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Introduction
Inhibitor of differentiation (Id) proteins are a family of
transcriptional regulators that have been implicated in
several developmental, physiological and pathological
processes. Their name relates to their ability to inhibit the
differentiation of a variety of cells by inhibiting the DNA
binding activity of many transcription factors that regulate
expression of cell-type specific genes. Id genes are widely
expressed in the animal kingdom from humans to zebra
fish[1]. Four Id genes, Id1-Id4 have been found in humans
and in rodents. A homologous Id-like gene, extramacro-chaetae has been identified in
drosophila[2].
The Id proteins are small proteins of approximately 13
kDa-20 kDa. All 4 Id proteins contain a relatively conserved
helix-loop-helix (HLH) structural motif in the middle of the
protein, but are otherwise quite divergent in sequences. The
4 Id proteins constitute 1 subclass (Class V) of the large
family of HLH transcriptional regulators. Unlike other HLH
proteins that can bind to DNA as either homodimers or
heterodimers, the Id proteins lack the basic amino acid
domain needed for DNA binding. Instead, they are believed to
function primarily by forming heterodimers with the
"ubiquitous" Class I HLH proteins known as E-proteins. This
prevents the E-proteins from interacting with each other and
with the cell-type specific Class II HLH proteins, inhibiting
their binding to DNA and blocks their ability to modulate
gene expression (Figure 1).
The first Id gene, Id1, was identified by virtue of the
ability of its encoded protein to inhibit muscle
differentiation and the activation of muscle-specific gene
promoters[3]. However, the Id proteins are now known to be important in
other physiological systems and pathophysiological
situa-tions. In addition to the E-protein partners, Id proteins
regulate other transcription factors such as ternary complex
factor (TCF)/ETS[4,5], Pax 5 and sterol regulatory element
binding protein-1[6]. Individual Id proteins might also interact
selectively with proteins not recognized by other Id family
members. For example, Id1 is the only Id protein shown to
bind the proteasomal protein S5a[7]. Similarly, only Id2 binds
to the tumor suppressor retinoblastoma protein Rb and
interferes with the ability of hypophosphorylated Rb to
suppress cell proliferation when both are ectopically expressed
(Figure 1)[8].
Evidence to date indicates that the Id proteins are likely
to carry out both common and distinct biological functions,
depending in part on when and where the proteins are
expressed. Consistent with this idea, mice engineered to be
deficient in a single Id gene are viable, albeit with developmental defects in certain specific cell lineages depending on
the particular gene that has been
inactivated[9-15]. For example, Id3-deficient mice have defects in both B
cell[14] and T cell[15] maturation and develop salivary gland defects
reminiscent of the autoimmune Sjogren¡¯s syndrome, but are
otherwise generally normal[16]. In contrast, mice with both
copies of Id1 and Id3 genes inactivated die in
utero (embryonic d 13.5) with severe vascular defects in the
forebrain, aberrant neuronal
differentiation[17] and multiple cardiac
abnormalities[18]. In fact, mice with both copies of
any 2 of the 3 Id genes (Id1-Id3) inactivated exhibit similar
cardiac defect and are embryonic lethal. Mice with loss of
1-3 copies of the Id1/1d3 genes are viable but exhibit increasing
degrees of resistance to tumor-induced
angiogenesis[17]. The lethality of the double knockout mice and the
dosage-dependent tumor angiogenesis phenotype clearly indicates that
the Id genes mediate overlapping function in some
developmental lineage. However, the developmental defects in
specific cell lineages manifested in single knockouts suggest
that Id genes are unable to compensate in some cells,
perhaps because they are not co-expressed or, as in the case of
Id2, because of specific dimerization with different protein
partners such as Rb.
Many excellent and extensive reviews covering the Id
family proteins have been published in recent
years[19-26]. Most of these reviews have dealt with the Id proteins as a
group and concentrated primarily on the potential biological
functions of the Id proteins. Relatively less attention has
been devoted to reviewing the molecular mechanisms that
regulate the expression and function of individual Id genes
and proteins.
The present review will focus on the third member of the
Id gene family, Id3, particularly on the mechanisms involved
in its regulation. The Id3 gene was first identified as a
serum-inducible immediate early gene in an established murine
fibroblastic cell line[27]. Subsequent studies have documented
its involvement in various biological processes, including T
and B cell development[15,14], skeletal muscle differentiation[28,29], vascular smooth muscle cell
proliferation[30,31], embryonic
neurogenesis[17],
osteogenesis[32] and tumor-induced
angiogenesis[17].
Expression and function of the protein is under many
complex layers of regulation (Figure 2) and, therefore, could
provide rich targets for therapeutic interventions.
Developmental and cell-type specific expres-sion pattern of Id3
The most direct way to regulate the function of a particular protein is to control when and where the gene encoding
the particular protein is expressed. Several studies have
characterized the expression of Id3 at either the mRNA or the
protein level. A wide range of techniques have been utilized,
including Northern, in situ hybridization, reverse
transcription with polymerase chain reaction, various genome
expression profiling assays, Western immunoblots and
immunocytochemical staining procedures.
Like other Id genes, the expression of Id3 is dynamically
regulated during embryonic development. The general
expression level is high at the early embryonic ages, but
progressively declines as the embryo
develops[27,33]. Id3 is widely expressed throughout the embryo proper. Its expression is
readily detectable within regions that are undergoing active
morphogenesis[34], but can also be detected in some
undifferentiated tissues[33].
The expression pattern of Id3 during embryonic
development overlaps with, but is not identical to that of, the
other Id genes. At an early embryonic age, Id1 and Id3 are
expressed in the tissues derived from the inner cell mass; Id2
is expressed in tissues derived from trophoblasts; but no Id4
expression is evident. In the primitive gut, Id1 and Id3
signals are expressed in the mesenchyme, whereas Id2
expression occurs within the
epithelium[34]. During early spinal cord development, expression of Id1 and Id2 are restricted to
the roof plate, whereas Id3 is expressed both in the roof and
the floor plate. At later stages, Id1 and Id3 expression is
detected in the dividing neuroblasts, whereas Id2 and 4 are
expressed in presumptive neurons undergoing maturation[35]. Generally speaking, the pattern of Id3 expression
most closely resembles that of Id1, but the coincidence is
not absolute[33].
Expression of Id3 in adult tissues is widely spread but
not universal and the level of expression varies
substantially among different tissues. Id3 is expressed in many cell
types in vivo and in both primary cultures and established
cell lines (Table 1). Depending on the cell and tissue type,
the expression might be constitutive or detectable only after
exposure to appropriate stimulus. The level of Id3
expression is generally high in proliferating, undifferentiated cells,
but downregulated when cells undergo terminal differentiation[28,29,36-39]. Expression of Id3 also tends to be higher in
immortalized cell lines, consistent with the putative
involvement of Id proteins in combating cellular
senescence[40,41] and maintaining the capacity for self-renewal in embryonic
stem cells[42].
Knowing what tissues and cell types express Id3 is,
however, probably akin to just seeing the tip of the iceberg.
The level of Id3 expression is not static, but varies dramatically with the growth and physiological state of the cells and
is modulated in response to diverse extracellular stimuli.
There are other layers of regulation superimposed upon the
regulation at the expression level (Figure 2). Additional
caveats should also be kept in mind when interpreting the
results from the aforementioned studies. Results using
immortalized cell lines need to be viewed with caution
because the process of immortalization might involve
alterations in Id3 expression not seen in
vivo. Direct examinations of tissue sections
in vivo or with primary cell cultures eliminate such concerns. However, the sensitivity of the
assays used for detecting Id3 expression in various studies
are not precisely known and might not always be comparable.
The specificity of the antibodies used for immunodetection
might not have always been adequately scrutinized.
Therefore, care should be taken in making a firm conclusion
as to whether Id3 is or is not expressed in a certain tissue or
cell type. Nevertheless, because Id3 is expressed at many,
but not all, cells indicates that its regulation is likely to
involve both ubiquitous as well as cell-type specific
regulatory mechanisms.
Altered patterns of Id3 expression in diseases
and pathophysiological situations
Perturbation of Id3 expression has been correlated with a
variety of disease states and pathological situations,
including cancer, aging, atherosclerosis, muscle atrophy, and
inflammation. Conversely, altered expression of Id3 has been
detected during the regenerative process following tissue
injury.
It is generally believed that members of the Id gene
fa-mily behave like oncogenes. Overexpression of one or more
Id genes has been detected in various cancers. The
situation with Id3 is consistent in most part with this
generalization[43-45], but there are some exceptions. In certain
neurological tumors, Id3 upregulation is observed not only in the
tumors themselves but also in the vascular tissues
surrounding the tumors[44]. In contrast, expression is reduced in
papillary thyroid carcinoma[46] and ovarian
carcinomas[47], and either
increased[48] or absent[49] in seminoma. The
expression pattern is even more complex during the development
of liver diseases and liver cancer. Id3 expression is low in
normal liver, increases with the progression of liver diseases
from chronic hepatitis to liver cirrhosis and is expressed at
high levels in well-differentiated hepatocarcinomas, but not
in the more advanced de-differentiated
tumors[50].
Variations in Id gene expression have also been
correlated with aging in animals. Expression of Id1, Id2, and Id3
increases in hind limb muscles of aging
rats[51]. Because
increased levels of Id proteins are associated with muscle
disuse atrophy[52], the upregulated Id expression in aging
muscle might contribute to the loss of muscle mass that
commonly accompanies aging. In contrast, Id3 expression
appears to be reduced in the pituitary gland in aged
rats[53]. Taken together, the results suggest that some other
aging-related physiological perturbations rather than aging per se
might be responsible for the altered Id expression in
different tissues.
Id3 expression level also changes in inflammatory and
atherogenic processes. Id gene expression is upregulated in
reactive astrocytes activated as part of the inflammatory
process following spinal cord
injury[54]. Id3 expression is also altered in vascular smooth muscle cells (VSMC) during
atherogenesis. It is expressed at low level in normal vessels
of the carotid artery, but is increased within 3 d of balloon
injury and remains high through 14 d
postinjury[30]. This is accompanied by the appearance of a novel differentially
spliced Id3 transcript.
Changes in Id3 expression are not limited to pathological
situations: increased Id3 expression has been implicated in
tissue regeneration. In the African clawed frog,
Xenopus laevis, which does not completely regenerate the missing
limb following amputation, Id3 expression is upregulated
transiently but returns to basal level when terminal
differentiation of the limb stump tissues is initiated. In the Japanese
newt, Cynops pyrrhogaster, which is capable of
regenera-ting a complete limb, expression of Id3 persists until the stage
of digit formation[55]. The earlier downregulation of Id3 in
the Xenopus might have contributed to premature
differentiation and the aborted regeneration program. Similarly, Id3
upregulation might also contribute to the liver regeneration
following partial hepatomy in mice[56].
The mechanisms accounting for the perturbation of
expression of Id3 under different conditions are largely
unknown. The presumption is that it involves changes in
transcription, but the hypothesis is as yet unproven. No
evidence has been found so far that would implicate either
gene amplification or deletion in the altered pattern of Id3
expression found in different cancers; therefore, the change
is probably epigenetic. There is some evidence that DNA
methylation or histone acetylation might contribute to Id3
regulation but exactly how such processes affect Id3
expression is not known (see below). In most cases, the change in
Id3 expression is likely to be either secondary to changes in
the cell physiology and/or in response to environmental
signals.
Stimulus and signaling pathways regulating Id3 expression
Id3 was originally identified as a serum-inducible gene in
Balb/c3T3 fibroblasts and found to be induced in these cells,
to a varying degree, by a variety of other
agents[27]. The Id3 transcript was induced rapidly and transiently, with peak
accumulation occurring at about 1 h after stimulation. In this
system, Id3 appears to behave as "immediate-early" or
"primary response" genes, and can be induced in the absence of
ongoing protein synthesis.
Id3 expression has been shown to be responsive to even
more diverse stimuli in a variety of cell types (Table 2).
Several conclusions can be drawn from this plethora of
information. First, although the ability to regulate Id3
expression is wide spread, not all agents regulate Id3
expression in the same manner in all cell types. For example, the
phorbol ester, phorbol 12-myristate 13-acetate (PMA),
stimulates Id3 expression in
thyrocytes[46] but downregulates Id3 levels in the SH-SY5Y neuroblastoma
cells[57]. This suggests that the regulatory pathways might be different among
different cell types. Second, the temporal pattern of Id3
expression is very complex, and differs depending on the cell
type and stimuli. In many cases, the induction is transient
but biphasic, with an early peak of expression followed
either by a later second peak or conversely by long-term
suppression. In other cases, the change appears to be more
persistent. For example, Id3 is induced transiently by
transforming growth factor-b (TGF-b) in B-lymphocyte
progenitors, but returns to basal level within 20
h[13]; whereas in epithelial cells, the transient increase is followed by
long-term suppression[58,59]. Id3 is also transiently induced by
bone morphogenetic proteins (BMP) in mesenchymal stem
cells[60], but a sustained induction is observed following BMP
treatment of epithelial cells[59]. Finally, and perhaps most
importantly, the differences in the patterns of expression
have immense biological significance. For example, insulin,
which is an adipogenic agent, induces Id3 transiently in
3T3L1 preadipocytes, but adipogenic differentiation itself is
accompanied by long-term downregulation of Id3 in 3T3F24A
cells[38]. Similarly, B cell receptor (BCR) engagement in
mature B cells results in transient Id3 induction and stimulation
of cell proliferation[14]. PMA, which is also mitogenic,
results in a biphasic response with a transient peak at 4 h and
a secondary peak at 24 h, around the time when the
stimulated cells are entering S[61]. In contrast, a more persistent
Id3 expression is induced by BCR engagement in immature B
cells and results in the inhibition of cell
proliferation[62].
Because Id3 expression is regulated by many cytokines,
hormones and other environmental signals, several different
signal transduction pathways presumably contribute to its
regulation. Pathways that have been implicated include the
Ras, the ERK1/2 pathway following TCR
engagement[63], the Smad-dependent pathway in response to
TGF-b and BMP[59,13] and the p38, ERK and calcium-dependent
pathways following superoxide free radical-induced oxidative
stress[64]. In the case of TGF-b, the biphasic response could
reflect the differential actions of 2 classes of
TGF-b receptors (Activin receptor-like kinase 1 and Activin receptor-like
kinase 2) that are preferentially coupled to different Smad
proteins[65]. In most cases, the precise signaling pathway(s)
responsible for regulating Id3 expression has not been
completely defined. In addition, it has not been conclusively
demonstrated that the change in transcript level reflects
authentic transcriptional regulation.
Regulatory elements and transcription factors
involved in Id3 promoter regulation
A systematic analysis of the Id3 promoter and the
mechanisms involved in its regulation has yet to be carried out.
Yeh and Lim reported in 2000 the cloning and initial
characterization of the promoter region of the mouse Id3 gene
extending approximately 1 kb upstream of the transcription
start site[66] and found that a 180 bp proximal Id3 promoter
fragment was sufficient for substantial transcriptional
activity in the proliferating myogenic cell line
C2C12[66]. Recently, a 254 bp Id3 promoter fragment (-200/+54) has been shown
also to be transcriptionally active and responsive to BCR
engagement in the WEHI-231 immature lymphoid
cells[67]. Several putative transcription factor binding sites have been
identified by computer-based analysis, but whether they are
bona fide regulatory motifs has not been determined (Figure
3). Using in vitro DNase protection assay, we have
identified 2-3 protected footprints within this region, at least 1 of
which (site 1) seems to be responsible for much of the Id3
promoter activity seen in proliferating C2C12
cells[67a]. Moreover, electrophoretic mobility shift assays detected
proteins in the nuclear extracts of proliferating C2C12 cells
that bind to the 180 bp Id3 promoter
frag-ment[66]. A mutation that eliminates the DNA binding to site 1 reduced the
transcriptional activity of the Id3 promoter, indicating that
the site is likely to be functional. Consistent with this idea,
protein binding to the site declined substantially when
incubated in vitro with nuclear extracts isolated from
differentiated muscle cells that no longer express
Id3[68]. It is yet to be determined whether the site in the endogenous Id3 promoter
is occupied by transcription factor in vivo.
The second DNase footprint (site 2) encompasses a
previously identified early growth response factor 1 (egr-1) site
that has been shown to bind recombinant egr-1 in
vitro[27]; whether the site binds
egr-1 in vivo has not been established. Others have reported that the upregulation of Id3 upon TCR
engagement involves egr-1, but direct egr-1 binding to the
promoter has not been demonstrated and the egr-1 binding
site responsible for the upregulation of Id3 promoter activity
has not been localized[63]. We have found, however, that
mutating the egr-1 site in footprint 2 does not affect the
promoter activity of the proximal promoter in proliferating
C2C12 cell[68]. Either other sites are involved in mediating
egr-1 dependent activation of the Id3 promoter or the
mechanism of promoter regulation differs between the muscle and
T-cell systems.
Several other transcription factors have been reported to
either directly or indirectly regulate Id3 expression. The zinc
finger transcription factor, gut-enriched kruppel-like factor
(GKLF), downregulates the expression of Id3 in response to
hydroxyl free radicals in VSMC, apparently by binding to a
GKLF site in the Id3 promoter[69]. Likewise, the
transcriptional repressor, B lymphocyte induced maturation
protein-1, also appears to act directly on the Id3 promoter region as
demonstrated by the chromatin immunoprecipitation assay
in mature B-lymphoblast cells[70].
Exactly how the other transcription factors affect Id3
expression is not known. For example, ectopic expression of
myoD in proliferating muscle cells upregulates
Id3[71], but it is not known whether this involves direct binding of myoD
to the Id3 promoter. We did not find any E-box motif
corresponding to myoD binding sites within the 1 kb region that
we have analyzed, but interactions at more distal sites have
not been ruled out. Other transcription factors, such as the
homeodomain protein AT binding factor 1A (ATBF1A), the
lymphocyte specific transcription coactivator
BOB.1/OBF.1, and the forkhead transcription factor FOXM1B, have all been
shown to either up or downregulate Id3 expression when
overexpressed, but in no case has direct interaction between
these factors and the Id3 promoter been
establish-ed[72,73,56]. Cells that are deficient in Smad4 fail to alter their Id3 level in
response to either TGF-b or BMP, suggesting that the Smad
proteins are involved in mediating the regulatory effect of
these cytokines[59,60]. However, direct binding of Smad on
the Id3 promoter has not been demonstrated.
Several lines of evidence suggest that DNA methylation
and histone acetylation might either directly or indirectly
regulate Id3 expression. In some non-lymphoid
hematopoietic cell lines, the lack of Id3 expression has been correlated
with hypermethylation of DNA upstream of the Id3 transcrip
tion start site[74]. Whether similar methylation events take
place in other cases where Id3 expression is silenced is not
known. Treatment with 5 azacytidine, an inhibitor of DNA
methyl transferase, blocks the neuronal differentiation of
PC12 cells induced by NGF and inhibits NGF-induced Id3
downregulation that occurs during
differentiation[36]. Conversely, Id3 expression is downregulated in
lymphoblastic cells from patients with immunodeficiency, centromere
instability and facial anomalies syndrome, a disease
syndrome caused by a defective DNA methyltransferase
(DNMT3B)[75]. It is not yet known whether the methylation
state of the Id3 promoter itself is directly affected in either
case. Similarly, addition of histone deacetylase inhibitors to
lung adnocarcinoma cells and the K562 hematoprogenitor
cells upregulates Id3 expression, but whether this represents
a direct effect on the histones associated with the Id3
promoter is not clear[76-78].
Regulation of Id3 isoform expression by differential splicing
The Id3 gene is composed of three exons and two introns.
The first exon includes the 5¡¯ untranslated region (UTR) and
the coding region corresponding to the first 100 amino acid
residues. The coding region is interrupted by a 105 bp
intron at the +357 position of the mouse Id3 gene. The second
exon contains the last 19 amino acid coding region and 26 bp
of the 3¡¯ UTR of the mouse Id3 transcript. In the mouse gene,
this is followed by a 506 bp second intron and the third exon
coding for the rest of the UTR[66]. Both the human and rat
Id3 genes appear to be similarly organized, although the
length and exact nucleotide sequence of the introns vary
substantially among species.
It has been shown in both rats and human that an
alternative transcript can be generated under certain conditions
by the retention of the first
intron[79,31], resulting in the production of a novel Id3 protein isoform with an altered
C-terminus. However, because of the divergent nucleotide
sequences in the intron, the novel Id3 C-terminal peptides
vary substantially in both length and sequences across
species. In humans, the novel terminus is 60 amino acids in
length; whereas in mice and rats it is only 29 amino acids
long, with 7 out of the 29 amino acids differing between the
two species. In contrast, the original protein isoform from
the mouse and rat differs by only 1 amino acid substitution
out of 119.
With such divergence in sequence among closely related
species, one might have predicted that the novel isoforms
(referred to as Id3L in humans and Id3a in rats) would have
dubious biological significance. Contrary to this expectation,
in situ hybridization and immunolocalization using
isoform-specific antibody indicates that the novel variant is not
produced in normal vasculature, but is dramatically upregulated
during the later stages of vascular lesion formation, whereas
the original Id3 variant is upregulated earlier in the
neoin-tima[30]. Furthermore, the 2 Id3 protein variants appear to be
functionally distinct. The human Id3L protein is a weaker
inhibitor of the binding of E-proteins to DNA in vitro than the original shorter Id3
isoform[31]. Overexpression of the original shorter rat Id3 protein in VSMC promotes
proliferation and S-phase entry and inhibits transcription of the cyclin
dependent kinase (cdk) inhibitor
p21Cip1, whereas overproduction of the novel Id3a does not inhibit p21 transcription,
and causes a decrease in cell number, presumably by
promoting apoptosis[30].
What accounts for the unique biological functions of
the novel Id3 isoform is perplexing, because the C-termini
encoded by the non-spliced Id3 variants would be very
different between humans and rats and differ substantially even
between the more closely related rodent species. One
possible explanation of this conundrum is that the altered
C-termini might lead to a protein that acts essentially like a
"dominant negative" mutant. In support of this possibility,
we have shown that truncation of the Id3 C-terminal to a site
roughly corresponding to the spliced junction resulted in a
protein that was incapable of blocking E-protein binding,
and the inhibition of E-box dependent transcription was
compromised[80]. Swapping the Id3 C-terminal with the
corresponding region of the Id2 C-terminal likewise reduced the
ability of the fusion protein to block E-protein activity. Why
the C-terminus of the Id3 protein is so critical for its activity
is presently unknown. Much remains to be learned about
how the alternative splicing is regulated and when and where
else the novel Id3 variant might be expressed. Because most
of the earlier studies did not take into account the existence
of the novel isoform, some of the expression data might need
to be revisited.
Regulation of Id3 transcript and protein stability
Like many other immediate early genes, the Id3 transcript
has a rather short half-life[81]. Examination of the cDNA
sequence revealed the presence of instability elements in the 3¡¯
UTR that bind to RNA-binding
protein[82,83]; sequence elements that regulate cytoplasmic polyadenylation are also
present[84]. These sequence motifs are likely to contribute to
the regulation of the stability and/or translation of the Id3
transcripts, but detailed studies have yet to be reported.
The Id3 protein is also rather short lived, with a half-life
of approximately 20 min when overexpressed in 293 cells. As
with other short-lived proteins, Id3 appears to be degraded
by proteasomes in an ubiquitination dependent
manner[85]. Treatment with proteasome inhibitors stabilizes Id3,
allowing it to accumulate. Cells with mutations in the E1 ubiquitin
activating enzyme show increased Id3 stability.
Co-expression of the bHLH protein E47 with Id3 significantly reduces
the rate of degradation of Id3[86]. In contrast, interaction
with the interferon-inducible protein p204, which is
upregulated during terminal muscle differentiation, enhances
Id3 degradation[87], suggesting that the stability of the Id3
protein might be affected by its dimerization partner.
Whether and how ubiquitination of Id3 is regulated by
the cellular environment is not known. Id3 has been shown
to interact physically with CSN5, a subunit of the COP9
signalsome complex that has been implicated in the
regulation of the ubiquitination of a large number of cellular proteins.
Inhibitors of the COP9-associated kinases increase the
ubiquitination of Id3 and accelerate its degradation, whereas
overexpression of another COP9 subunit CSN2 stabilizes the
Id3 protein. Given these data, it has been speculated that
CSN-mediated phosphorylation inhibits ubiquitination of
Id3[88].
Although the role of ubiquitination in Id3 degradation is
now well-documented, we found that replacing all 4 lysine
found in the mouse Id3 protein with arginine failed to
stabilize the protein. This suggests that Id3 might be added to an
increasing list of proteins like
myoD[89], Id2[90], and
p21cip1[91], that gets ubiquitinated at the
a-amino group of the N-terminal residue instead of an internal lysine residue.
How much the regulation at the level of protein stability
contributes to the overall regulation of Id3 expression level
is not presently known. In one study, experimental
denervation to the muscle of young rats results in an increase in Id3
protein levels in both the soleus (900%) and gastrocnemius
(80%) without apparently affecting the mRNA
level[51]. Similar regulation might occur under other conditions.
Regulation of protein localization and function
Although Id3 preferentially interacts with the class I HLH
proteins (E proteins) and exhibits little or no affinity towards
the class II bHLH proteins[92], it also binds to other
transcription factors such as TCF[4] and the homeodomain
protein Pax5[6] through the HLH domain. Co-expression of
E-proteins competes with Pax5 for binding to Id3. Other
protein partners might also compete with each other for binding.
The relative abundance of the various protein components
could, therefore, affect the precise compositions of the
protein complexes that are formed. This might in turn determine
the biological effects of Id3 under conditions where Id3 level
is limiting. In addition, because some E-protein isoforms can
act as transcriptional inhibitors[93], Id3 might even be
expected to activate gene expression under certain
circums-tances.
Dimerization between Id3 and its target proteins might
also affect its subcellular localization. When expressed alone
in COS cells, Id3 is predominantly cytoplasmic/perinuclear.
Co-expression with E-proteins causes it to accumulate in the
nucleus[94]. Whether other proteins or mechanisms might
control the subcellular distribution of Id3 is presently
unknown. Interestingly, the Id3 protein has been reported
to be localized to specific subcellular locations in some cell
types[48,95], but the mechanism responsible remains unknown.
The Id3 protein contains several potential
phosphorylation sites for various protein
kinases[96], including a conserved putative cdk2 site around Ser5 in the N-terminus,
which is phosphorylated in a cell cycle-dependent manner
(during late G1 to S). Id3 proteins with a mutation of Ser5 to
Asp5 to mimic phosphorylation are better able to block the
formation of heterodimers between E-protein and myoD but
are less able to block E-protein homodimerization.
Phosphorylation by cdk2 also interferes with the ability of Id3 to bind
to TCF proteins[5], suggesting that Ser5 phosphorylation
might alter the dimerization specificity of Id3. In fibroblasts,
the Id3 Asp5 mutant (mimicking phosphorylation) is unable
to promote S-phase transition, whereas the
non-phosphoryla-table Ala5 mutant is more effective than the wild
type[61].
In contrast, in VSMC, the non-phosphorylatable Id3 Ala 5
mutant activates the cdk inhibitor
p21cip1 promoter and is unable to promote an increase in cell number when
over-expressed[97]. Why the behavior is different between the
two cell types is unknown.
Conclusions
It is clear from this brief review that the expression and
function of the Id3 protein are regulated in a very complex
manner. Much remains to be learned about how the Id3
gene is regulated transcriptionally. Almost nothing is known
about how the alternative splicing event that generates a
potentially dominant negative protein is controlled.
Posttranslational modifications might impact the stability,
dimerization specificity and/or subcellular localization of the
protein, which might then affect the function of the protein.
In view of the many physiological and pathophysiological
situations where Id protein function is involved or perturbed,
understanding these issues will, no doubt, provide a fertile
ground for the development of potential therapeutic
interventions.
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