, at least in part, on its interaction with CBP and
p300. The functions of CBP and p300 appear interchangeable in
many published reports, yet both molecules also fulfill unique roles
as revealed by gene inactivation studies.5,12,13
During the last 5 years, numerous transcriptional regulators
have been found to interact with CBP and p300 (see Figure 1 for
examples; for review see Shikama et al8). CBP and p300 are widely
expressed and are believed to regulate gene expression in most cell
types. Consistent with a function in a wide range of tissues, CBP-1,
a C elegans factor closely related to CBP and p300, acts at an early
stage in development and is essential for all non-neuronal differentiation pathways.14 In mammals, the situation is more complex
because of the existence of at least 2 such molecules, CBP
and p300.
The complexity of protein-protein interactions surrounding
CBP and p300 has led to their description as molecular integrators.
Their ability to integrate multiple transcriptional signals is illustrated by the observation that many nuclear factors that interact
with CBP and p300 can synergize with each other when bound to
the same promoter in cis. On the other hand, inhibition between
these factors might occur if they are bound to different promoters.
Inhibition has been proposed to result at least in some cases
from competition between these factors for limiting amounts of
CBP and p300 in the nucleus.15,16 Genetic evidence for the idea that
CBP and p300 are limiting stems from the discovery that patients
who lack one allele of CBP suffer from RTS. Finally, normal
development of Drosophila embryos is highly dependent on CBP
gene dosage.17,18
Many of the protein interactions surrounding CBP and p300 are
regulated by cellular signals. For example, phosphorylation of the
transcription factor CREB regulates its interaction with CBP and
p300, and hormones such as estrogens, glucocorticoids, and
retinoic acid stimulate CBP and p300 binding to nuclear hormone receptors.
To add to the complexity, CBP and p300 can stimulate both the
activating and repressive functions of certain nuclear factors. For
example, although CBP and p300 increase p53 activity on certain
p53-dependent promoters,19-21 they can also augment p53-mediated
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745
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746
BLOOD, 1 FEBRUARY 2000 • VOLUME 95, NUMBER 3
BLOBEL
Figure 1. Structure of CBP adapted from Shikama et al.8 Not all known CBP
interacting proteins are shown. Amino acid numbers are approximate. HAT, histone
acetyltransferase domain; CH, cysteine/histidine-rich region; BROMO, Bromodomain. Bromodomains are found in most histone acetyltransferases and in many
chromatin-associated factors. Bromodomains specifically bind to acetylated lysine.167 CBP and p300 interact with tissue-specific (eg, MyoD), broadly expressed
(eg, nuclear receptors), and general (eg, TFIIB and TBP) transcription factors. In
addition, CBP and p300 interact with oncoproteins, including c-Jun and c-Fos, and
tumor supressor proteins such as p53. CBP and p300 also interact with other
HAT-containing molecules, such as p/CAF, SRC-1, and ACTR. Finally, CBP and p300
regulate the activity of signal-dependent transcriptional activators such as CREB and
the STATs.
transcriptional repression on others.22 Moreover, CBP and p300
support cellular differentiation, but can also cooperate with gene
products that interfere with it. Thus, promoter and cellular context
are critical determinants of CBP and p300 function.
A breakthrough in the understanding of CBP and p300 function
was the discovery that they act not only in a stoichiometric fashion,
as is the case for most transcriptional cofactors, but that they also
possess enzymatic activity. The laboratories of Bannister23 and
Ogryzko Nakatani24 found that CBP and p300 possess intrinsic
histone acetyltransferase (HAT) activity. Acetylation of histones is
associated with a relaxed chromatin configuration, which is thought
to facilitate transcription factor access to DNA. For example, work
by Hebbes and colleagues25 demonstrated a strong correlation
between the presence of acetylated core histones and DNase I
sensitivity at the chicken ␤-globin locus. DNase I sensitivity occurs
before transcription is initiated and might reflect a state poised for
transcriptional activation. The importance of a balance between the
acetylated and nonacetylated state of histones in transcriptional
regulation is supported by the discovery that certain transcriptional
repressors are associated with histone deacetylases (for review see
Pazin and Kadonaga26).
More recently, CBP and p300 have been shown to acetylate
nonhistone nuclear proteins, including the tumor suppressor protein p53,27-29 dTCF,30 EKLF,31 GATA-1,32,33 NF-Y,34 the basal
transcription factors TFIIE and TFIIF,35,36 and the architectural
transcription factor HMG I(Y).37 In the case of p53, acetylation
strongly increases DNA binding in vitro, providing a potential
mechanisms for CBP and p300-mediated transcriptional control.27-29 Given the large number of factors that interact by CBP and
p300, it is likely that some of these are also regulated by
acetylation. Additional mechanisms by which CBP and p300 might
operate are discussed later.
a requirement for CBP and p300 during gene regulation derived
from experiments showing that forced expression of E1A, but not
mutant forms of E1A defective for CBP and p300 binding,
interfered with expression of certain myeloid, erythroid, and
B-lymphocytic genes (Figure 3).
The following recurring themes are found in many of the studies
summarized here. First, the activities of most transcription factors
that interact with CBP and p300 are sensitive to coexpressed E1A.
Inhibition by E1A is possible even if transcription factor binding
occurs outside the E1A-binding domain of CBP and p300, suggesting that simple competition for CBP and p300 binding cannot
account for all the effects of E1A. Second, stimulation of transcription factor activity by CBP or p300 usually ranges between 2-fold
and 10-fold in transient transfection assays, indicating that CBP
and p300 are limiting under these conditions. Third, various
combinations of nuclear factors regulated by CBP and p300
synergize with each other when bound to the same promoter.
The following section is divided according to classes of CBP
and p300-regulated hematopoietic transcription factors (summarized in Figure 2) rather than according to hematopoietic cell
lineages, because most transcription factors are expressed in
multiple cell types. Moreover, the biological functions of CBP and
p300 in hematopoiesis are linked to the functions of the transcription factors with which they interact.
c-Myb
c-Myb is among the first hematopoietic transcription factors found
to be regulated by CBP. c-Myb is the cellular counterpart of the
v-Myb oncoprotein identified in the avian myeloblastosis virus
(AMV). In the E26 virus, which causes mixed leukemia in
chickens, v-Myb is part of a Gag-Myb-Ets fusion protein. Interestingly, Ets itself is regulated by CBP and p300 (see below). c-Myb
expression is highest in progenitor cells of the myeloid, erythroid
and lymphoid lineages and is downregulated during maturation/
differentiation of these cells (for review see Weston40). Forced
expression of c-Myb blocks differentiation of erythroid and myeloid cell lines.41-45 Expression of a dominant interfering form of
c-Myb results in enhanced erythroid differentiation,46 whereas
treatment with antisense oligonucleotides directed against c-Myb
reduces proliferation of immature cells of the erythroid, myeloid
and T-lymphoid lineages.47-49 Disruption of the c-Myb gene in mice
leads to lethal anemia during fetal liver hematopoiesis.50 Along
with the leukemogenic potential of c-Myb, the previously mentioned studies suggest that c-Myb functions in maintaining hematopoietic precursor cells in a proliferative state.
CBP was found to stimulate both c-Myb and v-Myb transcriptional activity in transient transfection experiments.51,52 c-Myb
Roles of CBP and p300 in hematopoiesis
The viral oncoprotein E1A has been an invaluable tool for
examining the requirements of CBP and p300 in gene expression
and differentiation in various cell types. The N-terminus of E1A
binds to dedicated domains within CBP and p300 and blocks their
function.38,39 Indeed, in numerous studies, the first clues suggesting
Figure 2. Structure of CBP indicating docking sites for hematopoietic transcription factors. See text for a detailed description of the listed factors. The domain(s) of
CBP responsible for EKLF binding has not yet been determined. The observation that
different factors interact with distinct domains of CBP might explain the transcriptional
synergy observed between many of these factors.
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BLOOD, 1 FEBRUARY 2000 • VOLUME 95, NUMBER 3
CBP AND P300 IN HEMATOPOIETIC TRANSCRIPTION
747
B-cells can E47 bind DNA and activate gene expression as a
homodimer.55 Targeted disruption of the E2A gene in mice leads to
perinatal death and a selective ablation of mature B-cells.56,57 The
cause of death is uncertain, but surprisingly, there are no obvious
abnormalities present in other hematopoietic and nonhematopoietic
tissues.56-58
Work by Eckner and colleagues59 demonstrated that p300 forms
a stable complex with E47 on DNA. In addition, p300 stimulates
E47 activity in transient transfection experiments by using a
reporter gene driven by an intact IgH enhancer or by isolated
E47-binding sites. p300 also interacts with bHLH proteins involved in myogenesis,59 suggesting that it has the capacity to target
various members of bHLH protein superfamily that might include
those involved in hematopoiesis. Along with the findings outlined
later, this suggests a role for CBP and p300 in B-lymphoid gene
expression.
GATA-1
Figure 3. Interference with CBP and p300 function in erythroid cells leads to a
block in differentiation. MEL cells stably expressing a conditional, estradioldependent form of E1A were left untreated (U), or were treated with the differentiationinducing agent DMSO (D), estradiol (E), or both (D/E). To monitor differentiation, cells
were stained with benzidine, which stains hemoglobin (brown), and counterstained
with May-Grunwald. Note the absence of benzidine-positive cells following estradiolinduced E1A activation (D/E). Control cell lines expressing mutant forms of E1A
defective for CBP and p300 binding had no effect (not shown). For details, see Blobel
et al.68
binds CBP in vivo and in vitro in a phosphorylation-independent
manner at a site that overlaps with the CREB-binding domain of
CBP. Expression of E1A, of antisense CBP RNA, or of dominantnegative CBP interferes with c-Myb-dependent transactivation.51,52
Although CBP moderately enhances c-Myb activity (approximately 3-fold), the presence of another CBP-regulated DNA
binding protein such as NF-M, strongly increases the effects of
CBP in a synergistic fashion.52
Given the requirement for CBP and p300 during differentiation
of various cell types, it seems paradoxical that CBP would
cooperate with gene products such as c-Myb or v-Myb that block
differentiation. A possible explanation is that factors inducing
differentiation and those stimulating proliferation compete for the
action of CBP, depending on their expression levels during cellular
maturation, or depending on cellular signals that regulate their
interaction with CBP and p300.
The E2A proteins
Work from more than a decade ago demonstrated that E1A can
repress the activity of the gamma 2b heavy chain (IgH) and the
kappa light chain genes in lymphoid cells.53,54 However, at that
time, the identity of transcription factors inhibited by E1A was
unknown. Recent studies suggest that the basic helix-loop-helix
(bHLH) proteins E47 and E12 might present critical targets for
inhibition by E1A. E12 and E47, which are both encoded by the
E2A gene (not to be confused with E1A), are essential regulators of
B-cell gene expression. In most cell types, E12 and E47 proteins
bind to DNA and regulate transcription as heterodimers with
tissue-specific bHLH proteins, such as the hematopoietic transcription factor tal-1/SCL or the muscle-determining factors of the
MyoD family. Remarkably, despite its broad distribution, only in
GATA-1, one of the best studied hematopoietic transcription
factors, is a zinc finger protein involved in the regulation of
virtually all erythroid and megakaryocytic genes. GATA-1 is
required for survival and maturation of primitive and definitive
erythroid precursor cells.60-64 In addition, GATA-1 plays a critical
role during megakaryocytic proliferation and differentiation.61,65
GATA-1 can trigger terminal differentiation and cell cycle arrest
when reintroduced into a GATA-1–deficient immortalized proerythroblastic cell line.66
Among the genes regulated by GATA-1 are the globin genes,
which, in turn, are under the influence of the locus control regions
(LCRs). The LCRs, which contain multiple functionally important
GATA-binding sites, are thought to act in part by regulating the
chromatin structure at the globin gene loci.67 Given that CBP has
histone acetyltransferase activity, it is noteworthy that GATA-1
interacts with CBP in vivo and in vitro.68 This interaction involves
the zinc finger region of GATA-1 and the E1A-binding domain of
CBP. CBP strongly augments GATA-1 activity in transient expression assays.68 Expression of E1A in the erythroid cell line MEL
leads to a complete block in differentiation and to reduced
expression of GATA-1–dependent genes, including the ␣- and
␤-globin genes (Figure 2).68 These findings are consistent with a
mechanism by which CBP and p300 mediate at least some
functions of GATA-1 in intact erythroid cells.
Other GATA factors, including GATA-2 and GATA-3, which
have distinct expression patterns in hematopoietic cells, are also
stimulated by CBP (G. A. Blobel, unpublished). GATA-2 levels are
high in progenitor cells and decline during erythroid maturation.69,70 In contrast, GATA-1 levels increase as cells mature.69,70
Thus, it is possible that as its levels rise, GATA-1 recruits CBP
away from factors required for proliferation of precursor cells such
as GATA-271 and c-Myb,50 using them for the activation of
differentiation-specific genes.
One mechanism by which CBP regulates GATA-1 activity
appears to involve direct acetylation of GATA-1 itself. Two reports
showed that CBP and p300 acetylate GATA-1 at 2 highly conserved
lysine rich motifs near the zinc fingers.32,33 In addition, CBP
stimulates acetylation of GATA-1 in vivo at the same sites
acetylated by CBP in vitro.33 In vivo acetylation of GATA-1 by
CBP is inhibited by E1A but not by mutant E1A defective for CBP
and p300 binding,33 establishing a correlation between acetylation
of GATA-1 and its transcriptional activity. Although Boyes et al32
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BLOOD, 1 FEBRUARY 2000 • VOLUME 95, NUMBER 3
BLOBEL
reported that acetylation by p300 stimulates DNA binding of
chicken GATA-1 in vitro, no change in DNA binding upon
acetylation was observed by Hung et al.33 This discrepancy may be
the result of using chicken GATA-1/p300 versus murine GATA-1/
CBP, respectively. However, several lines of evidence suggest that
changes in DNA binding might not be the mechanism by which
acetylation regulates GATA-1 activity in vivo. First, mutations in
the acetylation sites do not affect DNA binding of mammalian
expressed GATA-1 molecules but do affect the transcriptional
response to CBP and p300.32,33 Second, although CBP and p300
stimulate GATA-1 activity in transient transfection assays, no
evidence exists showing that this stimulation is associated with an
increase in DNA binding of GATA-1. Third, when assayed in the
context of differentiating erythroid cells, mutations in either of the
2 acetylation motifs impair the ability of murine GATA-1 to trigger
erythroid differentiation without affecting its ability to bind DNA.33
This indicates that the biological activity of the acetylation sites can
be uncoupled from their putative role in DNA binding.
Although acetylation of GATA-1 is likely to be important for
GATA-1 function in vivo, the underlying molecular mechanism
remains to be determined. Acetylation of GATA-1 does not affect
its interaction with Fog, CBP, or GATA-1 itself.33 However, it is
possible that acetylation leads to changes in the conformation of
GATA-1 or affects interaction with other as yet unidentified
cofactors. The acetylation motifs of GATA-1 might serve as
docking sites for interaction with such cofactors.
NF-E2
Given the large number of CBP-interacting proteins, it is likely that
the strong inhibitory effects of E1A on MEL cell differentiation and
globin gene expression might involve multiple CBP-interacting
factors. Indeed, a very recent report showed that NF-E2 binding
sites in the LCR are important in mediating E1A sensitivity of the
␤-globin LCR.72 Moreover, both NF-E2 and EKLF (see below),
have been reported to physically interact with CBP. The basic
zipper (bZip) transcription factor NF-E2 is composed of a hematopoietic-restricted p45 subunit and a widely expressed p18 subunit,
which is a member of the maf family of proteins73-75 (for review see
Blank and Andrews76). Other p45-related molecules capable of
interacting with maf family members include Nrf1, Nrf2, Nrf3,
Bach 1, and Bach 2 (for references see Kobayashi et al77). Multiple
functionally important NF-E2-binding sites are present in the
␣- and ␤-globin LCRs. Loss of a functional p45 gene leads to a
pronounced defect in platelet formation,78 whereas globin gene
expression and erythroid development are only mildly affected.79
This suggests that other members of the p45 family might
substitute for p45 function in erythroid cells.
In vitro binding experiments showed that the p45 subunit of
NF-E2 binds directly to CBP.80 This study further suggests that
CBP might participate in mediating the ligand-dependent stimulation of the thyroid hormone receptor by p45. This is of biologic
interest given the role of thyroid hormone during erythropoiesis.81
Although the functional and molecular consequences of the
p45-CBP interaction have not been studied in detail, it is conceivable that NF-E2 cooperates with GATA-1 and EKLF in the
formation at the LCR of a high molecular weight transcription
factor complex (enhanceosome) surrounding CBP and p300.
It is important to point out that NF-E2 activity on chromatinized
templates cannot be attributed solely to the recruitment of histone
acetyltransferases. A report by Armstrong and Emerson82 demonstrated that NF-E2 can disrupt chromatin structure on templates
containing regulatory regions of the ␤-globin locus, and that the
NF-E2-associated chromatin modifying activity is ATP-dependent.
EKLF
Another transcription factor regulated by CBP is the zinc fingercontaining erythroid Krüppel-like factor EKLF.83 EKLF is specifically required for the expression of adult ␤-globin but not ␣-globin
genes, and loss of EKLF function leads to lethal ␤-thalassemia in
mice.84,85 Moreover, EKLF ⫺/⫺ mice carrying a human globin
gene locus display a delayed ␥- to ␤-globin switch that normally
occurs at the onset of adult bone marrow erythropoiesis.86,87
Interestingly, absence of EKLF also results in a loss of DNase 1
hypersensitive site formation at both the transgenic and endogenous ␤-globin promoters,87 consistent with a role of EKLF in
remodeling chromatin at these promoters.
EKLF can interact with both CBP and p300, and the CBP- and
p300-associated acetyltransferase p/CAF in transfected cells. However, CBP and p300, but not p/CAF, acetylate EKLF in vitro.31
Acetylation most likely occurs at 2 residues that are part of an
inhibitory domain adjacent to the zinc finger region. Metabolic
labeling experiments that used [3H]acetate further suggest that
EKLF is acetylated in vivo.31 CBP and p300, but not p/CAF,
stimulate EKLF activity in transient transfection experiments that
used the erythroleukemia cell line K562.31 It will be interesting to
determine whether acetyltransferase activity of CBP and p300 is
required for stimulation of EKLF activity. Acetylation did not
affect DNA binding of EKLF, and the molecular consequences of
acetylation are not yet known.31
Together, the above reports suggest that erythroid transcription
factors controlling globin gene expression might cooperate in the
formation of a high molecular weight complex in which GATA-1,
NF-E2, and EKLF are linked through CBP and p300 (Figure 4).
Consistent with such a model is the observed synergy between
GATA-1 and EKLF in transactivation experiments.88
Figure 4. Hypothetical model in which NF-E2, GATA-1, and EKLF cooperate to
recruit CBP and p300 to the locus control region of the ␤-globin gene cluster.
This could lead to acetylation of nearby histones and transcription factors. Acetylation
of histones leads to changes in chromatin structure, and acetylation of transcription
factors might stabilize their interaction with DNA or alter their transcriptional activity. It
is conceivable that this high molecular weight complex also connects to the
promoters of the globin genes through a looping mechanism.
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BLOOD, 1 FEBRUARY 2000 • VOLUME 95, NUMBER 3
C/EBP
CCAAT-box/enhancer binding proteins (C/EBPs) belong to the
basic region/leucine zipper class of transcription factors and play a
role in the differentiation of a broad range of tissues. In the
hematopoietic system, C/EBP family members are expressed
mostly in the myelomonocyctic lineage and participate in the
regulation of macrophage and granulocyte-restricted genes, such as
the M-CSF receptor, G-CSF receptor, and GM-CSF receptor genes
(for review see Lekstrom-Himes and Xanthopoulos, and Yamanaka
et al89,90). Targeted disruption of the C/EBPd, C/EBP␤, or C/EBP⑀
genes resulted in defects predominantly affecting the granulocytic
lineage,91-94 whereas other hematopoietic lineages remained intact.
C/EBP transcription factors are also critical mediators of inflammatory and native immune functions (for review see Poli95).
Studies by Mink et al96 showed that C/EBP␤-dependent transcription is E1A-sensitive and that overexpressed p300 stimulates
C/EBP␤ activity on the macrophage/granulocyte-specific mim-1
promoter and, importantly, also on an endogenous C/EBPregulated gene, called 126. Moreover, p300 increases the synergy
between c-Myb and C/EBP␤. C/EBP␤ binds to the E1A-binding
region of p300 through its N-terminus. Overexpression of the
minimal C/EBP␤-binding domain of p300 reduced the activity of
C/EBP␤ presumably by interfering with the C/EBP␤-p300 interaction.96 The N-terminus of C/EBP␤ contains stretches of amino
acids conserved among C/EBP family members suggesting that
other C/EBP molecules might also be regulated by CBP and p300.96
Together, these results implicate CBP and p300 as important
cofactors during granulocytic gene expression.
Ets
The Ets family of transcription factors is a diverse group of
approximately 30 proteins that share a conserved DNA binding
domain.97 The c-ets-1 proto-oncogene is transduced by the E26
avian acute leukemia virus to form part of the Gag-Myb-Ets gene
fusion. This virus induces both erythroid and myelomonocytic
leukemias. Full transforming activity of E26 requires the presence
of both the Myb and Ets portions of the fusion protein.98,99 Ets-1 is
expressed predominantly in lymphoid cells and regulates a number
of lymphocyte-specific genes. Gene knockout studies demonstrated
a role for Ets-1 in T-cell proliferation and survival.100,101 Effects on
B-cell differentiation were also observed.100,101 Ets-1 and some of
its relatives synergize with a number of transcriptional regulators
known to interact with CBP and p300, such as AP-1,102 and
Myb.103-106 Especially striking is the frequently observed cooperativity between Ets-like factors and GATA-1 during the expression
of several megakaryocyte-restricted genes, including the ␣IIb,107
GPIX,108 GP1b␣,109 the thrombopoietin receptor (c-mpl),110 and
PF4 genes.111 The synergy of Ets proteins with CBP and p300regulated factors led to the hypothesis that they too are regulated by
CBP. Indeed, Yang et al112 showed that the Myb- and Ets-dependent
promoter of the myeloid-expressed gene CD13/APN is sensitive to
the expression of E1A but not mutant E1A defective for CBP and
p300 binding. Ets-1 activity is stimulated by coexpressed CBP, and
Ets-1 associates with CBP in nuclear extracts. In vitro, the
N-terminus of Ets-1 can form 2 contacts with CBP involving the
CH1 and CH3 domains of CBP. In support of the functional
importance of the physical interaction between Ets-1 and CBP, the
authors demonstrated a good correlation between binding of Ets-1
to the CH1 region and its ability to transactivate. In addition, Ets-1
coprecipitates with histone acetyltransferase activity, consistent
CBP AND P300 IN HEMATOPOIETIC TRANSCRIPTION
749
with its association with CBP and p300 and/or other acetyltransferases in vivo.112
Of note, another Ets family transcription factor, PU.1, was
recently found to interact with CBP through the activation domain
of PU.1 in a yeast 2-hybrid assay.113 CBP stimulates PU.1
transcriptional activity in transient transfection assays. PU.1 is
specifically expressed in hematopoietic organs with the highest
levels detected in myeloid and lymphoid cells.114 Thus, CBP and
very likely p300 target a broad range of myeloid and lymphoid
expressed transcription factors.
AML1
Another leukemogenic transcription factor controlled by p300 is
AML1.115 The AML1 gene is rearranged in several distinct
chromosomal translocations associated with acute myeloid leukemia (AML; t[8;21]), acute lymphatic leukemia (ALL; t[12;21]),
and myelodysplastic syndrome (t[3;21]) (for review see Look116).
The AML1 gene is the most frequent target for chromosomal
translocations in human leukemias. AML1 constitutes a family of
at least 3 factors derived from the same gene by alternative
splicing. The AML1 gene products bind to DNA as heterodimeric
complexes with CBF␤. Of note, the CBF␤ gene itself is involved in
chromosomal rearrangements found in cases of AML.116 Consistent
with its broad expression pattern and the presence of functionally
important AML1 binding sites in the promoters and enhancers of
myeloid and lymphoid expressed genes, knock-out studies revealed
that both AML1 and CBF␤ genes are essential for the formation of
all definitive blood lineages.117-121
AML1b, one of the AML1 isoforms containing an activation
domain, and p300 associate in vivo and in Far Western blots, and
p300 stimulates AML1b activity on the myeloperoxidase promoter
in transient transfection experiments.115 Overexpression of the
t(8;21) translocation product AML1-ETO in the IL-3-dependent
myeloid cell line L-G interferes with G-CSF–induced differentiation along the neutrophilic lineage. Forced expression of wild-type
AML1b can overcome the effects of AML1-ETO and restore
differentiation.115 In contrast, AML1a, which lacks an activation
domain, is inactive in this assay. The potential of various AML1b
constructs to induce differentiation is further enhanced by coexpression of p300 and correlates well with their ability to interact with
p300.115 This indicates that p300 plays a role in myeloid cell
differentiation and suggests that the rearranged AML genes found
in chromosomal translocations act as dominant negative alleles.
The latter notion is consistent with the recent finding that AMLETO associates with a transcriptional repressor complex containing
histone deacetylases and that this deactylase complex is required
for blocking differentiation of myeloid cells.122-124 This raises the
interesting possibility that the intrinsic (or associated) acetyltransferase activity of p300 might be required to overcome the
repressive effects of AML-ETO. Indeed, a truncated form of p300
lacking the acetyltransferase domain was impaired in its ability to
synergize with AML-1b. However, a more detailed mutagenesis of
p300 will be required to establish a correlation between its HAT
activity and its ability to cooperate with AML1b.
Finally, AML-1 synergizes with c-Myb and with C/EBP on
myeloid and lymphoid promoters.125-127 This synergy is apparently
not the result of cooperative DNA-binding,127,128 suggesting that it
is instead mediated through recruitment of a common cofactor such
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750
BLOBEL
as CBP and p300, similar to what has been proposed for other CBP
and p300 regulated factors.
CBP and p300 in leukemia-associated
chromosomal translocations
Both CBP and p300 bind the viral oncoproteins E1A and SV40 T.
This raised the possibility that alterations in the functions of CBP
and p300 might play a role in the development of malignancies in
humans. This suspicion was supported by the finding that 1 copy of
the CBP gene is inactivated in the rare disease Rubinstein-Taybi
syndrome,3 which is manifested by an increased propensity for
tumors (mostly of the nervous system), craniofacial malformations,
and mental retardation.129,130
The involvement of CBP and p300 in hematologic malignancies
was realized through the discovery of leukemia-associated chromosomal translocations involving the CBP and p300 genes. These
translocations generally result in fusion products that preserve most
of the CBP and p300 molecules, suggesting that the disease
mechanism does not simply involve loss of function of CBP, as is
the case in Rubinstein-Taybi syndrome. Instead, they suggest
altered function (dominant positive or dominant negative) through
fusion to another molecule. For example, AML-derived leukemic
blast cells containing the t(8;16)(p11;p13) translocation, which is
often associated with acute myelogenous leukemia subtype M4/
M5, have the CBP gene fused to the MOZ (monocytic leukemia
zinc finger) gene.131 This fusion results in a small deletion of the
N-terminal 266 amino acids of CBP leaving the rest of the molecule
intact.131 Interestingly, the MOZ gene also has a putative acetyltransferase domain that is retained in the MOZ-CBP fusion.
In principle, any translocation event could lead to gain or loss of
function of either fusion partner, to the formation of dominant
interfering alleles, or to entirely new activities. Fusion of CBP to a
given transcription factor might result in aberrant recruitment of
CBP to certain promoters, leaving less free CBP available for other
transcription factors involved in balancing proliferation and differentiation. In addition, it is possible that misdirected or deregulated
acetyltransferase activity by CBP and p300 fusion products causes
changes in gene expression profiles that contribute to the transformed state. One likely mechanism by which the MOZ-CBP
fusion contributes to malignant transformation involves constitutive recruitment of CBP to MOZ-regulated genes. The MOZ gene
contains 2 C4HC3 zinc finger regions, also found in CBP and p300,
and a C2HC zinc finger. These regions might serve as proteinprotein interaction domains and might target MOZ to chromatinassociated proteins and DNA.131 The MOZ-CBP fusion protein
contains the CBP-derived and the putative MOZ acetyltransferase
domain that together could be powerful regulators of chromatin
structure and transcriptional activity at MOZ-regulated genes.
Since their initial discovery, additional cases of AML with
t(8;16) translocations resulting in CBP and MOZ gene arrangements have been reported.132 However, in these cases no MOZCBP fusion transcripts were detected, raising the possibility that
CBP or MOZ gene rearrangements might contribute to leukemogenesis by alternative mechanisms.
Another clinically relevant example of the importance of
balancing histone acetylation and deacetylation comes from studies
of acute promyelocytic leukemia (APL)-associated translocations
that fuse the retinoid acid receptor alpha (RAR␣) to the PLZF or
PML genes. PML-RAR␣ and PLZF-RAR␣ fusion proteins have a
BLOOD, 1 FEBRUARY 2000 • VOLUME 95, NUMBER 3
high affinity for a transcriptional repressor complex containing
histone deacetylases. Although normal RAR responds to retinoic
acid (RA) by shedding the deacetylase complex, followed by
association with an acetyltransferase complex (which contains
CBP), PML-RAR␣ responds only to very high concentrations of
RA, and PLZF-RAR␣ is RA resistant.133-135 The ability of leukemic
cells to differentiate upon RA treatment correlates with the ability
of their translocation fusion proteins to displace the repressor
complex in response to RA. In fact, patients with PML-RAR␣ APL
typically achieve remission upon treatment with high doses of RA,
whereas PLZF-RAR␣ APL patients do not.
The chromosomal translocation, t(11;16), which is associated
with therapy-induced acute myeloid leukemia, therapy-induced
chronic myelomonocytic leukemia, and myelodysplastic syndrome, fuses the MLL and CBP genes such that most of the CBP
molecule stays intact.136-139 The MLL gene was also found to be
fused to the p300 gene in an AML patient carrying a t(11;22)
translocation.140 The MLL gene encodes a large multidomain
protein containing zinc fingers and AT-hook motifs,141-143 and is
involved in translocations with at least 40 different fusion partners
(for references see Sobulo et al137). This raises the question whether
the structural alterations of MLL itself or of its fusion partners are
critical for leukemogenesis. Together, these findings underscore the
importance of CBP and p300 function in balancing growth and
differentiation of hematopoietic cells.
Mechanisms of CBP and p300 function
Clues from studies of intact animals. Some unexpected insights
into the function of CBP and p300 have come from gene knock out
studies. The CBP and p300 null mice display similar phenotypes.13
The p300⫺/⫺ embryos die between days 9 and 11.5. Their main
defects are severe developmental retardation, reduced size, failed
neural tube closure, and altered cardiac ventricular trabeculation. A
fraction of the p300 ⫹/⫺ mice die early, displaying neural tube
closure defects similar to the p300⫺/⫺ mice, indicating a requirement for full p300 gene dosage during neural development. Mice
heterozygous for CBP deficiency suffer from skeletal abnormalities
and growth retardation, a phenotype resembling RTS in humans.4
CBP and p300 compound heterozygous mice die early and display
a phenotype very similar to the individual homozygous knock outs.13
More extensive analysis of mice heterozygous for CBP deficiency revealed defects in the hematopoietic system that only
became apparent in newborn pups beginning at 3 months of age.5
The CBP ⫹/⫺ animals have extramedullary myelopoiesis and
erythropoiesis, and display enlarged, hypercellular spleens. In the
peripheral blood, the most striking defect is a decrease in the
number of B-lymphocytes, whereas in the bone marrow, cells of the
erythroid, myeloid, and B-lymphocytic lineage were significantly
reduced. No overt malignancies were observed in the CBP ⫹/⫺
mice until the mice reached at least 1 year of age. Then, 4 of the 18
mice analyzed had overt tumors, 2 had histiocytic sarcomas, 1 had
myelomonocytic leukemia, and 1 had lymphocytic leukemia. In
light of the small number of cases studied, it is conceivable that
other types of hematologic neoplasms might occur at an increased
rate in CBP ⫹/⫺ mice. When splenocytes or bone marrow cells
from apparently tumor-free CBP⫹/⫺ donors were engrafted into
sublethally irradiated wild-type mice, the recipients developed
histiocytic sarcomas at a high rate with latency periods of 3 to 5
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BLOOD, 1 FEBRUARY 2000 • VOLUME 95, NUMBER 3
months. Grafts derived from 1 CBP ⫹/⫺ donor resulted in the
formation of plasmacytomas with monoclonal gammopathy and
renal amyloid deposition. DNA analysis of 1 plasmacytoma and 1
histiocytic sarcoma from bone marrow–transplanted mice revealed
the specific loss of the wild-type CBP allele with retention of the
targeted one. Loss of heterozygosity in these cases suggests that
CBP is a tumor supressor gene, similar to the RB family of proteins
that are also targeted by the E1A oncoprotein. Surprisingly, no
hematologic defect or cancer predisposition was observed in ageand strain-matched p300 targeted mice.5 This suggests that, despite
their similarity, CBP and p300 might play distinct roles in certain
cell types.
The tumors observed in CBP ⫹/⫺ in mice appear to be
restricted to the hematopoietic system, although additional types of
neoplasms might be found as more mice are analyzed. In contrast,
patients with RTS have an increased risk for tumors of various
origins, the most common tumors being neurally derived. Hematologic malignancies observed in RTS patients occur less frequently
and include acute lymphocytic leukemia, acute myelogenous
leukemia, and non-Hodgkin lymphoma.130
A very recent report describes the hematologic consequences of
homozygous CBP-deficiency in mice.6 In this study, disruption of
the CBP gene resulted in the formation of a truncated form of CBP
that retains the N-terminal 1084 amino acids (of 2441) but lacks the
HAT domain. Mice homozygous for this defect die between day 9.5
and 10.5 of embryogenesis similar to the CBP knock-out mice.
Before their deaths, embryos are anemic, and their yolk sacs
contain fewer erythroid cells and display a defective vascular
network. Although the number of yolk sac–derived erythroid
colony forming units is reduced, a few mature erythroid cells are
found, suggesting that CBP is not absolutely required for erythroid
maturation and that p300 might be able to partially compensate for
the CBP defect. To examine definitive hematopoiesis in the CBP
⫺/⫺ mice, organ culture was performed from E9.5 embryos with
tissue from the aorta-gonad-mesonephros (AGM) region, followed
by colony forming assays. These experiments revealed dramatically reduced numbers of definitive erythroid and granulocyte/
macrophage progenitor cells. Organ cultures from these embryos
also revealed a strong reduction in vasculo-angiogenesis.
The mechanisms by which CBP deficiency cause RTS in
humans and the severe hematologic and nonhematologic defects in
mice are entirely unknown. The answer to this question is
complicated by the enormous complexity of protein interactions
surrounding CBP and the multitude of mechanisms by which CBP
regulates gene expression. Analysis of gene expression profiles in
tissues from CBP-deficient mice, as well as gene complementation
experiments with mutant CBP gene constructs, could be used to
tackle this question. Progress in the understanding of the phenotypic defects that result from CBP deficiency requires a reductionistic approach involving the study of individual CBP- and p300binding transcription factors and the genes that they control. For
example, it is conceivable that the reduced number of B lymphocytes in CBP ⫹/⫺ mice results from reduced activity of the E47
transcription factor that interacts with CBP and p300, and that is
required for B-cell development.59
Strength in numbers. CBP and p300 interact with numerous
transcription factors. Many of these interactions might take place
simultaneously because they are mediated by distinct domains.
This could account for the observed synergy between factors
regulated by CBP. Thus, CBP might provide a platform for the
CBP AND P300 IN HEMATOPOIETIC TRANSCRIPTION
751
assembly of high molecular weight complexes (enhanceosomes;
for review see Carey144) containing multiple DNA-binding proteins
that position the complex in a sterically correct fashion at
promoters and enhancers. Because this complex is likely to include
non-DNA-binding proteins such as p/CAF, ACTR, or SRC-1,
which also possess acetyltransferase activity, it would constitute a
powerful regulator of chromatin structure.145-147 For example, a
high molecular weight complex centered on CBP and p300 could
form at the LCR, which participates in regulating chromatin
structure at the ␤-globin locus (Figure 4). The LCR contains
binding sites for GATA-1, EKLF, and NF-E2 all of which bind to
CBP and p300.31,33,68,80 Thus, CBP and p300 might integrate signals
from multiple transcriptional regulators and perhaps even present
targets for global regulators of gene expression, such as signaling
cascades used by growth/differentiation factors. The latter notion is
supported by the observation that CBP and p300 are acetylated and
phosphorylated.
CBP and p300 are also thought to mediate negative cross-talk
between transcription factors. Competition for limiting amounts of
CBP and p300 has been invoked to account for mutual inhibition of
CBP- and p300-regulated transcription factors when bound to
separate DNA templates.15 This might explain the inhibition of
GATA factors by ligand-activated nuclear hormone receptors
(NR).148-150 The observation that overexpression of CBP alleviates
NR-mediated repression of GATA-1, and that ligand-bound NR
reduce the stimulation of GATA-1 activity by CBP (G. A. Blobel,
unpublished) are consistent with such a model. Together, these
findings support a role of CBP and p300 as molecular integrators of
positive and negative transcriptional signals that govern hematopoietic gene expression.
Building a bridge. The large number and diversity of genes
and transcription factors regulated by CBP and p300 could be
explained if CBP and p300 were components of the basal transcription apparatus. In support of such a model, CBP and p300 have
been found to interact with TFIIB,151 TBP,152-155 and RNA polymerase II.156-160 Thus, recruitment of CBP by a DNA-bound transcription factor could facilitate the formation of a preinitiation complex
at relevant promoters (Figure 5). Such a mechanism would imply
that CBP and p300 act in a stoichiometric fashion. Although this
might be true on some promoters, additional evidence suggest that
CBP and p300 also act catalytically (see next paragraph).
Action by catalysis. The observation that CBP, p300, and some
of its associated factors possess acetyltransferase activity suggests
an enzymatic mechanism of gene regulation. Targeting of CBP and
p300 to the appropriate sites could lead to local increases in histone
acetylation, followed by rearrangement of chromatin structure
(Figure 4). This in turn could favor access of other transcriptional
regulators. Again, the LCR provides an example where such a
mechanism might be operating. As previously mentioned, histone
acetylation and open chromatin correlate well at the chicken
Figure 5. Hypothetical model in which CBP and p300 link DNA-bound nuclear
factors to components of the basal transcription machinery. GTFs, general
transcription factors; TBP, TATA-binding protein, Pol II, RNA polymerase II.
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752
BLOBEL
BLOOD, 1 FEBRUARY 2000 • VOLUME 95, NUMBER 3
␤-globin gene locus.25 However, depending on transcription factor/
promoter context, CBP and p300 can also act in a HAT-independent fashion.161
If some nuclear factors act by recruiting a histone-modifying
enzyme to trigger chromatin opening, how do they find access to
DNA in the first place? One possibility is that other transcription
factors might pave their way by opening chromatin structure in an
acetylation-independent fashion. An example for such a scenario is
provided by the observation that NF-E2 disrupts chromatin structure in a ATP-dependent manner on a chromatinized template
containing DNase1 hypersensitive site 2 of the ␤-globin LCR.82
This leads to increased access of GATA-1 to adjacent GATA sites.
Alternatively, GATA-1 might find access to chromatin without
the assistance of other factors. A recent report162 demonstrated that
chicken GATA-1, or a peptide comprising just its DNA-binding
domain, can bind to DNA packaged into a nucleosome. This leads
to a reversible breakage of histone/DNA contacts, thus perturbing
nucleosome structure.162 Once bound to DNA, the GATA-1associated acetyltransferase complex might modify adjacent histones, thus facilitating access of other transcription factors to DNA.
It is important to keep in mind that modification of chromatin is
not restricted to acetylation, and that numerous regulated chromatin
modifying complexes have been identified (for review see Kadonaga163). For example, an elegant study by Armstrong et al164
demonstrated that EKLF interacts with a complex, called E-RC1,
which contains components of the mammalian SWI/SNF complex,
an ATP-dependent chromatin remodeling machine.163 However,
E-RC1 does not appear to contain histone acetyltransferases
(Beverly Emerson, personal communication).
Acetylation of nonhistone proteins, including transcription
factors, might turn out to be of equal importance for CBP and p300
function. For example, acetylation of p53 leads to an increase in
DNA binding activity.27-29 It is likely that acetylation regulates
transcription factor activity by a variety of mechanisms. In the case
of the drosophila transcription factor dTCF, acetylation by CBP
decreased its affinity for its cofactor ␤-catenin/Armadillo, leading
to transcriptional inhibition.30 An interesting variation of this theme
is the finding that acetylation of the architectural transcription
factor HMG)-I(Y) by CBP leads to destabilization of an enhanceosome complex at the interferon ␥ gene promoter, resulting in
termination of transcription.37
It is conceivable that acetylation might be a widely used
mechanism to trigger allosteric changes in proteins, thereby
regulating protein-protein and protein-DNA interactions, similar to
what has been observed upon protein phosphorylation. In both
cases, the modification results in a change of charge, addition of a
negative charge in the case of phosphorylation, and neutralization
of a positive charge in the case of acetylation. Moreover, acetylation changes the size of the lysine side chain, which could be
important in protein folding.
relevant settings. Given that CBP and p300 share many functions
this will not be an easy task, especially because it has not been
possible so far to generate CBP and p300 double knock-out cell
lines. The mechanisms by which CBP and p300 act likely depend
on promoter and cellular context as well as the chromatin
configuration in which a given target gene is embedded. One
approach that would allow dissection of CBP and p300 functions in
a physiologic context would be to knock in mutant CBP and p300
alleles bearing mutations in domains associated with specific
functions such as the HAT domain or important protein docking
sites. Such experiments might also yield insights into the mechanism by which loss of CBP leads to RTS.
Given the broad variety of CBP and p300 regulated factors, an
important and challenging task will be the identification of the
relevant downstream target genes that mediate their function in
vivo. Subtractive hybridization and microarray technologies might
be useful approaches to identify genes most sensitive to changes in
CBP and p300 levels.
Although CBP and p300 are expressed in most tissues, their
importance in regulating gene expression and differentiation in
hematopoietic cells is illustrated by their involvement in leukemiaassociated chromosomal translocations. It remains to be determined why these chromosomal translocations result in leukemias
mostly of the myeloid/monocytic lineage.
Because CBP and p300 have intrinsic and associated acetylase
activity, they might present targets for pharmacological intervention. It can be envisioned that novel drugs might be developed that
alter their specific activity or substrate specificity, thereby allowing
for modulation of gene expression and cell differentiation. For
example, in cases in which CBP acetyltransferase activity might be
activated as a result of chromosomal translocations or point
mutations, interference with this activity might reverse the cellular
phenotype whether it is hypo- or hyperplastic. Alternatively, in
cases in which cellular CBP activity is reduced as a result of
haploinsufficiency or inactivating mutations, a compound that
stimulates acetyltransferase activity of the remaining allele or that
of p300 might allow for compensation of the defect. Treatment of
any disorder caused by defects involving the CBP and p300 genes
or CBP- and p300-regulated transcription factors rests entirely on a
thorough understanding of the molecular and cellular environment
in which CBP and p300 function.
An example for the successful manipulation of the acetylation
balance in the cell comes from studies that use the drug trichostatin
A. Trichostatin A, which is a deacetylase inhibitor, has been
successfully used to activate silenced transgenes in the context of
gene delivery vectors designed for use in gene therapy.165 Furthermore, drugs targeting histone deacetylases have been used against
malaria and toxoplasmosis.166 Thus, a detailed understanding of the
role of protein acetylation might reveal new approaches to controlling gene expression and treating human diseases.
Summary and perspective
Acknowledgments
CBP and p300 are large, multifunctional molecules that can exert
both positive and negative effects on transcription and cell differentiation. It is likely that additional factors will be discovered to
interact with CBP and p300, and that a subset of these might be
regulated by acetylation. The challenge that lies ahead will be to
determine the significance of such interactions in physiologically
I want to thank Margaret Chou, Merlin Crossley, Richard Eckner,
Stuart Orkin, Morty Poncz, and Mitchell Weiss for helpful suggestions and critical reading of the manuscript. Naturally, the survey of
a burgeoning field such as this might not do justice to all
contributions. Therefore, I apologize to those whose work is not
represented here.
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BLOOD, 1 FEBRUARY 2000 • VOLUME 95, NUMBER 3
CBP AND P300 IN HEMATOPOIETIC TRANSCRIPTION
753
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2000 95: 745-755
CREB-binding protein and p300: molecular integrators of hematopoietic
transcription
Gerd A. Blobel
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