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Molecular and Cellular Biology, December 1998, p. 7423-7431, Vol. 18, No. 12
Unité de Biologie Moléculaire de
l'Expression Génique,
Received 19 March 1998/Returned for modification 18 May
1998/Accepted 1 September 1998
The Notch receptor is involved in many cell fate determination
events in vertebrates and invertebrates. It has been shown in
Drosophila melanogaster that Delta-dependent Notch
signaling activates the transcription factor Suppressor of Hairless,
leading to an increased expression of the Enhancer of Split
genes. Genetic evidence has also implicated the kuzbanian
gene, which encodes a disintegrin metalloprotease, in the Notch
signaling pathway. By using a two-cell coculture assay, we show here
that vertebrate Dl-1 activates the Notch-1 cascade. Consistent with
previous data obtained with active forms of Notch-1 a
HES-1-derived promoter construct is transactivated in cells
expressing Notch-1 in response to Dl-1 stimulation. Impairing the
proteolytic maturation of the full-length receptor leads to a decrease
in HES-1 transactivation, further supporting the hypothesis
that only mature processed Notch is expressed at the cell surface and
activated by its ligand. Furthermore, we observed that Dl-1-induced
HES-1 transactivation was dependent both on Kuzbanian and
RBP-J activities, consistent with the involvement of these two proteins
in Notch signaling in Drosophila. We also observed that
exposure of Notch-1-expressing cells to Dl-1 results in an increased
level of endogenous HES-1 mRNA. Finally, coculture of
Dl-1-expressing cells with myogenic C2 cells suppresses differentiation
of C2 cells into myotubes, as previously demonstrated for Jagged-1 and
Jagged-2, and also leads to an increased level of endogenous
HES-1 mRNA. Thus, Dl-1 behaves as a functional ligand for
Notch-1 and has the same ability to suppress cell differentiation as
the Jagged proteins do.
The Notch gene family encodes
transmembrane receptors that have been implicated in many aspects of
cell fate determination in vertebrates and invertebrates. In
Drosophila melanogaster, one consequence of activation of
the Notch signaling pathway is the maintenance of the receiving cells
in an uncommitted state through a process called lateral inhibition.
For example, during peripheral neurogenesis, this signaling pathway is
involved in the choice of a single precursor among a group of
equivalent proneural cells. Following cell-cell interaction, one cell
differentiates into a sensory organ precursor and inhibits its
neighbors from adopting a neural fate. This inhibitory signal is
mediated by ligand-induced activation of the Notch pathway. Different
genes have been implicated in the Notch pathway, including
Delta (Dl) and Serrate
(Ser), encoding two structurally related transmembrane ligands of Notch; Suppressor of Hairless
[Su(H)], which encodes a DNA binding protein;
and genes of the Enhancer of Split complex [E(spl)] (see references 3
and 9 for reviews). The E(spl) gene products
accumulate in response to Notch activation and were shown to be
downstream targets of the Notch pathway (6, 17, 20, 40). The
E(spl) proteins would in turn repress transcription of differentiation
factors, such as the proneural Achaete-Scute genes (32,
37, 48). Recently, Kuzbanian/Sup-17, a newly recognized component of the Notch cascade, has been isolated in Drosophila and Caenorhabditis elegans (49,
52, 58, 68). This gene encodes a transmembrane metalloprotease
which acts cell-autonomously in the Notch-expressing cell, upstream of
the activated Notch receptor (49, 52, 58, 68).
Vertebrate homologs of these genes have been identified. To date, four
Notch genes are known to exist in mammals (18, 38, 63, 66,
67). Much evidence supports a role for Notch in cell fate
decisions in vertebrates. In particular, intracellular forms of Notch,
similar to forms producing a gain-of-function phenotype in
Drosophila, are able to suppress muscle cell differentiation (34, 35, 43, 47, 57) as well as neuronal differentiation (47). In addition, injection of such an activated form of
Xenopus laevis Notch into Xenopus embryos causes
changes in cell determination (11). Retinal ganglion cell
differentiation in chickens and Xenopus has also been shown
to be inversely correlated with the level of Notch activity (5,
15).
Similarly, vertebrate counterparts of the two
Drosophila genes Delta and Serrate
have been isolated: Delta-(like-)1
in mice and chickens (Dll-1 and Dl-1,
respectively) (7, 23) and Delta-like-3 (Dll-3) in mice (16); Delta-2 in
Xenopus (30); and the potential orthologs of
Serrate, Jagged-1 in rats and humans (41,
43) and Jagged-2 in rats, mice, and humans (43,
56, 64). These genes encode transmembrane proteins that, like the
Drosophila ligands, all include in their extracellular
region EGF repeats and a DSL (for Delta-Serrate-Lag-2) domain, which
could be involved in interactions with Notch (46). These
genes have also been implicated in cell fate determination in
vertebrates. Notably, it has been shown that both Jagged-1
and Jagged-2, when expressed at the surface of fibroblasts,
are able to inhibit the differentiation of cocultivated C2 myoblast
cells, whether or not they are transfected with the Notch-1 cDNA
(41, 43). Suppression of muscle differentiation induced by
activated forms of Notch or by presentation of a Serrate-like ligand
are very similar in phenotype and lead to activation of identical
subsets of genes (43). Since at least three Notch homologs (Notch-1, -2, and -3) are expressed in C2 cells
(43), it has been postulated that inhibition of the
differentiation of C2 cells by Serrate-like ligands is mediated by
Notch signaling. Taken together, these data suggest that vertebrate
homologs of Notch ligands can modulate cell fate through activation of
a Notch receptor.
Homologs of Drosophila E(spl) genes have been
identified, including HES-1 (33, 54). Retroviral
infection studies leading to overexpression of HES-1 and
phenotypic analysis of murine HES-1-null embryos have
demonstrated a role for HES-1 in neurogenesis and retinal
differentiation (26, 27, 61).
Homologs of the Su(H) gene product have been
isolated in humans (KBF2 [also called CBF1]) (22, 28),
mice (RBP-J) (19), nematodes (Lag-1) (10), and
Xenopus (69) and are hereafter referred to as
RBP-J. The RBP-J protein recognizes the same DNA sequence as its
Drosophila counterpart (62).
The Notch pathway in vertebrates probably involves the same
components as in Drosophila. The implication of RBP-J and
HES-1 downstream of Notch-1 has been suggested by experiments done with extracellularly truncated active forms of the Notch-1 receptor. RBP-J
has been shown to interact with the intracellular part of Notch-1
directly (4, 29, 60). Moreover, these RBP-J-Notch-1 complexes can transactivate a HES-1 gene promoter construct
by direct interaction with RBP-J binding sites (29, 34).
These results suggest a model in which, following ligand activation, processing occurs, releasing the intracellular part of Notch, which
associates with RBP-J and activates transcription of its target genes.
How ligand binding triggers signal transduction is not known, however.
To provide evidence for ligand-dependent Notch signaling, we set up a
two-cell coculture assay, and we show here that Dl-1 is able to
activate the Notch-1 receptor, leading to activation of a
HES-1 promoter construct as well as activation of the
endogenous HES-1 gene. As previously suggested (8, 42,
49), our data confirm the hypothesis that maturation of the
mammalian receptor is required for its activity. Furthermore, we
demonstrate that mammalian homologs of components of the Notch pathway
in Drosophila are implicated in Dl-1-induced Notch-1
signaling. Indeed, both Kuzbanian and RBP-J activities are required for
Dl-1-induced transactivation of the HES-1 promoter. Taken
together, our data suggest that Dl-1-induced Notch-1 activation results
in HES-1 gene transactivation in the Notch-1-expressing
cells, a process reminiscent of Notch signaling in
Drosophila. We also show that, like Jagged-1 and Jagged-2, Dl-1 suppresses myogenic differentiation of C2 cells while at the same
time increasing the level of HES-1 mRNA. Thus, Dl-1 behaves as a functional ligand for Notch-1 and has the same ability to suppress
myogenic cell differentiation as the Jagged proteins do.
Cells.
HeLa and HeLa-N1 cells were grown in Dulbecco's
modified Eagle's medium (DMEM) supplemented with 10% fetal calf
serum. C2 cells were grown in DMEM supplemented with 20% fetal calf
serum. QT6 and QT6-Dl1 cells were grown in Ham F-10 medium supplemented with 10% tryptose phosphate, 5% fetal calf serum, and 1% chicken serum. HeLa cells were stably transfected by calcium phosphate precipitation with the murine Notch-1 cDNA cloned into
pCDNA3 (Invitrogen). Following G418 selection (0.8 mg/ml), a clone was selected for further studies and named HeLa-N1. QT6 cells were infected
by the RCAS-Dl1 and RCAS-Dl1dn constructs (24) as follows. The retroviral vectors were transfected into a primary culture of chick
fibroblasts, as previously described (45). After 5 days of
culture, when 100% of the cells were infected, the supernatant containing the viral particles was added to QT6 cells for 6 h and
subsequently replaced by QT6 medium supplemented with 1% glutamine. Following 7 days of culture, 100% of the QT6 cells were infected and
expressed the transgene.
Transfection experiments.
Transfection of HeLa-N1 cells
(5 × 105/plate) was performed by calcium phosphate
precipitation in 6-well plates with 0.4 µg of luciferase vector
(either HES-1-luc or HES-1- Antibodies and immunofluorescence.
Expression at the cell
membrane was assessed by indirect immunofluorescence, as previously
described (29). Notch expression was detected with
affinity-purified rabbit IC antiserum (42), used at 1/100
dilution. This antiserum is directed against amino acids 1759 to 2306 of the intracellular domain of murine Notch-1. To detect Dl-1
expression, we used a rabbit antiserum directed against the
extracellular part of chicken Dl-1 at 1/15 dilution (24) (a
gift of I. Le Roux). To detect troponin T expression, we used a mouse
monoclonal troponin T antiserum (catalog no. T6277; Sigma Chemical Co.)
at 1/100 dilution. Slides were mounted and viewed with a confocal laser
scanning microscope (Zeiss) (magnification, ×63; numerical aperture,
1.4).
Differentiation assay.
C2 cells were plated in
3.5-cm-diameter plates so that they would reach 70% confluence the
following day. QT6 or QT6-Dl1 cells (106) were then added.
One day later the medium was changed to differentiation medium (DMEM
supplemented with 2% fetal calf serum). After 6 days, the cells were
fixed, and the expression of troponin T was assessed by indirect
immunofluorescence as described above and viewed with a Nikon
fluorescence microscope (magnification, ×40).
Northern blot analysis.
HeLa-N1 cells were plated in
10-cm-diameter plates so that they would reach 50% confluence the
following day. QT6 or QT6-Dl1 cells (6 × 106) were
then added or cultured alone, and the cells were grown in QT6 medium
for 25 h. Total RNA was isolated from cultured cells with TriZol
(Life Technologies). C2 cells (1.9 × 106) were plated
in 10-cm-diameter plates. Two days later, 6 × 106 QT6
or QT6-Dl1 cells were added, and the cells were grown in DMEM
supplemented with 20% fetal calf serum for 17 h.
Poly(A)+ RNA was then isolated by using the polyAtract
system (Promega). Total RNA (25 µg) or 2 µg of poly(A)+
RNA was analyzed by Northern blotting as described previously (53), except that the filters were hybridized in Church
buffer. The probe used to detect HES-1 expression was the
full-length rat HES-1 cDNA (a gift from R. Kageyama and S. Nakanishi). To normalize RNA amounts, we used as a probe either rat
GADPH cDNA or S26 cDNA (65) (a gift of
F. Aurade), which encodes a ribosomal protein expressed at a high and
constant level in adult human tissues. In addition, this S26
probe does not hybridize with QT6 RNAs, allowing normalization of the
RNA from Notch-1-expressing cells only. Other probes used to analyze
ligand expression were human Jagged-1 cDNA (a gift of S. Artavanis-Tsakonas), murine Dll-1 cDNA (a gift of A. Gossler), and murine Dll-3 cDNA (a gift of R. Beddington).
In order to analyze the intracellular events induced by Notch
activation, we attempted to reconstitute an ex vivo system where the Notch signaling pathway could be activated in a
ligand-dependent manner. Therefore, we first constructed a cell line
expressing the Notch-1 receptor: HeLa cells were stably transfected
with the murine Notch-1 cDNA and a subclone was further
characterized and named HeLa-N1. As Delta-expressing cells, we used
quail QT6 cells infected by a retrovirus expressing the chicken
Dl-1 cDNA (24). These cells were named
QT6-Dl1. As control cells, we used indifferently both wild-type QT6
cells or QT6 cells infected by RCAS retrovirus incorporating
antisense Dl-1 cDNA (see Materials and Methods)
(24). Expression was assessed by indirect
immunofluorescence, and staining that included the membranes as well as
the secretory pathway was observed for both proteins (Fig.
1). Membrane staining was confirmed
by fixing the cells without permeabilization.
Interaction of Dl-1-expressing cells with Notch-1-expressing cells
leads to transactivation of the HES-1 promoter in the
Notch-expressing cells.
We and others have previously shown that
active forms of the Notch receptor can activate transcription from the
HES-1 promoter (29, 34). We postulated that if
active truncated forms of Notch mimic normal Notch activation,
stimulation of the Notch receptor by a ligand would have the same
effect on HES-1 transcription. Thus, to follow Notch
activation, we transiently transfected HeLa-N1 cells with the reporter
luciferase gene under the control of the HES-1 promoter
(HES-1-luc [29]). QT6-Dl1 cells or QT6 control cells
(either wild-type QT6 or QT6 retroinfected with an antisense cDNA for
cDl-1) were then added and cocultivated for 24 h (see Materials
and Methods). As a positive control, a constitutively active
membrane-tethered form of Notch,
0270-7306/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.
Delta-1 Activation of Notch-1 Signaling Results in
HES-1 Transactivation
ABSTRACT
Top
Abstract
Introduction
Materials & Methods
Results
Discussion
References
INTRODUCTION
Top
Abstract
Introduction
Materials & Methods
Results
Discussion
References
MATERIALS AND METHODS
Top
Abstract
Introduction
Materials & Methods
Results
Discussion
References
ABluc [29]) alone or in
combination with 0.8 µg of pCS2-E (29, 36), 1.6 µg of
pCDNA3-
1PDX (42), or 1.6 µg of pCMV-mKuz DN
(42). One day later, 2 × 106 QT6 or
QT6-Dl1 cells were added and cocultivated for 24 h in QT6 medium
(coculture with 106 QT6 or QT6-Dl1 cells led to the same
results). The final calcium concentration was adjusted to 0.08 g/liter.
Luciferase activity was determined as previously described
(29) in a Berthold luminometer 48 h after transfection.
All transfections were performed in duplicate.
RESULTS
Top
Abstract
Introduction
Materials & Methods
Results
Discussion
References
View larger version (42K):
[in a new window]
FIG. 1.
Membrane localization of Notch-1 and Delta-1 in the
stable cell lines used. Immunofluorescence analysis of HeLa control
cells (A), HeLa-N1 cells (B), QT6 control cells (C), and QT6-Dl1 cells
(D) is shown. (A and B) Cells were stained with the IC antiserum
(42), which recognizes the intracellular part of Notch-1; (C
and D) cells were stained with an antiserum directed against the
extracellular domain of Dl-1 (24). The pictures were taken
with a confocal laser scanning microscope (Zeiss). Magnification, ×63;
numerical aperture, 1.4.
E (29, 36), was
cotransfected with HES-1-luc in the Notch-1-expressing cells.
E construct
(Fig. 2A, compare bars 2 and 4). The lower activity of E in
HeLa-N1 cells compared to that in HeLa cells is probably due to
clonal variation. Therefore, HES-1 transactivation is
dependent on the presence of Notch-1 in stimulated cells and the
presence of Dl-1 in stimulating cells. We conclude that Dl-1 is a
functional ligand for Notch-1.
View larger version (17K):
[in a new window]
FIG. 2.
Coculture of QT6-Dl1 cells with HeLa-N1 cells leads to
transactivation of the HES-1 promoter in HeLa-N1 cells. (A)
HeLa-N1 cells were transfected with 400 ng of a luciferase gene
construct under the control of HES-1 promoter (HES-1-luc
[29]) alone (bars 1, 3, and 4) or together with 800 ng
of the active form of Notch-1 E (29, 36) (bar 2). One day
later, QT6 control cells (bar 3) or QT6-Dl1 cells (bar 4) were added
and cocultivated for 24 h with the transfected HeLa-N1 cells.
Luciferase activity was measured 48 h after transfection in a
luminometer (Berthold). The mean fold inductions from 11 independent
experiments performed in duplicate are shown. Luciferase activation
represents the ratio between individual luciferase activity and the
activity measured with the luciferase plasmid alone. The bars represent
the standard errors. (B) Control HeLa cells were transfected with 400 ng of HES-1-luc alone (bars 1, 3, and 4) or together with 800 ng of the
E construct (bar 2). One day later, QT6 control cells (lane 3) or
QT6-Dl1 cells (lane 4) were added and cocultivated for 24 h with
the transfected HeLa cells. Luciferase activity was measured 48 h
after transfection, as described above. The mean fold inductions from
three independent experiments performed in duplicate are shown.
Luciferase activation represents the ratio between individual
luciferase activity and the activity measured with the luciferase
plasmid alone. The bars represent the standard errors.
Inhibition of HES-1-luc transactivation by an inhibitor of Notch
maturation.
It has been shown that the Notch receptor undergoes a
constitutive proteolytic cleavage in the extracellular part of the
protein during its transport to the cell membrane and that only this
mature form is detectable at the cell surface (8, 42, 49).
Logeat et al. showed that a furin-like convertase is responsible for Notch constitutive maturation and, as suggested by others
(8), that the processed extracellular part remains attached
to the membrane-tethered C terminus of the molecule. Further
experiments showed that this proteolytic maturation step was required
for Notch surface expression and that it was severely impaired in a
stable cell line expressing an inhibitor of furin-like
convertase, 1-antitrypsin Portland (known as 1PDX
[2]) (42).
1PDX in HeLa-N1
cells would reduce the amount of mature Notch-1 receptor at the
cell surface and as a consequence would inhibit transactivation of the
HES-1-luc reporter. To test this hypothesis, we cotransfected the
cDNA encoding 1PDX with the HES-1-luc reporter in HeLa-N1 cells. When these transfected HeLa-N1 cells were cocultivated with the QT6-Dl1 cells, a significant inhibition of HES-1-luc transactivation was observed (Fig. 3,
bars 7 and 8), whereas cotransfection of the cDNA encoding 1PDX did
not decrease E-induced HES-1-luc transactivation (Fig. 3, bars 3 and
4) or HES-1-luc levels when HeLa-N1 cells were cocultivated with
control QT6 cells (Fig. 3, bars 5 and 6). These results show that
maturation of the Notch receptor is necessary for activation by its
ligand and thus that only the mature form of Notch-1 is functional.
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Dl-1-induced transactivation of HES-1-luc is inhibited by a
truncated dominant-negative form of Kuzbanian.
Genetic experiments
with Drosophila and nematodes have suggested that a membrane
metalloprotease, Kuzbanian (Kuz), is a previously unrecognized
component of the Notch signaling pathway and that it is involved in
Notch activation (49, 52, 58, 68). At least one ortholog of
kuzbanian has been isolated in vertebrates (49).
Deletion studies of this protein have defined a truncated form of
either Drosophila or murine Kuz which lacks the
prodomain and the metalloprotease domain of the Kuz protein and
acts phenotypically in Drosophila as a dominant-negative
molecule (Kuz DN [49]). In addition, injection of this
truncated form of murine Kuz in Xenopus embryos resulted
in overproduction of primary neurons (49). We thus
postulated that if Kuz is implicated in Notch-1 activation in our
system, then introducing a dominant-negative form in Notch-1-expressing
cells should alter Notch-1 signaling. To test this hypothesis, we
cotransfected murine Kuz DN (mKuz DN2 [49]) with the
HES-1-luc reporter gene in HeLa-N1 cells prior to cocultivation with
the QT6-Dl1 cells. A reproducible inhibition of Dl-1-induced
transactivation of the HES-1 promoter could be
observed (Fig. 4, bars 7 and 8),
but inhibition of E-induced HES-1-luc transactivation (Fig. 4,
bars 3 and 4) or of the HES-1-luc activity elicited by incubation
with control QT6 cells (Fig. 4, bars 5 and 6) was not observed. We
conclude from these results that Kuzbanian activity is needed for
transcriptional response to Dl-1-induced Notch-1 signaling in our
system. In addition, Kuzbanian acts upstream of E, suggesting that
the extracellular part of Notch-1 is required in this process.
|
RBP-J is implicated in Dl-1-induced transactivation of the
HES-1 promoter.
We have previously shown that active
forms of Notch transactivate the HES-1 promoter through the
RBP-J binding sites. To investigate whether the presence of these
sites is required for Dl-1-induced transactivation of the
HES-1 promoter, we used a mutant form of the
HES-1 reporter construct, from which the two RBP-J
binding sites, A and B, had been deleted (HES-1-ABluc
[29]). As shown in Fig.
5, when this mutant form of the
HES-1 promoter was used, Dl-1- (Fig. 5, bars 7 and 8) as
well as E (Fig. 5, bars 3 and 4)-induced transactivation was
abolished. We conclude that Dl-1 stimulates Notch-1 signaling through
an RBP-J-dependent pathway in HeLa-N1 cells.
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HES-1 expression is increased in Notch-1-expressing cells cocultured with Dl-1-expressing cells. To determine if transcription of the endogenous HES-1 gene was affected in the HeLa-N1 cells after coincubation with the QT6-Dl1 cells, we performed Northern blot analysis. As shown in Fig. 6, no signal for HES-1 could be detected in RNA from either QT6 cells (lane 1) or QT6-Dl1 cells (lane 2) with a probe derived from the rat HES-1 cDNA, most likely because the probe does not cross-hybridize. Therefore, the HES-1 signal in RNA from cocultured cells represents HES-1 expression in the HeLa-N1 cells. HeLa-N1 cells exhibited a weak signal (Fig. 6, lane 3), which was strongly increased by cocultivation with QT6-Dl1 cells (lane 5), but not with control QT6 cells (lane 4). These results correlate with those obtained by the luciferase assay, and confirm the hypothesis that HES-1 is a target of the Notch signaling pathway in HeLa-N1 cells.
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Dl-1 suppresses muscle cell differentiation. As a mean of validating the physiological relevance of our system, we decided to test whether Dl-1 was able to inhibit the differentiation of Notch-expressing cells, as it has been shown for Jagged-1 and Jagged-2, two Serrate-related mammalian proteins (41, 43). When C2 cells are grown in a low-serum medium (i.e., differentiation medium), they start to express the troponin T protein as a marker of differentiation (44) and fuse into myotubes (Fig. 7A). When C2 cells were cocultivated with QT6-Dl1 cells, myotube formation was inhibited and troponin T expression was decreased (Fig. 7C) compared to the effect of cocultivation with QT6 control cells (Fig. 7B). Thus, the two vertebrate Notch ligand types are able to inhibit myogenic differentiation of C2 cells.
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HES-1 expression is increased in C2 cells cocultured with Dl-1-expressing cells. To determine if transcription of the endogenous HES-1 gene was also affected in the C2 cells after coincubation with the QT6-Dl1 cells, we performed Northern blot analysis, using the same probe derived from the rat HES-1 cDNA. C2 cells cocultivated with control QT6 cells (Fig. 8, upper panel, lane 1) exhibited a weak signal, which was increased by cocultivation with QT6-Dl1 cells (Fig. 8, upper panel, lane 2). The intensities of the signals were quantified by phosphorimager and, after normalization with GADPH (Fig. 8, bottom panel, lanes 1 and 2), a reproducible increase of three- to fourfold in HES-1 transcripts was observed. Thus, as in HeLa-N1 cells, there is an increase in the level of endogenous HES-1 mRNA in C2 cells exposed to Dl-1. This result supports the hypothesis that a Notch signaling pathway is activated in the C2 cells cocultivated with Dl-1-expressing cells.
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DISCUSSION |
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Top
Abstract
Introduction
Materials & Methods
Results
Discussion
References
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We report here the ex vivo reconstitution of a Delta-1-induced Notch-1 signaling cascade. Our results demonstrate that Dl-1 can act as a ligand to activate the Notch-1 receptor and prevent cellular differentiation.
Previous results from our laboratory have shown that maturation of the
Notch-1 receptor by a member of the furin family of convertases is
required for cell surface expression (42). Here we confirm
and extend these results by showing that inhibition of this proteolytic
step prevents Notch signaling. In the presence of 1PDX the receptor
is trapped within the cell (42) and therefore is not exposed
to the ligand presented by QT6 cells. However, 1PDX is unlikely to
affect ligand-dependent processing, since activation of HES-1-luc by
E was unaffected in these studies. Thus, the functional form of the
mammalian Notch-1 receptor is the heterodimeric molecule composed of
the two cleavage products, which are associated at the cell surface.
We also present evidence that mammalian counterparts of Drosophila components of the Notch pathway are indeed implicated in Dl-1-dependent Notch-1 signaling.
Genetic studies with Drosophila and C. elegans
have highlighted a role for a metalloprotease, Kuzbanian/Sup-17, in at
least a subset of Notch-dependent biological events (49, 52, 58, 68). Laser ablation experiments (68), as well as
kuz genetic mosaic analysis during Drosophila
neurogenesis, wing margin formation, vein width specification, and
adult sensory bristle development (49, 52, 58) or
nematode vulval development (68), have shown that Kuz
acts cell autonomously in the Notch-expressing cell. In addition,
gain-of-function phenotypes elicited by intracellular forms of either
Notch or Lin-12 are similar in kuz/sup-17 mutant or
kuz/sup-17 wild-type backgrounds, indicating that Kuz acts upstream of intracellular Notch signaling (49, 58, 68). Thus, Kuz may play a role in Notch maturation or activation. When using
a truncated form of murine Kuz, which acts as a dominant-negative inhibitor when overexpressed in Drosophila (49),
we observed a decrease in Dl-1-dependent transactivation of the
HES-1 promoter. Moreover, this dominant-negative form of Kuz
did not lower E-induced HES-1-luc transactivation. E is a
membrane-tethered, active form of Notch-1 which lacks nearly all of the
extracellular part of the receptor. We therefore conclude that Kuz
activity is required to elicit transcriptional activation in HeLa-N1
cells in response to Dl-1-induced Notch-1 stimulation and that Kuz
activity is required upstream of the postulated processing event which
releases the intracellular region of Notch. These data are consistent
with results obtained with invertebrates with intracellular Notch
protein in a kuz mutant background (49, 58, 68),
and furthermore, they confirm that Kuz acts upon the extracellular
portion of mammalian Notch-1.
In Drosophila, Notch activation leads to an increase in E(spl) proteins through transcriptional activation of the genes, which represent downstream targets of the Notch cascade (6, 31, 40). The Su(H) protein has been suggested to be responsible for this transcriptional activation by directly binding to E(spl) gene regulatory regions (6, 17, 20, 40). We and others have shown that truncated active forms of Notch-1 stimulate transcription of a HES-1-derived promoter construct (29, 34). Reminiscent of E(spl) transactivation by Su(H), truncated Notch-dependent transactivation of the HES-1 promoter was mediated by the RBP-J protein through binding sites present in the HES-1 promoter (29). In agreement with these findings, we show in this study that Dl-1 failed to induce transactivation of a mutated HES-1 promoter construct, from which the two RBP-J binding sites have been deleted. Thus, RBP-J activity is indeed required for Dl-1-induced Notch-1 activation.
The results presented above also show that coculture of Dl-1- and Notch-1-expressing cells, besides inducing transactivation of a transfected HES-1 promoter in the Notch-1 expressing cells, also leads to an increase in the level of endogenous HES-1 mRNA, strongly suggesting that this increase is a result of RBP-J-mediated gene transactivation. These data indicate that the HES-1 gene is a bona fide target of Dl-1-dependent Notch-1 signaling in HeLa-N1 cells. HES-1 has been shown to inhibit cellular differentiation when overexpressed in MyoD-induced 10T1/2 cells (54) or murine retinal progenitors (27, 61), suggesting that it functions as a negative regulator of myogenesis and neurogenesis. Supporting this hypothesis, disruption of the HES-1 gene leads to up-regulation of proneural basic helix-loop-helix factors and premature neurogenesis in mouse embryos (26). These data strongly suggest that HES-1 and Notch-1 could function in the same pathway. However, Northern blot analysis revealed that the level of HES-1 mRNA was not changed in RBP-J and Notch-1 knockout embryos (13). Nevertheless, these results do not exclude the possibility that HES-1 expression could be regulated by Notch signaling in some particular developmental events, possibly depending on the cellular context. Development of the retina could be a good candidate, as overexpression of Delta-1 or activated forms of Notch-1 inhibits retinal progenitor differentiation (1, 5, 14, 15, 24), which is accelerated in HES-1-null mutant mouse embryos (61).
We and others recently proposed a model in which ligand binding
induces Notch processing. As an attempt to test this model, we tried to
detect a processed intracellular form of Notch-1 following exposure
to Dl-1. However, we were unable to detect such a molecule by Western
blotting or to detect any nuclear antigenicity by immunofluorescence or
gel shift experiments. One explanation could be that the actual number
of activated Notch-1 receptors is too low to allow detection by these
techniques, although it is sufficient to support transactivation. A
recent report by Schroeter et al. also demonstrated that undetectable amounts of transfected E are sufficient to transactivate the HES-1 promoter (55). Accordingly, when we
performed immunoprecipitations on [35S]Met-labelled
extracts of 293T cells transiently transfected with the E construct,
we were unable to detect any intracellular processing (our unpublished
data). In contrast, when the same experiment was performed with a
C-terminally truncated E lacking the PEST domain, the processed form
was clearly detectable (our unpublished data and reference
36). PEST sequences are found in proteins which
undergo rapid turnover (51), and evidence exists that PEST
regions can serve as signals for proteolytic degradation
(see reference 50 for a review). Our observations suggest that the E-derived processed intracellular form has a very short half-life. Consistent with this hypothesis, the use of a
specific proteasome inhibitor allowed detection of a E-derived processed form (our unpublished data). Thus, it is possible that the combination of a limited number of Dl-1-mobilized Notch-1 molecules
with rapid turnover of the induced intracellular cleaved forms
precludes detection of such a processed form. Alternatively, it may
be that Dl-1-induced stimulation of the Notch-1 receptor does not
lead to intracellular processing. Nevertheless, recent studies done
with transgenic flies expressing a Notch-Gal4 chimera to allow
detection of the intracellular cleaved fragment (39, 59), or
overexpression of Notch-1 and Jagged-1 by transient cotransfection in
mammalian cells (55), strongly suggest that ligand
activation of the Notch receptor indeed results in processing of the
intracellular part of the receptor.
We also showed that exposure of myoblastic C2 cells to Dl-1 results in the suppression of muscle differentiation and in increased levels of endogenous HES-1 mRNA in the C2 cells. These results suggest that Dl-1 activates similar Notch pathways in HeLa-N1 cells and in C2 cells. Since C2 cells endogenously expressed different Notch genes, it remains to be determined which Notch receptor is activated by Dl-1 in these cells and whether transactivation of HES-1 is required for suppression of muscle differentiation.
| |
ACKNOWLEDGMENTS |
|---|
We thank F. Schweisguth (ENS, Paris, France) for critical reading of the manuscript; B. Reina San Martin for help with the figures; R. Hellio (Institut Pasteur, Paris, France) for excellent confocal microscopy assistance; D. Henrique (Instituto de Histologia e Embryologia, Lisbon, Portugal) for helping in the construction of the QT6-Dl1 cells; I. Le Roux and D. Ish-Horowicz (Imperial Cancer Research Fund, London, United Kingdom) for the kind gift of serum against Dl-1; D. J. Pan and G. M. Rubin (Frederick, Md.) for the gift of mKuz DN2-encoding cDNA; R. Kageyama and S. Nakanishi (Kyoto University Faculty of Medicine, Kyoto, Japan), A. Gossler (The Jackson Laboratory, Bar Harbor, Maine), R. Beddington (National Institute for Medical Research, London, United Kingdom), S. Artavanis-Tsakonas (Yale University, New Haven, Conn.), and F. Aurade (Institut Pasteur) for hybridization probes; and C. Pinset and D. Montarras (Institut Pasteur) for the gift of the C2 cells.
S.J. is the recipient of a fellowship from FRM. This work was supported by grants from ARC, ANRS, INSERM, and Ligue Nationale contre le Cancer to A.I. The confocal microscope was purchased with a donation from Marcel and Liliane Pollack.
| |
FOOTNOTES |
|---|
* Corresponding author. Mailing address: Unité de Biologie Moléculaire de l'Expression Génique, URA 1773 CNRS, Institut Pasteur, 25 rue de Dr Roux, 75724 Paris Cedex 15, France. Phone: (33) 1 45 68 85 53. Fax: (33) 1 40 61 30 40. E-mail: aisrael{at}pasteur.fr.
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REFERENCES |
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Top
Abstract
Introduction
Materials & Methods
Results
Discussion
References
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Lan, K., Kuppers, D. A., Robertson, E. S.
(2005). Kaposi's Sarcoma-Associated Herpesvirus Reactivation Is Regulated by Interaction of Latency-Associated Nuclear Antigen with Recombination Signal Sequence-Binding Protein J{kappa}, the Major Downstream Effector of the Notch Signaling Pathway. J. Virol.
79: 3468-3478
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Hahn, K. L., Johnson, J., Beres, B. J., Howard, S., Wilson-Rawls, J.
(2005). Lunatic fringe null female mice are infertile due to defects in meiotic maturation. Development
132: 817-828
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Lehar, S. M., Dooley, J., Farr, A. G., Bevan, M. J.
(2005). Notch ligands Delta1 and Jagged1 transmit distinct signals to T-cell precursors. Blood
105: 1440-1447
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Six, E. M., Ndiaye, D., Sauer, G., Laabi, Y., Athman, R., Cumano, A., Brou, C., Israel, A., Logeat, F.
(2004). The Notch Ligand Delta1 Recruits Dlg1 at Cell-Cell Contacts and Regulates Cell Migration. J. Biol. Chem.
279: 55818-55826
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Pece, S., Serresi, M., Santolini, E., Capra, M., Hulleman, E., Galimberti, V., Zurrida, S., Maisonneuve, P., Viale, G., Di Fiore, P. P.
(2004). Loss of negative regulation by Numb over Notch is relevant to human breast carcinogenesis. JCB
167: 215-221
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Schonhoff, S. E., Giel-Moloney, M., Leiter, A. B.
(2004). Minireview: Development and Differentiation of Gut Endocrine Cells. Endocrinology
145: 2639-2644
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Kalinichenko, V. V., Gusarova, G. A., Kim, I.-M., Shin, B., Yoder, H. M., Clark, J., Sapozhnikov, A. M., Whitsett, J. A., Costa, R. H.
(2004). Foxf1 haploinsufficiency reduces Notch-2 signaling during mouse lung development. Am. J. Physiol. Lung Cell. Mol. Physiol.
286: L521-L530
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Zayzafoon, M., Abdulkadir, S. A., McDonald, J. M.
(2004). Notch Signaling and ERK Activation Are Important for the Osteomimetic Properties of Prostate Cancer Bone Metastatic Cell Lines. J. Biol. Chem.
279: 3662-3670
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Yvon, E. S., Vigouroux, S., Rousseau, R. F., Biagi, E., Amrolia, P., Dotti, G., Wagner, H.-J., Brenner, M. K.
(2003). Overexpression of the Notch ligand, Jagged-1, induces alloantigen-specific human regulatory T cells. Blood
102: 3815-3821
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Searfoss, G. H., Jordan, W. H., Calligaro, D. O., Galbreath, E. J., Schirtzinger, L. M., Berridge, B. R., Gao, H., Higgins, M. A., May, P. C., Ryan, T. P.
(2003). Adipsin, a Biomarker of Gastrointestinal Toxicity Mediated by a Functional {gamma}-Secretase Inhibitor. J. Biol. Chem.
278: 46107-46116
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Vigouroux, S., Yvon, E., Wagner, H.-J., Biagi, E., Dotti, G., Sili, U., Lira, C., Rooney, C. M., Brenner, M. K.
(2003). Induction of Antigen-Specific Regulatory T Cells following Overexpression of a Notch Ligand by Human B Lymphocytes. J. Virol.
77: 10872-10880
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Takizawa, T., Ochiai, W., Nakashima, K., Taga, T.
(2003). Enhanced gene activation by Notch and BMP signaling cross-talk. Nucleic Acids Res
31: 5723-5731
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Tsuji, H., Ishii-Ohba, H., Ukai, H., Katsube, T., Ogiu, T.
(2003). Radiation-induced deletions in the 5' end region of Notch1 lead to the formation of truncated proteins and are involved in the development of mouse thymic lymphomas. Carcinogenesis
24: 1257-1268
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Six, E., Ndiaye, D., Laabi, Y., Brou, C., Gupta-Rossi, N., Israel, A., Logeat, F.
(2003). The Notch ligand Delta1 is sequentially cleaved by an ADAM protease and {gamma}-secretase. Proc. Natl. Acad. Sci. USA
100: 7638-7643
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Yamada, T., Yamazaki, H., Yamane, T., Yoshino, M., Okuyama, H., Tsuneto, M., Kurino, T., Hayashi, S.-I., Sakano, S.
(2003). Regulation of osteoclast development by Notch signaling directed to osteoclast precursors and through stromal cells. Blood
101: 2227-2234
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Oates, A. C., Ho, R. K.
(2003). Hairy/E(spl)-related (Her) genes are central components of the segmentation oscillator and display redundancy with the Delta/Notch signaling pathway in the formation of anterior segmental boundaries in the zebrafish. Development
129: 2929-2946
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Kunisato, A., Chiba, S., Nakagami-Yamaguchi, E., Kumano, K., Saito, T., Masuda, S., Yamaguchi, T., Osawa, M., Kageyama, R., Nakauchi, H., Nishikawa, M., Hirai, H.
(2003). HES-1 preserves purified hematopoietic stem cells ex vivo and accumulates side population cells in vivo. Blood
101: 1777-1783
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Espinosa, L., Ingles-Esteve, J., Robert-Moreno, A., Bigas, A.
(2003). Ikappa Balpha and p65 Regulate the Cytoplasmic Shuttling of Nuclear Corepressors: Cross-talk between Notch and NFkappa B Pathways. Mol. Biol. Cell
14: 491-502
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Mishra-Gorur, K., Rand, M. D., Perez-Villamil, B., Artavanis-Tsakonas, S.
(2002). Down-regulation of Delta by proteolytic processing. JCB
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Sakamoto, K., Yamaguchi, S., Ando, R., Miyawaki, A., Kabasawa, Y., Takagi, M., Li, C. L., Perbal, B., Katsube, K.-i.
(2002). The Nephroblastoma Overexpressed Gene (NOV/ccn3) Protein Associates with Notch1 Extracellular Domain and Inhibits Myoblast Differentiation via Notch Signaling Pathway. J. Biol. Chem.
277: 29399-29405
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Yan, B., Raben, N., Plotz, P.
(2002). The Human Acid alpha -Glucosidase Gene Is a Novel Target of the Notch-1/Hes-1 Signaling Pathway. J. Biol. Chem.
277: 29760-29764
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Wang, W., Campos, A. H., Prince, C. Z., Mou, Y., Pollman, M. J.
(2002). Coordinate Notch3-Hairy-related Transcription Factor Pathway Regulation in Response to Arterial Injury. MEDIATOR ROLE OF PLATELET-DERIVED GROWTH FACTOR AND ERK. J. Biol. Chem.
277: 23165-23171
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Wang, W., Prince, C. Z., Mou, Y., Pollman, M. J.
(2002). Notch3 Signaling in Vascular Smooth Muscle Cells Induces c-FLIP Expression via ERK/MAPK Activation. RESISTANCE TO Fas LIGAND-INDUCED APOPTOSIS. J. Biol. Chem.
277: 21723-21729
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Jeffries, S., Robbins, D. J., Capobianco, A. J.
(2002). Characterization of a High-Molecular-Weight Notch Complex in the Nucleus of Notchic-Transformed RKE Cells and in a Human T-Cell Leukemia Cell Line. Mol. Cell. Biol.
22: 3927-3941
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Sriuranpong, V., Borges, M. W., Strock, C. L., Nakakura, E. K., Watkins, D. N., Blaumueller, C. M., Nelkin, B. D., Ball, D. W.
(2002). Notch Signaling Induces Rapid Degradation of Achaete-Scute Homolog 1. Mol. Cell. Biol.
22: 3129-3139
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Berechid, B. E., Kitzmann, M., Foltz, D. R., Roach, A. H., Seiffert, D., Thompson, L. A., Olson, R. E., Bernstein, A., Donoviel, D. B., Nye, J. S.
(2002). Identification and Characterization of Presenilin-independent Notch Signaling. J. Biol. Chem.
277: 8154-8165
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Kawamata, S., Du, C., Li, K., Lavau, C.
(2002). Notch1 Perturbation of Hemopoiesis Involves Non-Cell- Autonomous Modifications. J. Immunol.
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Lieber, T., Kidd, S., Young, M. W.
(2002). kuzbanian-mediated cleavage of Drosophila Notch. Genes Dev.
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Cossins, J., Vernon, A. E., Zhang, Y., Philpott, A., Jones, P. H.
(2002). Hes6 regulates myogenic differentiation. Development
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Sasaki, Y., Ishida, S., Morimoto, I., Yamashita, T., Kojima, T., Kihara, C., Tanaka, T., Imai, K., Nakamura, Y., Tokino, T.
(2002). The p53 Family Member Genes Are Involved in the Notch Signal Pathway. J. Biol. Chem.
277: 719-724
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Oswald, F., Tauber, B., Dobner, T., Bourteele, S., Kostezka, U., Adler, G., Liptay, S., Schmid, R. M.
(2001). p300 Acts as a Transcriptional Coactivator for Mammalian Notch-1. Mol. Cell. Biol.
21: 7761-7774
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Wu, G., Lyapina, S., Das, I., Li, J., Gurney, M., Pauley, A., Chui, I., Deshaies, R. J., Kitajewski, J.
(2001). SEL-10 Is an Inhibitor of Notch Signaling That Targets Notch for Ubiquitin-Mediated Protein Degradation. Mol. Cell. Biol.
21: 7403-7415
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Wang, C.-D., Chang, G.-D., Lee, Y.-K., Chen, H.
(2001). A Functional Composite Cis-Element for NF{kappa}B and RBPJ{kappa} in the Rat Pregnancy-Specific Glycoprotein Gene. Biol. Reprod.
65: 1437-1443
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Jaleco, A. C., Neves, H., Hooijberg, E., Gameiro, P., Clode, N., Haury, M., Henrique, D., Parreira, L.
(2001). Differential Effects of Notch Ligands Delta-1 and Jagged-1 in Human Lymphoid Differentiation. JEM
194: 991-1002
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Iso, T., Sartorelli, V., Chung, G., Shichinohe, T., Kedes, L., Hamamori, Y.
(2001). HERP, a New Primary Target of Notch Regulated by Ligand Binding. Mol. Cell. Biol.
21: 6071-6079
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Ohishi, K., Varnum-Finney, B., Serda, R. E., Anasetti, C., Bernstein, I. D.
(2001). The Notch ligand, Delta-1, inhibits the differentiation of monocytes into macrophages but permits their differentiation into dendritic cells. Blood
98: 1402-1407
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Faux, C. H., Turnley, A. M., Epa, R., Cappai, R., Bartlett, P. F.
(2001). Interactions between Fibroblast Growth Factors and Notch Regulate Neuronal Differentiation. J. Neurosci.
21: 5587-5596
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Mizutani, T., Taniguchi, Y., Aoki, T., Hashimoto, N., Honjo, T.
(2001). Conservation of the biochemical mechanisms of signal transduction among mammalian Notch family members. Proc. Natl. Acad. Sci. USA
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Zine, A., Aubert, A., Qiu, J., Therianos, S., Guillemot, F., Kageyama, R., de Ribaupierre, F.
(2001). Hes1 and Hes5 Activities Are Required for the Normal Development of the Hair Cells in the Mammalian Inner Ear. J. Neurosci.
21: 4712-4720
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Dalbiès-Tran, R., Stigger-Rosser, E., Dotson, T., Sample, C. E.
(2001). Amino Acids of Epstein-Barr Virus Nuclear Antigen 3A Essential for Repression of J{kappa}-Mediated Transcription and Their Evolutionary Conservation. J. Virol.
75: 90-99
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Hirsinger, E, Malapert, P, Dubrulle, J, Delfini, M., Duprez, D, Henrique, D, Ish-Horowicz, D, Pourquie, O
(2001). Notch signalling acts in postmitotic avian myogenic cells to control MyoD activation. Development
128: 107-116
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Shimizu, K., Chiba, S., Hosoya, N., Kumano, K., Saito, T., Kurokawa, M., Kanda, Y., Hamada, Y., Hirai, H.
(2000). Binding of Delta1, Jagged1, and Jagged2 to Notch2 Rapidly Induces Cleavage, Nuclear Translocation, and Hyperphosphorylation of Notch2. Mol. Cell. Biol.
20: 6913-6922
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Jeffries, S., Capobianco, A. J.
(2000). Neoplastic Transformation by Notch Requires Nuclear Localization. Mol. Cell. Biol.
20: 3928-3941
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Rand, M. D., Grimm, L. M., Artavanis-Tsakonas, S., Patriub, V., Blacklow, S. C., Sklar, J., Aster, J. C.
(2000). Calcium Depletion Dissociates and Activates Heterodimeric Notch Receptors. Mol. Cell. Biol.
20: 1825-1835
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Delfini, M, Hirsinger, E, Pourquie, O, Duprez, D
(2000). Delta 1-activated notch inhibits muscle differentiation without affecting Myf5 and Pax3 expression in chick limb myogenesis. Development
127: 5213-5224
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Zheng, J., Shou, J, Guillemot, F, Kageyama, R, Gao, W.
(2000). Hes1 is a negative regulator of inner ear hair cell differentiation. Development
127: 4551-4560
[Abstract] -
Kondo, T, Raff, M
(2000). Basic helix-loop-helix proteins and the timing of oligodendrocyte differentiation. Development
127: 2989-2998
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Cau, E, Gradwohl, G, Casarosa, S, Kageyama, R, Guillemot, F
(2000). Hes genes regulate sequential stages of neurogenesis in the olfactory epithelium. Development
127: 2323-2332
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Jouve, C, Palmeirim, I, Henrique, D, Beckers, J, Gossler, A, Ish-Horowicz, D, Pourquie, O
(2000). Notch signalling is required for cyclic expression of the hairy-like gene HES1 in the presomitic mesoderm. Development
127: 1421-1429
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Shimizu, K., Chiba, S., Kumano, K., Hosoya, N., Takahashi, T., Kanda, Y., Hamada, Y., Yazaki, Y., Hirai, H.
(1999). Mouse Jagged1 Physically Interacts with Notch2 and Other Notch Receptors. ASSESSMENT BY QUANTITATIVE METHODS. J. Biol. Chem.
274: 32961-32969
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Sestan, N., Artavanis-Tsakonas, S., Rakic, P.
(1999). Contact-Dependent Inhibition of Cortical Neurite Growth Mediated by Notch Signaling. Science
286: 741-746
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Artavanis-Tsakonas, S., Rand, M. D., Lake, R. J.
(1999). Notch Signaling: Cell Fate Control and Signal Integration in Development. Science
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Kurooka, H., Honjo, T.
(2000). Functional Interaction between the Mouse Notch1 Intracellular Region and Histone Acetyltransferases PCAF and GCN5. J. Biol. Chem.
275: 17211-17220
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Hirata, H., Ohtsuka, T., Bessho, Y., Kageyama, R.
(2000). Generation of Structurally and Functionally Distinct Factors from the Basic Helix-Loop-Helix Gene Hes3 by Alternative First Exons. J. Biol. Chem.
275: 19083-19089
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McLarren, K. W., Theriault, F. M., Stifani, S.
(2001). Association with the Nuclear Matrix and Interaction with Groucho and RUNX Proteins Regulate the Transcription Repression Activity of the Basic Helix Loop Helix Factor Hes1. J. Biol. Chem.
276: 1578-1584
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Gupta-Rossi, N., Le Bail, O., Gonen, H., Brou, C., Logeat, F., Six, E., Ciechanover, A., Israel, A.
(2001). Functional Interaction between SEL-10, an F-box Protein, and the Nuclear Form of Activated Notch1 Receptor. J. Biol. Chem.
276: 34371-34378
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Mizutani, T., Taniguchi, Y., Aoki, T., Hashimoto, N., Honjo, T.
(2001). Conservation of the biochemical mechanisms of signal transduction among mammalian Notch family members. Proc. Natl. Acad. Sci. USA
98: 9026-9031
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Gao, X., Chandra, T., Gratton, M.-O., Quelo, I., Prud'homme, J., Stifani, S., St-Arnaud, R.
(2001). HES6 acts as a transcriptional repressor in myoblasts and can induce the myogenic differentiation program. JCB
154: 1161-1172
[Abstract] [Full Text]
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