Original Paper
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Acta Biochim Biophys
Sin 2007, 39: 923930
doi:10.1111/j.1745-7270.2007.00366.x
Contribution of CDP/Cux, a transcription factor, to cell
cycle progression
Xifeng Fei1, Zhenghong Qin1,2, and Zhongqin Liang1,2*
1
Department of Pharmacology, Soochow University School of Medicine, Suzhou 215123,
China;
2 Laboratory of Aging and Nervous Diseases,
Soochow University School of Medicine, Suzhou 215123, China
Received: May 12,
2007
Accepted: August 8,
2007
This work was supported
by the grants from the National Natural Science Foundation of China (No.
30672452) and the Natural Science Foundation of High Education Bureau of
Jiangsu Province (No. 05KJB310117)
*Corresponding
author: Tel, 86-512-65880119; Fax, 86-512-65190599; E-mail,
Abstract CCAAT-displacement protein/Cut homeobox (CDP/Cux) was
initially identified as a transcriptional repressor. However, a number of
studies have now suggested that CDP/Cux is a transcriptional activator as well.
Stable DNA binding activity of CDP/Cux is up-regulated at the G1/S
transition by two mechanisms, dephosphorylation by the Cdc25A phosphatase and
proteolytic processing to generate a 110 kDa amino-truncated isoform, CDP/Cux
p110. The generation of CDP/Cux p110 stimulates the expression of reporter
plasmid containing the promoter sequences of some S phase-specific-genes such
as DNA polymerase a gene, dihydrofolate reductase
gene, carbamoyl-phosphate synthase/aspartate
carbamoyl-transferase/dihydroorotase gene, and cyclin A gene. However, DNA
binding activity of CDP/Cux is down-regulated at G2 phase through a binding of
cyclin A-cyclin-dependent kinases1 (Cdk1) to CDP/Cux. Furthermore, another CDP/Cux
isoform, CDP/Cux p75, has been found to be associated with breast tumors
indicating this isoform is involved in the abnormal proliferation of tumor
cells. The differences in DNA binding of CDP/Cux isoforms in S and G2 phases
suggest important roles of CDP/Cux in cell cycle progression. In this review,
we discuss the functions of CDP/Cux with a focus on its roles in cell cycle
regulation and its possible potency leading to the cell cycle reentry of
neurons.
Keywords CDP/Cux; CDP/Cux p110; cyclin A-Cdk1; DNA binding;
transcriptional repressor
CCAAT-displacement protein/Cut
homeobox (CDP/Cux) belongs to a family of transcription factors present in all
metazoans and is involved in the control of proliferation and differentiation
[1]. The first member of the family that was discovered was the Drosophila
melanogaster Cut protein. Several lethal and viable mutations within the
cut locus have been reported. One mutation preventing the function of a distant
wing-specific enhancer caused the formation of truncated or cut wings. This is
the phenotype that gave its name to the locus cut [2]. CDP/Cux was originally
identified in vertebrates for its CCAAT displacement activity and later
determined to be homologous to the D. melanogaster Cut protein. The
human and mouse homologs are designated CDP and Cux-1, respectively [3,4].
Later, a second cux gene was identified in mouse. In contrast to mouse
Cux-1, which is expressed in most tissues, Cux-2 was found to be expressed
primarily in nervous system tissues [5,6]. Here the term CDP/Cux is used to
describe the protein in mammalian cells.
Genetic analyses in D.
melanogaster indicate that Cut mediates phenotypic effects in a large
number of tissues. Inactivation of Cux-1 by gene targeting in the mouse has
revealed several phenotypes, including growth retardation, delayed
differentiation of lung epithelia, altered hair follicle morphogenesis, male
infertility, and a deficit in T and B cells [7,8]. In contrast to the small
size of Cux-1 knockout mice, transgenic mice expressing Cux-1 showed multiorgan
hyperplasia and organomegaly. Thus, from genetic studies both in Drosophila
and in the mouse, it is clear that the CDP/Cux/Cut gene plays an important role
in tissue homeostasis in many organs [9].
CDP/Cux gene and proteolytic processing
CDP/Cux gene
At the molecular level,
CDP/Cux is a complex protein with four evolutionarily conserved DNA binding
domains: the Cut homeodomain (HD); and the three Cut repeats (CR1, CR2, and CR3),
three regions of approximately 70 amino acids that share 52%–63% amino acid identity with each other
[3,10–13]. The full-length protein,
refered to as CDP/Cux p200, is proteolytically processed at the G1/S
transition of the cell cycle, thereby generating the CDP/Cux p110 isoform that
contains three DNA binding domains, CR2, CR3, and HD [14]. An individual Cut
repeat can not bind to DNA on its own but needs to cooperate with a second Cut
repeat or with the Cut homeodomain. CR1CR2 rapidly and transiently binds to
DNA, whereas CR2CR3HD and CR3HD bind to DNA more slowly but stably [15]. It is
predicted that CDP/Cux p110 has DNA binding properties similar to that of
CR2CR3HD and CR3HD. However, CDP/Cux p200 behaves more like CR1CR2 and makes an
unstable interaction with DNA, suggesting that DNA binding by CR3HD is
inhibited in the context of the full-length protein [14,15].
Proteolytic processing of
CDP/Cux
Specific proteolysis plays a
significant role in the regulation of many basic cellular processes [16]. The
control of cholesterol metabolism by proteolytic regulation of transcription
factor SREBP [17], the cleavage of amyloid precursor protein that might affect
the development of Alzheimer? disease [18], the proteolytic
activation of Notch during development [19,20], and the intricate pathway of
proteolytic cleavage of caspases and cytoskeletal proteins resulting in cell
apoptosis [21–23]. In the field of
transcription, proteolytic processing of transcription factors result in
altering localization of these proteins or generating specific isoforms with
different biochemical properties [16,17,24].
In the case of CDP/Cux,
proteolytic processing of CDP/Cux by cathepsin L [25] generates an isoform with different
DNA binding properties [14]. The resultant isoform can accelerate entry of
cells into S phase, although it is not essential for cell cycle progression
[26]. However, not all kinds of cathepsin L can process CDP/Cux; only the one
that is devoid of a signal peptide in the nucleus can process CDP/Cux. Indeed,
it has been proved that cathepsin L, which belongs to lysosomal cysteine
proteases, can localize to the nucleus through a mechanism involving
translation initiation at downstream AUG sites and the synthesis of proteases
that are devoid of a signal peptide [25].
Roles of CDP/Cux in cell cycle
regulation
Function as a transcriptional
repressor
CDP/Cux was initially
identified as a transcriptional repressor. It has been shown to bind to a variety
of promoters or enhancer sequences of genes involved in cell differentiation,
including myeloid cytochrome gp91-phox [27], dog heart myosin heavy chain [28],
rat tyrosine hydroxylase [29], mouse N-CAM [4], and c-mos [30]. Overexpression
of CDP/Cux revealed that it functions as a repressor of these target genes in
proliferating precursor cells. In terminally differentiated cells, these target
genes are induced when CDP/Cux DNA binding activity is down-regulated. The
similar effects have been observed in the regulation of the osteocalcin gene.
Endogenous CDP/Cux complex in osseous cells is proliferation-specific and
down-regulated at the cessation of cell growth [31]. It is thus proposed that
CDP/Cux functions as a transcriptional repressor that inhibits gene expression
in terminally differentiated cells.
The repression of gene
expression involves two distinct mechanisms: active repression through the
recruitment of the histone deacetylase 1; and competition for binding site
occupancy, probably through its CCAAT displacement activity [32,33].
Up-regulated DNA binding of
CDP/Cux in S phase
A role for CDP/Cux in cell
cycle progression, particularly at the G1/S transition, a very important
moment of the cell cycle at which the cell decides whether it should
proliferate, differentiate or die, has been suggested by a number of studies
[34–36]. The ability of CDP/Cux binding to
DNA is cell cycle-dependent. Its binding to the ATCGAT sequence (a consensus
binding site of CDP/Cux p110) increases as the cell cycle progresses into S
phase [14,34]. Using the ATCGAT site as a probe, little CDP/Cux DNA binding was
detected in G0
or early G1
phases. In contrast, strong DNA binding was observed in S phase. In NIH 3T3
cells transfected with the Myc-Cut-HA vector and then synchronized in G0, early
G1,
mid-G1,
and S phases, the 110 kDa protein was not detected in the population of cells
enriched in G0
phase. It was barely detectable in early G1 and mid-G1 phases,
but was highly expressed in S phase. Pulse-chase labeling using NIH 3T3 cells
indicates that the 110 kDa protein derives from the 200 kDa full-length CDP/Cut
protein [14]. Thus the up-regulated DNA binding is due to the presence of
CDP/Cux p110.
The increase in DNA binding
involves two regulatory events, a specific proteolytic cleavage and
dephosphorylation of the Cut homeodomain by the Cdc25A phosphatase, an
important regulator of the G1/S transition [34,37,38]. Cdc25A, one of
the three members of Cdc25 homologs in human, is a tyrosine phosphatase and one
of its activities is to remove an inhibitory phosphate molecule from the G1
cyclin-dependent kinases (CDK) [39]. Many E2F-regulated genes encode proteins
that are involved in DNA replication in cell cycle progression [40]. Cdc25A is
also a target of E2F and can cooperate with cyclin E, another target of E2F, to
induce S phase. As cells progress into S phase, a fraction of CDP/Cux p200
molecules are proteolytically processed into an amino-truncated form of 110
kDa, CDP/Cux p110 [14].
It is generally assumed that
transcriptional activation requires stable DNA binding with the promoter.
CDP/Cux p200 and CDP/Cux p110 show similar DNA binding affinity but very
different DNA binding kinetics [15]. It is found that CDP/Cux p200 only
transiently binds to DNA [14,15,35]. The presence of the N-terminal region in
the full-length CDP/Cux protein inhibits its DNA binding activity and
interferes with its transcriptional activation ability. Antibodies recognizing
the N-terminal region of CDP/Cux p200 can enhance its DNA binding [41].
However, p110 has a slow and stable interaction with the DNA binding sequence
[14]. Importantly CDP/Cux p110, but not CDP/Cux p200, is capable of stimulating
expression of a reporter containing the promoter from the DNA polymerase a gene (DNA pola).
These data suggest that proteolytic processing of CDP/Cux to generate CDP/Cux
p110 is an important mechanism for cell cycle regulation [14,26,35].
At the molecular level, CR3HD makes
contact within the minor and major groove and wraps around the DNA, whereas
CR1CR2 makes contact within the major groove only, only one side of the double
helix. These differences in DNA binding are likely to explain the higher
stability of the CR3HD-DNA complex compared with CR1CR2 [15]. This might
further explain the molecular basis for CDP/Cux p110 binding to DNA more
stably.
Down-regulated DNA binding of
CDP/Cux p110 in G2 phase
CDP/Cux DNA binding activity is
changed in different phases of the cell cycle. Phosphorylation of serine
residues in the region of the Cut homeodomain reduced DNA binding in G1 phase,
whereas increased DNA binding in S phase coincided with dephosphorylation at
the same sites [34]. Similarly, DNA binding of CDP/Cux decreases as cells
progress from S to G2 phase because of the interaction between
CDP/Cux and cyclin A-Cdk1, which can phosphorylate two serines in the Cut
homeodomain and inhibit DNA binding activity of CDP/Cux [42].
In addition to cyclin A-Cdk1,
cyclin A-Cdk2 also interacts with CDP/Cux, but it can not phosphorylate the
same sites in CDP/Cux and can not inhibit DNA binding by the wild-type CDP/Cux.
In actuality, cyclin A-Cdk2 might stimulate its transcriptional activity [43].
In eukaryotic cells, one cell
cycle encompasses the coordination of growth, replication, and cell division
processes. Cyclin-Cdk complexes are serine/threonine kinases that play crucial
roles in regulating these processes. Cyclin A-Cdk1 associates with CDP/Cux in
vitro and inhibits its DNA binding activity. Furthermore, overexpression
of cyclin A-Cdk1 inhibits DNA binding of the wild-type CDP/Cux but not a mutant
CDP/Cux protein in which serines 1237 and 1270 were replaced with alanine [42].
These results are in accordance with the findings that CDP/Cux DNA binding
activity decrease in G2 phase, the phase of the cell cycle when
the cyclin A-Cdk1 complex becomes prominent. All of these findings indicate
that cyclin A-Cdk1 complex is important for the down-modulation of CDP/Cux
activity [42,43].
Interaction of CDP/Cux with
cyclin A-Cdk1 complex
The interaction between cyclin
A-Cdk1 and CDP/Cux results in the decrease of CDP/Cux DNA binding activity. Both
the Cut homeodomain and the region encompassing the cyclin-binding motif (Cy
motif) appear to be needed for efficient binding to cyclin A-Cdk1 as weak or no
binding was observed with a protein (CR1HD) that contains the Cut homeodomain
without the Cy motif, or with a protein that contains the carboxy terminal
domain (CTD) without the Cut homeodomain in pull-down assays. In the five
Cy-related sequences of CDP/Cux, only the one starting at amino acid 1298,
downstream of the Cut homeodomain, was able to bind to cyclin A-Cdk1. Moreover,
in the in vitro kinase assay, removal of the Cy sequence reduced the
efficiency of phosphorylation of CDP/Cux. Yet cyclin A-Cdk1 was still able to
phosphorylate a CR3HD fusion protein in which the Cy sequence had been removed.
So the removal of the Cy sequence diminished but did not abolish the effect of
cyclin A-Cdk1 on the activity of CDP/Cux. In another words, the Cy motif in the
CTD increases the efficiency of phosphorylation by cyclin A-Cdk1 [42].
Mechanisms of cell cycle
regulation by CDP/Cux
CDP/Cux, a part of the histone
nuclear factor D (HiNF-D)
Progression into early S phase
requires induction of histone gene expression, because de novo synthesis
of histone nucleosomal proteins is essential for the ordered packing of newly
replicated DNA into chromatin [44,45].
HiNF-D is a
proliferation-specific promoter factor [46] and its nuclear abundance is cell
cycle-dependent in normal diploid cells [47]. Many findings support that HiNF-D
can bind to the promoters of several S phase-specific histone genes, including
H4,
H3,
and H1
[48–50]. Regulation of the interaction of
HiNF-D with these genes correlates with modulations in histone gene expression.
In the case of H4 gene expression, HiNF-D interacts with
the domain of H4
promoter site II and another two nuclear factors, then HiNF-P and HiNF-M
stimulate the expression of H4 [49]. A similar situation occurs in
H3
and H1
gene expression [51]. As a complicated complex, the identification of the
DNA-binding subunit of HiNF-D is essential for understanding the role of this
factor in cell cycle regulation of histone gene transcription. In 1994, van
Wijnen et al. found that HiNF-D contains CDC2, cyclin A, and a retinoblastoma
(RB)-related protein. They failed to prove which is the DNA-binding subunit of
HiNF-D, but the experiments showed a 76 kDa factor that might represent an
intrinsic DNA-binding component of HiNF-D [51]. Two years later, the
researchers identified that CDP/Cux was the DNA-binding subunit of HiNF-D/ H4 site II
and related complexes in the histone H3 and H1 gene [36].
In short, HiNF-D can bind to
the promoters of the H4, H3, and H1 genes
through its intrinsic DNA-binding subunit CDP/Cux at the same time in the cell
cycle when these genes are induced and function as transcriptional activators
[36,46,52,53]. This fact also implies the role of CDP/Cux, as a part of HiNF-D
complex, in cell cycle progression.
It is interesting to mention the
proliferation-dependent characteristic of HiNF-D. In HL60 cells, HiNF-D
activity is clearly present in growing cells but the DNA binding activity of
this factor is down-regulated dramatically during differentiation [46]. HiNF-D
declines during the cessation of proliferation in both ROS 17/2.8 bone tumor
cells and normal diploid osteoblasts [54]. This characteristic is similar to
the transcriptional repression function of CDP/Cux, but the exact relationship
is unclear.
CDP/Cux p110, stimulating the
expression of S phase-specific genes
A search of the promoter
database with the CDP/Cux consensus binding site revealed that the promoter
sequences of the DNA pola gene contained several
putative CDP/Cux binding sites in both D. melanogaster and humans
[35]. Using reverse transcription-polymerase chain reaction, Truscott et al.
confirmed that DNA pola mRNA expression was
up-regulated in S phase following re-entry of NIH 3T3 cells into the cell
cycle. Using NIH 3T3 cells co-transfected with a luciferase reporter plasmid
containing the sequence from –1561 to +47 of the human DNA
pola gene and either an empty vector or a
vector expressing CDP/Cux p110, it was found that CDP/Cux p110 had little or no
effect on the expression of the DNA pola
reporter when transfected NIH 3T3 cells were allowed to grow asynchronously. In
contrast, expression of the DNA pola
reporter was stimulated in the presence of CDP/Cux p110 when NIH 3T3 cells were
synchronized in S phase either by thymidine blockage or by serum starvation and
restimulation. Full-length CDP/Cux protein was unable to stimulate DNA pola expression. In vivo, endogenous
CDP/Cux p110 protein also binds to the promoter of the DNA pola gene and this binding is altered during
the cell cycle [35].
In addition to the DNA pola gene promoter, CDP/Cux p110 could
stimulate the expression of reporter plasmid containing the promoter sequences
of other S phase-specific genes such as the dihydrofolate reductase,
carbamoyl-phosphate synthase/aspartate carbamoyl-transferase/dihydroorotase,
and cyclin A genes, although the effect was less than that observed with the
DNA pola reporter [35,43] (Fig. 1).
Inhibition of CDK inhibitor
during G1-S
transition
Besides stimulating the
expression of S phase-specific genes, CDP/Cux can repress the expression of CDK
inhibitors p21 and p27, which can result in cell cycle arrest.
CDP/Cux can repress p21 by
occupying the p21 promoter in a region containing the TATA box and an Sp1
binding site during S phase [34]. Similar to p21, p27 is also found to be
repressed by CDP/Cux both in the early stages of nephrogenesis prior to
terminal differentiation and in CMV/Cux-1 transgenic mice with ectopically
expressed Cux-1 [55]. Similar to p21 promoter, there are two Sp1 sites [56] and
a CCAAT site in p27 promoter [32], both targets of CDP/Cux. Thus CDP/Cux might
negatively regulate the expression of p27 through binding of these sites.
P21 is also found to inhibit
proliferation cell nuclear antigen (PCNA) whose role is to confer processivity
to DNA polymerase d. As the result of CDP/Cux on
p21, this inhibition is removed in S phase [34]. However, it is worthwhile
pointing out one exception. In Drosophila, when cells are in a
differentiated state, Cut is recruited to the Drosophila PCNA (dPCNA)
promoter regions, by way of DRE as well as URE, or around these sites, and acts
with other factors to switch off dPCNA gene expression [57]. This is unlike the
down-regulated CDP/Cux DNA binding activity on terminal differentiation in
mammalian cells and different from the situation in which CDP/Cux can activate
PCNA by repressing the expression of p21 [34]. The mechanism that causes the
difference between Drosophila and the mammalian counterpart is unclear
but might be due to the various combinations of the four DNA binding domains of
CDP/Cux.
Phosphorylation of CDP/Cux in
G2
phase
Sequence analysis of CDP/Cux
reveals the presence of 23 potential C phosphorylation sites, SerPro, or
ThrPro. Only two sites, Ser-1237 and Ser-1270 of the Cut homeodomain, are situated
within or close to a DNA binding domain. These two sites are also in close
proximity to the putative Cy site at position 1301–1303.
The findings above are in accordance with the fact that phosphorylation within
a region encompassing the Cut homeodomain was previously shown to correlate
with inhibition of DNA binding. In a mutant assay, mutation of serine 1270 with
alanine only slightly reduced the level of phosphorylation, whereas mutation of
serine 1237 had a greater effect. Mutation of the two serines at the same time
further reduced the level of phosphorylation. So serine residues 1237 and 1270
represent major and minor sites, respectively, of phosphorylation by cyclin
A-Cdk1 [42] (Fig. 2).
Possible function of CDP/Cux in cancers
From the research outlined
above we can conclude that CDP/Cux contributes to cell proliferation and,
especially, cell cycle progression in S phase. We could speculate that this
function might stimulate the growth of some cancers. It has been reported that a
majority of uterine leiomyomas expressed a higher level of CDP/Cux protein. In
particular, the proteolytically processed isoforms of CDP/Cux, including
CDP/Cux p110 and CDP/Cux p100, were expressed at a higher level in leiomyomas
[58].
Apart from CDP/Cux p110, there
is another isoform, CDP/Cux p75, that is detected in many breast tumor cell
lines and breast tumors. It was found that its expression was activated in
breast tumor cell lines and in primary human breast tumors. Like CDP/Cux p110,
CDP/Cux p75 can localize to the nucleus, repress the P21WAF1/CIP1
reporter, and stimulate expression of the DNA pola
reporter. Studies indicated higher expression of p75 in invasive carcinoma is
associated with a more diffused growth pattern [59]. The oncogenic potential of
CDP/Cux p75 was further studied by Cadieux et al. with p75 transgenic
mice. In their experiment, they found that transgenic mice overexpressing
CDP/Cux p75 developed a myeloproliferative disease-like myeloid leukemia. Thus
increased p75 expression might play a causative role in the neoplastic process
[60].
Here we noted that the
identification of a CDP-related 76 kDa DNA binding subunit of HiNF-D, detected
by van Wijnen et al. [36] is most likely related to the CDP/Cux p75,
although there is no evidence to prove this idea and they seem to have
different functions in different cell lines. However, at least, both of them
should be devoid of the CR1 repeat.
Summary
In summary, in addition to
being a transcriptional repressor, CDP/Cux might also act as a transcriptional
activator. It is believed that proteolytic processing of CDP/Cux by cathepsin L
in the nucleus generates the CDP/Cux p110 isoform at the beginning of S phase
[25]. In other words, cathepsin L in the nucleus triggers the activation of CDP/Cux.
CDP/Cux p110 can stimulate the promoters of DNA pola
gene and other S phase-specific genes. CDP/Cux p110 is also a part of HiNF-D.
Taken together, these observations strongly suggest CDP/Cux might play an
important role in cell cycle progression.
An abortive cell cycle attempt might be
involved in neuronal apoptosis [61]. In recent studies, we found that cathepsin
L could relocate to the nucleus of dopaminergic neurons on intoxication with
6-hydroxydopamine. This might cause a re-entry of dopaminergic neurons into
cell cycle, suggesting that the activation of cathepsin L probably contributes
to apoptosis of dopaminergic neurons. These observations have opened a new
field for elucidating the pathogenic mechanisms in Parkinson’s disease and
warrant further investigation.
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