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Mol Cell Biol, August 1998, p. 4807-4818, Vol. 18, No. 8
Howard Hughes Medical Institute, Departments
of Microbiology and Biochemistry, University of California, San
Francisco, California 94143-0414
Received 10 March 1998/Returned for modification 14 April
1998/Accepted 26 May 1998
Wnt signaling is thought to be mediated via interactions between
Since the initial identification of
Wnt-1 as a proto-oncogene (45), Wnt-1 and Wnt-related genes
have been shown to encode secreted signaling molecules that regulate
many developmental processes in both vertebrates and invertebrates
(reviewed in references 19, 39, 44, 45, 50, and
64). The molecular mechanism of the Wnt signaling
pathway has been elucidated by genetic analysis in Drosophila
melanogaster and Caenorhabditis elegans and by
biochemical studies in Xenopus laevis and mammalian tissue
culture cells. In response to a Wnt signal in vertebrates or to a
wingless signal in Drosophila, a receptor encoded by the
frizzled gene family (4, 73) is activated and conveys the
signal to cytoplasmic downstream components (reviewed in reference
25). These components included dishevelled (dsh),
zeste-white 3 kinase (zw3), and armadillo (arm), which are homologous
to the vertebrate proteins Dsh (63), GSK3 (20,
63), and In addition to its function in the Wnt signaling pathway, A potential mechanism for the function of free Lymphoid enhancer-binding factor (LEF-1) is a member of the family of
high-mobility group (HMG) proteins that recognizes the nucleotide
sequence 5'CCTTTGAACT (68, 72) and is expressed in lymphoid cells and at multiple sites of organogenesis in the developing mouse (47, 68, 71). LEF-1 is closely related to
T-cell factor 1 (TCF-1), which has a similar expression pattern in the
mouse (47, 70), and to TCF-3 and -4 (26, 38).
Functional and biochemical characterization of LEF-1 has indicated that
this protein has no transcriptional activation potential by itself and
is unable to stimulate transcription from a synthetic enhancer containing multimerized LEF-1 binding sites (68, 72).
However, LEF-1 stimulates the function of the T-cell receptor Three distinct regions of LEF-1 have been shown to interact with other
proteins. The amino-terminal 76 residues of LEF-1 can associate
directly with In this study, we examine the regulation of transcription by LEF-1 in
response to Wnt-1 signaling and association of LEF-1 with endogenous,
rather than overexpressed, Plasmids and oligonucleotides.
The pLEF-CAT reporter gene
construct was generated by inserting a XhoI-XbaI
fragment, containing seven multimerized wild-type (wt) LEF-1 binding
sites, into a plasmid, p301fosCAT, containing the minimal
fos promoter linked to the chloramphenicol acetyltransferase (CAT) gene (3). pmLEF-CAT was created by inserting six
multimerized oligonucleotides containing mutated LEF-1 binding sites
into p301fosCAT. The nucleotide sequences of the wt and mutated LEF-1
binding sites are as follows: wt, 5'GCACCCTTTGAAGCTC;
mutated, 5'GCACCaaTTcAAGCTC.
0270-7306/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.
Modulation of Transcriptional Regulation by LEF-1
in Response to Wnt-1 Signaling and Association with
-Catenin
ABSTRACT
Top
Abstract
Introduction
Materials & Methods
Results
Discussion
References
-catenin and members of the LEF-1/TCF family of transcription factors. Here we study the mechanism of transcriptional regulation by
LEF-1 in response to a Wnt-1 signal under conditions of endogenous -catenin in NIH 3T3 cells, and we examine whether association with
-catenin is obligatory for the function of LEF-1. We find that Wnt-1
signaling confers transcriptional activation potential upon LEF-1 by
association with -catenin in the nucleus. By mutagenesis, we
identified specific residues in LEF-1 important for interaction with
-catenin, and we delineated two transcriptional activation domains
in -catenin whose function is augmented in specific association with
LEF-1. Finally, we show that a Wnt-1 signal and -catenin association
are not required for the architectural function of LEF-1 in the
regulation of the T-cell receptor 
enhancer, which involves
association of LEF-1 with a different cofactor, ALY. Thus, LEF-1 can
assume diverse regulatory functions by association with different
proteins.
INTRODUCTION
Top
Abstract
Introduction
Materials & Methods
Results
Discussion
References
-catenin (33), respectively. In response to a Wnt signal, Dishevelled inhibits, through an as-yet-unknown mechanism, the function of the serine/threonine kinase GSK3
(53), resulting in the cytoplasmic accumulation of
hypophosphorylated -catenin and the transmission of the Wnt signal
to more downstream targets (52, 53, 74).
-catenin
is also an essential component of adhesion complexes (18, 24). -Catenin is directly associated with cadherins and
couples these calcium-dependent, membrane-bound adhesion molecules to components of the cytoskeleton (1, 23). Distinct functions of -catenin in Wnt signaling and cell adhesion have been implicated by studies with Drosophila and Xenopus (11,
48, 60). -Catenin is also associated with the adenomatous
polyposis coli (APC) protein, which regulates the half-life of
-catenin that is not complexed with cadherins (42, 49).
Wnt signaling has been shown to increase the pool of -catenin-APC
complexes and the pool of free, or uncomplexed, -catenin (49,
58). The free -catenin has been proposed to transmit the Wnt
signal by interactions with downstream effectors (36).
-catenin in Wnt
signaling has been suggested by the observation that -catenin can
associate with the transcription factor LEF-1 (2, 22) and
the closely related XTCF-3 protein (38). A
Drosophila ortholog of LEF-1, termed pangolin or dTCF, has
been shown genetically to act downstream of armadillo (7,
69). Murine LEF-1 can bind the wingless-responsive enhancer of
the Drosophila ultrabithorax gene and regulate the enhancer
in an armadillo-dependent manner in vivo (56). Likewise,
binding sites for LEF-1/TCF proteins coincide with Wnt-responsive
sequence elements in the promoters of the Xenopus siamois
and the nodal related 3 genes (5, 34). However, these
previous studies have not established whether and how a Wnt signal
results in transcriptional activation by LEF-1 in cells expressing
normal levels of -catenin.
(TCR) enhancer in collaboration with other DNA-binding proteins
(6, 15, 32, 68, 72). LEF-1 acts as an architectural
transcription factor that introduces a sharp bend in the DNA (13,
31) and contains a context-dependent activation domain which
functions only in a specific context of other transcription factors
(8, 14).
-catenin (2, 22). A similar -catenin interaction domain has been identified in the LEF-1-related proteins TCF-1, TCF-3, and TCF-4, which in combination with overexpressed -catenin can stimulate transcription from multimerized LEF/TCF binding sites (26, 38). In addition, the protein ALY was
shown to interact with the context-dependent activation domain of LEF-1 and with AML-1, another TCR-binding protein, to stimulate the function of the TCR enhancer (6). Finally, Pendulin, a
protein distantly related to -catenin, can interact with a
carboxyl-terminal nuclear localization signal of LEF-1 and may regulate
the nuclear localization of LEF-1 (55). The interaction of
LEF-1 with multiple proteins raises the questions of whether they
confer distinct regulatory properties upon LEF-1, or whether they
collaborate with, or antagonize, each other in mediating a particular
transcriptional response.
-catenin. We identify specific residues
in LEF-1 that are required for interaction with -catenin, and we
study the mechanism by which -catenin augments transcriptional
activation by LEF-1. Finally, we address the question of whether the
association with -catenin is obligatory for the function of LEF-1.
MATERIALS AND METHODS
Top
Abstract
Introduction
Materials & Methods
Results
Discussion
References
-catenin were generated by
site-directed mutagenesis with primers that contain mismatches to alter
specific amino acids and introduce restriction sites. The mutated
codons in the primers are underlined and the mutated nucleotides are in
lowercase letters, as follows: m1LEF-1,
5'CTCTGCGCCACCGcgGcGATGATCCCCTTC; m2LEF-1,
5'GATGATCCCCTTCgcGGcCGcAGGCGATCCCCAG; m3LEF-1,
5'GGCGATCCCCAGgcGGccgcGATCTTCGCCGAG; m4LEF-1,
5'GAGGAGGGCGACgcAGtCGcgATCgcGTCATCTTTGGTTAACG;
and DP-catenin, 5'GGATTGCCTTTACCAgctAGcGcAGGAGCTGTGGTAGcGGCACCAGcATGGATTCCAGcGT CCAGGTAAGACTG.
The expression plasmids for LEF-1 or -catenin were generated
by linking the appropriate cDNAs as XbaI/KpnI
fragments to the cytomegalovirus enhancer-promoter in the pCG vector
(14). Subclones containing the amino-terminal deletion
mutant LEF-1
56 and the LEF-1HMG domain were constructed by using
naturally occurring restriction enzyme sites, HpaI and
NdeI, respectively. For the construction of
pCMV-DP-catenin, we first introduced point mutations in
Bluescript--catenin by site-directed mutagenesis. Subsequently, we
used a PCR-generated mutant DNA fragment (encoding amino acids 1 to 90 of -catenin) to replace the corresponding DNA fragment in
pCMV--catenin. All -catenin constructs used in this study contain
a bacteriophage T7 epitope tag at the amino terminus and were derived
from a -actin promoter--catenin construct (2). The
construction of amino- and carboxyl-terminal deletion mutants of
-catenin was performed in two steps. First, we prepared DNA fragments encoding amino acids 132 to 781 (N) and 1 to 695 (C) by
PCR and inserted the fragments in frame into pEVRFT7 vectors (6). To avoid the introduction of mutations by PCR, we
subsequently subcloned an SnaBI fragment (N) and a
BstBI-XbaI fragment (C) and replaced the
corresponding regions in pCMV--catenin. The chimeric
-catenin-LEF-1 and -catenin-GAL4 plasmids were constructed with
PCR-generated fragments. In brief, DNA fragments encoding amino acids 1 to 131 or amino acids 696 to 781 of -catenin were obtained by PCR.
The purified PCR products were subcloned either into the
XbaI site at codon 3 of LEF-1 in plasmid pCMV-LEF-1 or into
the BamHI site in the polylinker of pGAL4DBD (6).
For the construction of the plasmid encoding the chimeric
CD8--catenin, we prepared a DNA fragment encoding amino acids 1 to
211 of CD8 by PCR from the plasmid pSp65.F1.1T8 (30) and
subcloned it into the XbaI and SmaI sites of the
pCG vector. Subsequently, a full-length -catenin fragment was
isolated from the -actin promoter--catenin construct by
digestion with BamHI and inserted into the pCG-CD8 plasmid.
Nucleotide sequences of the coding regions for all expression plasmids
were verified by sequencing.
Cell culture, transient transfections, and reporter gene
assays.
NIH 3T3, HeLa, and Cos7 cells were cultured at 37°C in
Dulbecco's modified Eagle medium, supplemented with 5% fetal bovine serum. Neuro2A cells were grown in Eagle's minimal essential medium with Earle's balanced salt solution medium containing 5% fetal bovine
serum. Transient transfections were generally performed by the
DEAE-dextran-chloroquine procedure (16). A Rous sarcoma virus--galactosidase control plasmid was included in each
transfection experiment to control for the efficiency of transfection.
The total DNA concentration in each transfection experiment was kept constant by adding vector plasmid DNA if necessary. CAT and
-galactosidase assays were performed as described in the work of
Starr et al. (66). After background subtraction, the CAT
activity was normalized to -galactosidase activity as an internal
transfection control. Transfections of NIH 3T3 cells for
immunoprecipitation and immunoblot analysis were performed by
electroporation.
Cell lysis, immunoprecipitation, and immunoblot analysis.
For immunoprecipitations, cytoplasmic cell extracts were prepared from
transfected cells by adding lysis buffer (100 mM NaCl, 50 mM Tris-HCl
[pH 7.5], 0.5% Nonidet P-40, 0.5 mg of leupeptin per ml, 1 mg of
pepstatin per ml, and 0.2 mM phenylmethylsulfonyl fluoride) and
preclearing the lysates by centrifugation. The cell extracts were
preabsorbed with protein G-Sepharose and normal mouse immunoglobulin G
(IgG) (Pharmacia) for 1 h at 4°C prior to the addition of
-catenin monoclonal antibody (Signal Transduction). After incubation
for 1 h at 4°C, the immunoprecipitates were washed three times
with lysis buffer, solublized in sodium dodecyl sulfate (SDS)-sample
buffer, and analyzed by SDS-polyacrylamide gel electrophoresis (PAGE).
Immunocytochemistry.
For immunocytochemistry to detect LEF-1
and -catenin, NIH 3T3 cells were allowed to settle on
poly-D-lysine-coated coverslips the day before transfection by the
Lipofectamine procedure (GIBCO-BRL). Cells on the coverslips were fixed
in freshly made 4% paraformaldehyde in phosphate-buffered saline
(PBS), 36 to 48 h after transfection. After fixation, cells were
blocked in Block Buffer (1× PBS, 0.1% Tween 20, 20% normal goat
serum [Sigma], 3% bovine serum albumin [Sigma]) for 30 min at room
temperature. For immunodetection, rabbit polyclonal anti-LEF-1 antibody
or anti--catenin monoclonal antibody (Transduction Laboratories) was
used at a 1:750 or 1:100 dilution, respectively. Washes were performed
in 1× PBS containing 0.1% Tween 20, and fluorescein
isothiocyanate-conjugated donkey anti-rabbit IgG (heavy plus light) and
Texas Red-conjugated donkey anti-mouse IgG (heavy plus light) (Jackson
Immunochemicals) were used at a 1:250 dilution as secondary antibodies.
After washing, the coverslips were mounted in Fluoromount G and the
cells were photographed.
In vitro translation, protein purification, nuclear extracts, and
DNA binding analysis.
In vitro-translated proteins were
synthesized with a coupled transcription and translation (TnT) kit
(Promega). wt and mutant LEF-1 proteins were expressed from Bluescript
KS+ constructs, and the efficiencies of in vitro
translation reactions were assessed by SDS-PAGE of parallel translation
reactions performed in the presence of [35S]methionine
(Amersham). To study the interaction between LEF-1 and -catenin, in
vitro-translated LEF-1 was incubated with recombinant six-His-tagged
-catenin in the presence of a 32P-labeled duplex
oligonucleotide probe, containing a LEF-1 binding site. The binding
reaction contained 20 mM HEPES buffer (pH 7.9), 75 mM NaCl, 1 mM
dithiothreitol, 2 mM MgCl2, 10% glycerol, 0.1 mg of bovine
serum albumin per ml, 10 µg of salmon sperm DNA per ml, and ~40,000
cpm of labeled DNA probe. The protein-DNA complexes were analyzed by
electrophoretic mobility shift assays as described in the work of
Travis et al. (68). The six-His-tagged protein -catenin
was expressed in bacteria and purified with Ni-nitrilotriacetic acid
agarose beads (Qiagen) according to the manufacturer's instructions. Nuclear extracts from Cos7 cells were prepared according to the method
of Schreiber et al. (62).
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RESULTS |
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Top
Abstract
Introduction
Materials & Methods
Results
Discussion
References
|
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Wnt-1 augments transcriptional activation by LEF-1.
To examine
the effects of Wnt signaling on transcriptional activation by LEF-1 in
a mammalian tissue culture system, we used murine NIH 3T3 cells, which
contain endogenous -catenin but lack LEF-1 (68). Cells
were transfected transiently with a CAT reporter gene, containing
multimerized LEF-1 binding sites linked to the minimal fos
promoter (LEF-CAT), together with increasing amounts of a LEF-1
expression plasmid (Fig. 1A). As
anticipated from previous experiments (68), expression of
LEF-1 alone did not augment the activity of the reporter gene. However,
coexpression of LEF-1 and Wnt-1 stimulated reporter gene activity in a
dose-dependent manner, with a maximal level of eightfold over that with
LEF-1 alone. This transcriptional activation was not observed with a reporter gene containing multimerized mutant LEF-1 binding sites, indicating that the transcriptional response to Wnt-1 signaling is
dependent on the presence of functional LEF-1 binding sites.
|
-Catenin is a component of the Wnt signaling pathway and has been
shown to interact directly with LEF-1 (2, 22). Coexpression of LEF-1 and -catenin in NIH 3T3 cells augmented reporter gene activity by a factor of 14 relative to the level observed with expression of LEF-1 alone (Fig. 1B). This transcriptional activation is
independent of a Wnt signal, consistent with a role for -catenin as
a downstream component of the Wnt signaling pathway.
Identification of amino acids in LEF-1 that are important for
association with -catenin.
Association assays in a yeast
two-hybrid system and in glutathione S-transferase pull-down
experiments have indicated that the amino-terminal 56 residues of LEF-1
are necessary and sufficient for mediating the interaction with
-catenin (2, 22). The amino terminus of LEF-1 is highly
conserved among members of the LEF-1/TCF family in various species
(Fig. 2A). To further define the
-catenin interaction domain of LEF-1, we used site-directed mutagenesis to introduce point mutations into the amino terminus of the
protein (Fig. 2B). We examined the interaction of purified recombinant
-catenin with in vitro-translated wt and mutant LEF-1 polypeptides
in an electrophoretic mobility shift assay, with a radiolabeled LEF-1
binding site as a DNA probe. Incubation of -catenin with wt LEF-1
yielded a complex that migrated at a lower mobility than that of the
complex generated with LEF-1 alone, consistent with the formation of a
ternary complex (Fig. 2C, lanes 3 and 4). In contrast, the formation of
a ternary complex was not observed with the LEF-1 deletion mutant
56, in which the -catenin interaction domain had been removed,
although this deletion did not alter DNA binding by LEF-1 (lanes 5 and
6). The mutant LEF-1 proteins m1, m4, and m5 also failed to interact
with -catenin at detectable levels (lanes 7, 8, and 13 to 16),
whereas the mutations in m2 and m3 had no significant effect on the
association with -catenin (lanes 9 to 12). Together, these point
mutations define two distinct regions in the amino terminus of LEF-1
that are important for association with -catenin.
|
-catenin expression plasmids,
into Neuro2A cells, which contain low levels of endogenous -catenin.
The LEF-1 mutations in m1 and m4 reduced transcriptional activation by
a factor of 10 and 3, respectively. Transcriptional activation was not
detected with the double mutant m5 and the deletion mutant 56. Thus,
the potential of LEF-1 to interact with -catenin correlates with
transcriptional activation, although the effects of the m1 and m4
mutations in the transfection assays are less pronounced than those
observed in the association assays in vitro. The molecular basis for
this difference is unclear, but these observations raise the
possibility that modifications or additional factors may contribute to
the transcriptional activation by LEF-1 and -catenin in vivo.
Nuclear translocation of -catenin in response to Wnt-1
signaling.
Overexpression of -catenin and LEF-1 results in
nuclear translocation of -catenin (2, 22). To examine
whether the expression of LEF-1 is sufficient for the nuclear
translocation of endogenous -catenin, we performed indirect
immunocytochemistry on NIH 3T3 cells that had been transfected with
LEF-1 (Fig. 3A, first panel). Antibodies
directed against LEF-1 detected strong nuclear expression of LEF-1 in
transfected cells, whereas anti--catenin antibodies detected
-catenin only in the cytoplasm, even in cells that contained nuclear
LEF-1. In contrast, expression of Wnt-1 resulted in nuclear localization of -catenin in cells that expressed LEF-1 (Fig. 3A,
second panel). Nuclear -catenin was not detected in control cells
that were transfected with Wnt-1 alone (data not shown). To confirm the
specificity of nuclear translocation of endogenous -catenin in
response to Wnt signaling, we expressed the mutant m1 LEF-1 protein,
alone or in combination with Wnt-1. In cells expressing the mutant
LEF-1 protein, a markedly reduced nuclear accumulation of -catenin
was observed in the presence of a Wnt-1 signal (Fig. 3A, third and
fourth panels). Thus, expression of LEF-1 and a Wnt-1 signal are both
required for the nuclear localization of endogenous -catenin.
|
-catenin can collaborate with LEF-1 to
activate transcription in the absence of nuclear -catenin, we
generated a fusion protein in which the transmembrane protein CD8 was
linked to the amino terminus of -catenin (see below and Fig. 5A and
B). This fusion protein also contains a hemagglutinin (HA) epitope tag
at the carboxyl terminus. Expression of the CD8--catenin fusion
protein together with LEF-1 stimulated the expression of a LEF-CAT
reporter gene in Neuro2A cells to a level three- to fivefold higher
than that observed with wt -catenin (see below and Fig. 5C).
For immunocytochemical analysis of the subcellular localization of
CD8--catenin and endogenous -catenin in transfected NIH 3T3
cells expressing LEF-1, we used an anti-CD8, anti--catenin, or
anti-HA antibody (Fig. 3B). With the anti-CD8 antibody, we detected
abundant expression of the fusion protein at the plasma membrane (Fig.
3B, first panel), whereas with the anti--catenin antibody,
-catenin was also found in the nucleus of cells expressing LEF-1
(Fig. 3B, second panel). The -catenin detected in the nucleus of
these cells could represent either a proteolytic degradation product of
the CD8--catenin fusion protein or alternatively endogenous -catenin. However, nuclear staining was not detected with the anti-HA antibody (third panel). This observation suggests that expression of a membrane-tethered form of -catenin can result in
nuclear localization of endogenous -catenin in cells expressing LEF-1.
Signaling by Wnt-1 has been shown to increase the free cytosolic pool
of -catenin (49). To examine the accumulation of endogenous -catenin in response to either Wnt-1 signaling or the
expression of the CD8--catenin fusion protein, we performed an
immunoblot analysis with cytosolic lysates from transfected NIH 3T3
cells. In cells transfected with a Wnt-1 expression plasmid, the level
of endogenous cytosolic -catenin was significantly increased
relative to the level observed in cells transfected with vector DNA
(Fig. 4A). Notably, a similar increase in
the level of cytosolic -catenin was detected in cells expressing the
CD8--catenin fusion protein. The molecular mass of -catenin that
accumulated at high levels in cells expressing the fusion protein was
identical to that of endogenous -catenin, suggesting an increase in
the pool of free endogenous -catenin rather than accumulation of a
degradation product of the fusion protein. We also determined the
amount of total cellular -catenin and found that it was similar for
all lysates examined (Fig. 4B). Thus, the increase in the pool of
cytosolic -catenin correlates with the immunological detection of
-catenin in the nucleus and transcriptional activation by LEF-1.
This can occur either naturally in response to Wnt signaling or
artificially as a consequence of the presence of a membrane-tethered
-catenin.
|
-Catenin contains two transcriptional activation domains.
Mutations in the amino terminus of -catenin (74) and
mutations in the -catenin-interacting protein APC (41,
59) increase the pool of free -catenin in the absence of Wnt
signaling. To examine whether a constitutive increase in the pool of
free -catenin alters transcriptional activation by LEF-1, we deleted
the amino terminus of -catenin (N) or generated a DP form of
-catenin by mutating serine residues that have been previously shown
to affect protein stability (74) (Fig.
5A). Immunoblot analysis of cytosolic
extracts from COS cells transfected with wt or mutant -catenin
expression plasmids indicated a higher abundance of the mutant forms of
-catenin than of the wt protein (Fig. 5B). In transfection
experiments with Neuro2A cells, the mutant DP and N -catenins
augmented transcription by LEF-1 to a significantly larger extent (up
to 10-fold) than did wt -catenin (Fig. 5C).
|
-catenin contains
sequences that mediate transcriptional activation. In particular, the
carboxyl terminus of armadillo, the Drosophila ortholog of -catenin, has been shown genetically to be involved in signaling by
wingless (51). Moreover, the carboxyl-terminal region of -catenin functions as a transcriptional activation domain in fusion
with the GAL4 DNA-binding domain (69). To examine whether the carboxyl terminus of -catenin is the sole determinant for transcriptional activation in association with LEF-1, we generated the
deletion mutant C (Fig. 5A). Expression of this mutant -catenin with LEF-1 in transfected Neuro2A cells stimulated the activity of the
LEF-CAT reporter gene to a level similar to that with the wt
-catenin (Fig. 5C). Since this deletion removed the epitope recognized by the anti--catenin antibody, we could not compare the
accumulation of the mutant protein to that of the wt protein. Nevertheless, the data suggest that -catenin may contain additional sequences that contribute to transcriptional activation. Alternatively, overexpression of exogenous forms of -catenin may result in an increase in the pool of free cytosolic endogenous -catenin which would obscure the mapping of transcriptional activation domains.
To identify transcriptional activation domains in -catenin, we
generated fusion proteins in which various portions of -catenin were
linked to the GAL4 DNA-binding domain. Expression of GAL4 fusion
proteins containing the amino- or carboxyl-terminal region of
-catenin stimulated transcription of a GAL-CAT reporter gene in
transfected Neuro2A cells by a factor of 8 or 14, respectively (Fig.
6A). In comparison, a 50-fold activation
of the reporter gene was observed with a GAL4-VP16 expression plasmid
in which the transcriptional activation domain of the viral protein
VP16 is linked to GAL4 as a positive control. We confirmed a similar accumulation of both GAL4--catenin fusion proteins by
electrophoretic mobility shift assays with nuclear extracts from COS
cells transfected with the corresponding expression plasmids (Fig. 6B).
Thus, -catenin contains two distinct transcription activation
domains that can function in a heterologous context. However, the
levels of transcriptional activation by the GAL4--catenin fusion
proteins are significantly lower than those observed in cotransfections
of Neuro2A cells with LEF-1 and -catenin, raising the possibility
that the transcriptional activation domains of -catenin collaborate
with one another or with LEF-1.
|
Functional collaboration between LEF-1 and the activation domains
of -catenin.
The association of -catenin with LEF-1 could
simply serve to tether the transcriptional activation domains of
-catenin to specific sites in DNA. Alternatively, the
transcriptional activation domains of -catenin could collaborate
with other regions in LEF-1 to regulate transcription. To distinguish
between possibilities, we linked the amino- or carboxyl-terminal
domains of -catenin to either full-length LEF-1 (catN-LEF and
catC-LEF) or the HMG domain of LEF-1, which mediates DNA binding
(catN-HMG and catC-HMG [Fig. 7A]). We
examined the steady-state accumulation and DNA binding abilities of
these fusion proteins by transient transfection of COS cells and
electrophoretic mobility assays of nuclear extracts (Fig. 7B).
Protein-DNA complexes that migrated with different mobilities
corresponding to the relative molecular masses of the fusion proteins
were detected. The levels of the complexes containing LEF-1 or the
-catenin-LEF fusion proteins were similar but were slightly lower
than those of the complexes containing the -catenin-HMG fusion
proteins. The specificity of DNA binding by these complexes was
confirmed by competition experiments with excess unlabeled LEF-1
binding site oligonucleotide (data not shown).
|
-catenin-LEF-1 fusion
proteins was detected, although the level of activation by the catC-LEF
protein was approximately twofold higher than that by the catN-LEF
protein (Fig. 7C). Notably, transcriptional activation by the catN-HMG
and catC-HMG proteins was reduced by factors of 9 and 12 relative to
the corresponding -catenin-LEF fusion proteins. In comparison, a
fusion protein in which the VP16 activation domain was linked to the
HMG domain stimulated the reporter gene at levels only twofold lower
than those observed with a VP16-LEF-1 fusion protein. A fusion protein of glutathione S-transferase and full-length LEF-1 was used
as a negative control and did not result in transcriptional activation (data not shown). To rule out that endogenous -catenin can interact with the -catenin-LEF fusion proteins, we also examined
transcriptional activation by a chimeric protein in which the
carboxyl-terminal domain of -catenin was linked to the 56 LEF-1
protein (catC-LEF56). The level of transcriptional activation was
comparable to that observed with the catC-LEF protein. Taken together,
these data suggest that the transcriptional activation domains of
-catenin can functionally collaborate with protein domains of
DNA-bound LEF-1 to stimulate transcription.
Distinct regulatory properties of LEF-1 in association with
-catenin and ALY.
In response to Wnt signaling and association
with -catenin, LEF-1 can activate transcription from a synthetic
enhancer containing multimerized binding sites. In contrast, LEF-1 has
been shown to activate the natural TCR enhancer in a specific
context of other transcription factors (8, 14, 68, 72). In
the TCR enhancer, LEF-1 collaborates with the lymphoid-specific
proteins AML-1 and Ets-1 and with the ubiquitous protein CREB (15,
32). The potential of LEF-1 to activate the TCR enhancer is
further augmented by the protein ALY, which associates with the
context-dependent activation domains of LEF-1 and AML-1 (6).
Thus, the question arises as to whether the LEF-1-interacting proteins
ALY and -catenin play overlapping or distinct roles in
transcriptional activation and Wnt signaling.
-catenin,
we expressed the wt or the m1 mutant LEF-1 protein, alone or in
combination with Wnt-1 (Fig. 8A). In
transfected NIH 3T3 cells, the m1 mutation, which impairs association
of LEF-1 with -catenin in vitro (Fig. 2), abrogated transcriptional
activation by LEF-1 in response to Wnt signaling. We also examined
whether ALY, by itself or in combination with -catenin, could
modulate the function of LEF-1. Using a LEF-CAT reporter gene in
transfected Neuro2A cells, we found that ALY neither stimulated
transcription by LEF-1 alone nor altered its activation potential in
combination with -catenin (Fig. 8B).
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enhancer. The function of the TCR enhancer
in HeLa cells was reconstituted by transfecting expression plasmids
encoding AML-1, Ets-1, and LEF-1. Expression of wt LEF-1 protein
augmented the activity of the enhancer to a similar extent as did
expression of mutant LEF-1 protein (Fig. 8C). We further compared the
regulation of the TCR enhancer by LEF-1 in association with ALY with
that by LEF-1 in association with -catenin. As anticipated from
previous experiments (6), LEF-1, in combination with ALY,
augmented the activity of the enhancer by a factor of 14 (Fig. 8D).
This transcriptional activation was not significantly changed by using
the mutant m1 LEF-1 protein or by coexpression of -catenin. In
contrast, a fourfold stimulation of the TCR enhancer was observed
with LEF-1 alone or in combination with -catenin. Notably, ALY and
-catenin appear to act independently to modify the function of
LEF-1, and both proteins interacted with LEF-1 independently of each
other in an in vitro association assay (data not shown). Taken
together, these data suggest that LEF-1 can exert at least two distinct
regulatory roles. In association with -catenin, LEF-1 can mediate
transcriptional activation in a context-independent manner, whereas in
association with ALY, LEF-1 regulates transcription only in a
particular context of other proteins.
| |
DISCUSSION |
|---|
|
Top
Abstract
Introduction
Materials & Methods
Results
Discussion
References
|
|---|
In this study, we examine the transcriptional regulation by LEF-1
in response to a Wnt-1 signal under conditions of normal endogenous
-catenin expression. We find that that Wnt signaling augments
transcriptional activation by LEF-1 in association with -catenin and
show that a Wnt signal is necessary but not sufficient for the nuclear
localization of endogenous -catenin. We have identified amino- and
carboxyl-terminal activation domains in -catenin whose function is
specifically augmented by juxtaposition with LEF-1 but not with the
DNA-binding domain of LEF-1, suggesting a reciprocal interaction
between these proteins. Finally, we show that association of LEF-1 with
different proteins, -catenin and ALY, confers distinct regulatory
properties upon LEF-1.
In the NIH 3T3 tissue culture model, we find that endogenous
-catenin is localized in the nucleus only in cells that both express
LEF-1 and receive a Wnt-1 signal, or in cells in which an artificial
membrane-tethered form of -catenin is present. However,
overexpressed -catenin is localized to the nucleus of Neuro 2A or
NIH 3T3 cells that express LEF-1, independent of a Wnt signal
(2, 22; also data not shown). Thus, expression of
LEF-1 may result only in nuclear localization of free -catenin which
is generated either by activation of the Wnt signaling pathway or by
overexpression of -catenin. Likewise, overexpression of Wnt-1 in a
mammary epithelial cell line leads to the formation of a nuclear
complex between -catenin and TCF-4 protein (27). None of
these data, however, bear on the mechanism by which -catenin is
translocated into the nucleus. -Catenin could either associate with
newly synthesized LEF-1 protein in the cytoplasm, resulting in nuclear
translocation via LEF-1, or alternatively be translocated by other
means into the nucleus and accumulate through association with LEF-1.
Recently, -catenin has been shown to be imported into the nucleus by
binding directly to the nuclear pore complex, similar to importin
-like factors, suggesting that -catenin localizes to the nucleus
independently of interaction with LEF-1/TCF proteins (12).
The stimulation of transcription by LEF-1 in collaboration with a
membrane-tethered form of -catenin raises the question of the
mechanism of stimulation of transcription by LEF-1. In cells expressing
both the CD8--catenin fusion protein and LEF-1, we detected a
significant amount of nuclear -catenin that has the molecular mass
of endogenous -catenin. Thus, overexpression of a membrane-tethered
-catenin may competitively liberate endogenous -catenin from
either E-cadherin or APC. Consistent with this interpretation,
expression of a membrane-tethered form of -catenin in
Xenopus embryos increases the pool of free -catenin that
is associated with APC rather than with E-cadherin (37).
This interpretation may also account for the observation that a
membrane-tethered form of plakoglobin induces neural axis duplication
in Xenopus embryos (35).
Nuclear -catenin has also been detected under conditions of
overexpression in vivo. For example, expression of a dominant negative
form of GSK3 in Xenopus embryos results in nuclear
localization of -catenin on the dorsal side of the embryo
(74). Likewise, TCF--catenin or LEF-1--catenin
complexes have been identified in nuclear extracts from mammalian cell
lines that either are defective in APC or carry mutations in the amino
terminus of -catenin, conditions which both result in accumulation
of endogenous free -catenin (41, 54, 59). In addition, a
small group of cells in the dorsalizing center of normal
Xenopus embryos contains nuclear -catenin
(61). However, to date, immunocytochemical analysis has
failed to detect nuclear -catenin in mouse embryos, even in cells
known to express LEF-1 or in tissues that show a developmental defect
in LEF-1-deficient mice, for example, tooth germs and hair follicles
(12a, 28, 71). Possibly, the techniques used are not
sensitive enough to detect small amounts of nuclear -catenin that
may suffice for a functional response in normal cells. Alternatively, only a small subset of yet-unidentified LEF-1-expressing cells may
contain nuclear -catenin.
Our functional analysis of point mutations in the -catenin
interaction domain of LEF-1 indicates that the transcriptional response
to Wnt signaling is dependent upon association of LEF-1 with
-catenin. Moreover, the ability of LEF-1 to interact with recombinant -catenin in vitro correlates with transcriptional activation by LEF-1 in response to a Wnt-1 signal in transfected NIH
3T3 cells. The mechanism of transcriptional activation by LEF-1--catenin complexes is still obscure. Consistent with previous reports (47, 54, 65), we identified a domain in the
carboxyl-terminal region of -catenin that mediates transcriptional
activation when fused to the GAL4 or LEF-1 DNA-binding domain. In
addition, we show that the amino-terminal 131 residues of -catenin,
which regulate protein stability (41, 43, 59, 74), can
confer transcriptional activation upon heterologous DNA-binding
domains. Unlike the prototypic transcriptional activation domain of
VP16, the function of both activation domains of -catenin is
significantly augmented by fusion with full-length LEF-1 compared to
fusions with the DNA-binding domain of LEF-1 or GAL4. This observation suggests that the transcriptional activation domains of -catenin functionally collaborate with specific domains in LEF-1. A
transcriptional activation domain which interacts with ALY and
activates transcription only in a specific context of other DNA-binding
proteins has been identified in a region between amino acids 99 and 256 of LEF-1 (6, 8, 14). However, the -catenin-LEF fusion
protein does not show a dependence on a specific context of other
transcription factors, and therefore, sequences in LEF-1 that are
distinct from this context-dependent activation domain may collaborate
with -catenin.
In principle, the activation domains of -catenin, when tethered to
LEF-1 by protein-protein interaction or by covalent protein fusion,
could augment transcription through direct interactions with components
of the basal transcription machinery. According to this view, the
association of -catenin with LEF-1 would generate a composite
transcriptional activation surface. Alternatively, the activation
domains in -catenin could stimulate transcription indirectly by
bringing LEF-1 to a particular compartment of the nucleus or by
recruiting enzymes that posttranslationally modify the complex with
LEF-1. Finally, -catenin could mediate interaction with other
transcription factors, although we consider this scheme unlikely
because LEF-1--catenin complexes can act at synthetic enhancers
containing only multimerized LEF-1 binding sites.
Are all effects of Wnt signaling mediated by LEF-1 and TCF proteins? In
Drosophila, mutations in the pangolin/dTCF gene suppress the
phenotype of constitutively activated armadillo (7, 69). This observation has been interpreted to suggest that all signaling by
wingless is mediated by the action of this transcription factor. However, signaling by Wnt proteins involves diverse physiological responses that include inductive and mitogenic events as well as
changes in cell adhesion and mitotic spindle orientation (10, 17,
21, 45, 57, 67). Wnt-1 signaling in mammalian cells can induce
cell growth and transcriptional activation by LEF-1 and TCF proteins
(27, 54, 75; also this study). Likewise, mutations
in APC or -catenin in colon carcinomas and melanomas correlate with
constitutively active TCF-4--catenin complexes (26, 41,
59). However some responses to Wnt signaling may be independent
of LEF/TCF--catenin complexes. For example, overexpression of
-catenin in Xenopus embryos can increase cell-cell
adhesion in the absence of zygotic transcription (17).
Moreover, a mutant form of -catenin (S37A), which can mediate
transcriptional activation of a LEF/TCF reporter gene in Rat-1 cells,
fails to elicit the proliferative response that is normally observed in
cells expressing wt -catenin or Wnt-1 (75). Finally, Wnt
signaling in C. elegans can induce changes in mitotic
spindle orientation and cytoskeletal polarity that are independent of
the -catenin-like protein WRM-1 (57, 67).
Different Wnt proteins may also elicit distinct physiological
responses. Cellular transformation assays in epithelial cells and axis
duplication assays in Xenopus suggest that the 16 currently known Wnt genes can be classified into at least two groups (reviewed in
reference 39). Xenopus Wnt-1, XWnt-8, and
other Wnt proteins can induce a secondary axis, whereas XWnt-5a and
related Wnt proteins decrease cell-cell adhesion but fail to induce a
secondary axis (10, 40). Although our data indicate that
signaling by Wnt-1 results in transcriptional activation by LEF-1 in
association with -catenin, we cannot extrapolate to a general
function of LEF-1/TCF protein in signaling by other Wnt proteins.
The association of -catenin with LEF-1 also raises the question of
whether this protein-protein interaction is obligatory for
transcriptional activation by LEF-1. Our study indicates that Wnt
signaling may not be required for all functions of LEF-1. The TCR
gene is a target for regulation by LEF-1 and TCF-1 in vivo because
experimentally induced mutations in both transcription factor genes in
the mouse result in a severe defect in endogenous TCR gene
expression in purified immature CD8 single positive T cells
(46). However, we found that regulation of the TCR enhancer by LEF-1, which is augmented by ALY, is independent of association with -catenin because mutations in the -catenin interaction domain of LEF-1 have no detectable effect on
transactivation. In contrast, LEF-1 can stimulate the activity of a
synthetic enhancer containing multimerized LEF-1 binding sites in
association with -catenin, but not with ALY. Thus, LEF-1 can assume
different regulatory functions in association with -catenin and ALY.
In association with ALY and in the context of the TCR enhancer, LEF-1 appears to play an architectural role in the assembly and function of a higher-order nucleoprotein complex in which DNA bending
and a context-dependent activation domain facilitate interactions between multiple DNA-binding proteins (6, 8, 13-15, 32). In
association with -catenin, LEF-1 can activate transcription independent of a specific context of other DNA-binding proteins.
Multiple target genes in which LEF-1/TCF proteins function in
collaboration with -catenin or armadillo have been recently identified. The Ubx enhancer in Drosophila contains a
functionally important binding site for LEF/TCF proteins, and
expression of LEF-1 in transgenic embryos regulates this enhancer in an
armadillo-dependent manner (56). Moreover, the regulation of
the Ubx gene is impaired in pangolin/dTCF-deficient embryos
(69). Recently, Wnt-responsive sequence elements in the
siamois and Xnr3 promoters of Xenopus have been found to be
regulated by LEF-1/XTCF-3 proteins in embryo injection assays (5,
34). Notably, the regulation of the wingless/Wnt response in
these systems is also dependent upon a particular context of other
transcription factor binding sites. The regulation of the Ubx enhancer
in response to wingless signaling requires a juxtaposition of the
LEF/TCF binding site with a response element for decapentaplegic
signaling (56). Likewise, the Wnt responsiveness of the Xnr3
promoter is dependent upon both a LEF/TCF binding site and a binding
site for a putative homeodomain protein (34). Thus, the
regulation of Wnt-responsive target genes by LEF/TCF proteins in vivo
may require a specific context of transcription factor binding sites.
Wnt signaling has the interesting property of collaborating with other
signaling pathways such as sonic hedgehog, fibroblast growth factor,
activins, and others (39). The ability of LEF-1 to function
as an architectural protein that stimulates transcription only in
collaboration with other proteins may contribute to the integration of
signaling pathways and allow for diversity in the transcriptional
response.
| |
ACKNOWLEDGMENTS |
|---|
We thank W. Birchmeier for providing human -catenin cDNA and
Neuro2A cells, and we are grateful to Jackie Papkoff for providing cytomegalovirus-Wnt-1. We also thank Jan Kitajewski for communicating results prior to publication and Danesh Moazed, Tannishtha Reya, and
Mary O'Riordan for their helpful comments on the manuscript. We thank
members of the Grosschedl laboratory for valuable discussions.
This work was supported by the Howard Hughes Medical Institute. Shu-Chi Hsu was supported by a postdoctoral fellowship from the Leukemia Society of America.
| |
FOOTNOTES |
|---|
* Corresponding author. Mailing address: Howard Hughes Medical Institute, Departments of Microbiology and Biochemistry, University of California, San Francisco, CA 94143-0414. Phone: (415) 476-6954. Fax: (415) 476-8201. E-mail: rgross{at}itsa.ucsf.edu.
| |
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Abstract
Introduction
Materials & Methods
Results
Discussion
References
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