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Institut de Génétique et de Biologie Moléculaire
et Cellulaire (E.L., B.B., E.Z., J-M.W., D.M., P. S-C.) 67404
Illkirch-Strasbourg, France
Biologia Generale e Genetica
Medica (B.B.) Università di Pavia 27100 Pavia, Italy
Abteilung für Pädiatrische Genetik (T.M.S.)
Kinderpoliklinik der Ludwig Maximilians Universität 80336,
München, Germany
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONRESULTSDISCUSSIONMATERIALS AND METHODSREFERENCES |
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V269)
found in adrenal hypoplasia patients impair silencing. These findings
suggest that transcriptional silencing by DAX-1 plays a critical
role in the pathogenesis of adrenal hypoplasia congenita. |
INTRODUCTION |
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TOPABSTRACTINTRODUCTIONRESULTSDISCUSSIONMATERIALS AND METHODSREFERENCES |
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The DAX-1 protein has an unusual structure. The N-terminal portion can be divided into three repeats of a 65- to 67-amino acid (aa) motif and a fourth incomplete repeat. Extensive search has revealed no sequence similarity between this domain and other known protein sequences. The DAX-1 C terminus shares significant homology to the ligand-binding domain (LBD) of some members of the nuclear hormone receptor superfamily (2).
Recently we have shown that DAX-1 binds to DNA hairpin structures and blocks steroidogenesis in adrenal cells by inhibiting the expression of the steroidogenic acute regulatory protein (StAR) (6). Here we show that the DAX-1 C-terminal domain is endowed with transcriptional silencing activity. This property is restricted to a subset of the members of the nuclear hormone receptor superfamily: the thyroid hormone receptor (TR) and the related oncogene product v-erbA, retinoic acid receptor (RAR), and the chicken ovalbumin upstream promoter transcription factor (COUP-TF) (7, 8). Silencing domains in nuclear receptors are located in the C terminus of the protein (corresponding to the LBD). They function in the absence of ligand and have a modular nature, since they can be transferred to a heterologous DNA-binding domain. It has recently been shown that nuclear receptor ligand-independent silencing activity is mediated by the recruitment of corepressor factors termed TRACs (TR- and RAR-associated corepressors) (9, 10, 11).
Here we present a structural model of the
DAX-1-silencing domain, based on the homology with the ligand-binding
domain of apo-RXR
and holo-RAR
(12, 13). The DAX-1-silencing
domain is bipartite in its nature, since the integrity of the
-helical modules H12 and H3 is required for its function. We show
that two different single amino acid mutations, responsible for the AHC
phenotype, abolish DAX-1-silencing activity. Our findings indicate that
a direct relationship exists between the loss of DAX-1 transcriptional
repression and AHC. Importantly, all DAX-1 mutations found in AHC
patients have the common feature to alter its C terminus.
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RESULTS |
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TOPABSTRACTINTRODUCTIONRESULTSDISCUSSIONMATERIALS AND METHODSREFERENCES |
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, which has about 35% similarity with DAX-1 C terminus,
has recently been solved (12). Based on apo-RXR and holo-RAR (13)
structures, which have defined the existence of a common fold for the
LBD of nuclear receptors (14, 15), and on the alignments of the
sequences of human DAX-1 (2) and mouse Dax-1 (16), we have
been able to identify in DAX-1 C terminus the domains corresponding to
-helices 1–12, which represent the hallmark of the nuclear receptor
LBD structure (H1–12; Fig. 1
).
Surprisingly, we have found that helix H1 encompasses the region
previously defined as the last and incomplete repeat. In the light of
this finding, we have reconsidered our view of the DAX-1 structure.
Indeed, the three highly conserved repeats in the N terminus are
followed by a short stretch of five residues linking the third repeat
to H1. The structure of the human DAX-1 C terminus, based on the model
defined for apo-RXR and holo-RAR, is presented in Fig. 2. Structural analysis of various LBDs
has shown that H1 is an integral part of the hormone-binding domain
(15), contacting H3, H5, and H8. The residues involved in H1 contacts
follow two alternative patterns: [(I,L)lx(A,I)Exx] in RXRs and
steroids receptors and [hxcAHxxT] in the RAR/TR subgroup (c, charged;
l, long side-chain; h, hydrophobic; x, any amino-acid residue).
In both cases, residues contained in the pattern anchor H1 to the LBD
core (15). The first hydrophobic residue (V193 in hRAR; I235 in
hRXR) is buried and forms key contacts together with the adjacent
histidine (H197 in hRAR) or glutamate (E239 in hRXR). This last
glutamate forms a buried salt bridge with R371 in H8 of hRXR. In
hDAX-1, the residue corresponding to hRXR R371 (S332 in hRAR) is
a lysine (K382). This suggests the presence of a RXR-like pattern for
DAX-1 in H1. The pattern identified in DAX-1 is [(V,T)Sx(N,D)Qxx],
and the deeply buried glutamate forming the salt bridge with the lysine
in H8 is predicted to be located in H5 (E298). This glutamate residue
corresponds to a serine in hRXR and to an arginine in hRAR, which
both point to the H197 and E239 in H1 of hRXR and hRAR,
respectively. The residue preceding this histidine and glutamate in the
H1 pattern is an alanine, which is in close contact with an arginine at
the end of H3 (R246 as in hRAR). This arginine is highly conserved
among many members of the nuclear receptor superfamily. In DAX-1, this
residue is replaced by a tyrosine (Y271 in hDAX-1), and either an
asparagine or an aspartate (N221 in hDAX-1) are substituted for the
alanine in the H1 pattern.
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and 2), which lies in the proximity of the predicted ligand-binding
pocket. This insertion represents an outstanding feature of DAX-1,
being absent in hRAR, in hRXR, and in most other members of the
nuclear receptor superfamily. The conservation of this insertion in
both human and mouse sequences suggests that it can play a relevant
role for DAX-1 function. Since structural predictions of loops whose
length is greater than about 10 residues are most likely to be
inaccurate, we have chosen to replace it in Fig. 2 by a residue stretch
similar in length to the hRAR loop 6–7.
Another remarkable feature of DAX-1 is a conserved amphipathic
-helix motif in H12, whose integrity has been shown to be essential
for the function of the ligand-dependent AF-2 activation domain of
other nuclear receptors (17, 18).
Intriguingly, all mutations in AHC patients have the common
feature to alter DAX-1 C terminus. Most of these mutations are
deletions, nonsense and frameshift mutations in the coding sequence
(2, 3, 4, 5). Two AHC patients present single amino acid changes (3). Both
mutations reside in the N-terminal portion of the putative LBD; in one
case arginine 267 is replaced by proline (3), while in the other
case a 3-bp deletion suppresses valine 269, leaving the remainder of
the sequence in frame (3). Structure prediction localizes the sites of
these mutations in H3, inside (V269) or immediately adjacent (R267) to
the conserved hydrophobic residues belonging to the core of the nuclear
receptor structure (Fig. 2).
The C Terminus of DAX-1 Possesses Transcriptional Silencing
Activity
We have recently shown that DAX-1 represses StAR promoter
activity in Y-1 mouse adrenal cells (6). Repression is dependent on the
presence of a hairpin secondary structure, which functions as the
DAX-1-binding site, in the StAR promoter (located between positions
-61 and -27 in the human StAR promoter), and results in a complete
block of steroid production in Y-1 cells stably transfected with human
DAX-1 (6). To assess the impact that the R267P and V269 mutations
have on DAX-1 transcriptional properties, we have studied the effect of
DAX-1 proteins harboring these mutations on StAR promoter activity in
Y-1 cells. While wild type DAX-1 efficiently represses both basal and
forskolin-stimulated StAR promoter expression, the presence of either
mutation in DAX-1 results in impairment of the repression effect (Fig. 3a). This cannot be accounted for by
differences in DNA binding, since both mutant proteins bind with
comparable affinity as wild type DAX-1 to the StAR promoter hairpin
structure (Fig. 3b). The mutated proteins are expressed at levels
comparable to the wild type DAX-1 in transfected cells (Fig. 3c).
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V269 mutations
may affect this property.
A Bipartite Silencing Domain in DAX-1
To identify the domains essential for transcriptional silencing in
DAX-1, a series of deletions of its C terminus (aa 207–470) was
produced and fused in-frame to the yeast GAL4 DNA-binding domain (aa
1–147). In addition, GAL4/DAX-1 fusion constructs containing either
the R267P or the V269 mutation were generated, as well as constructs
where R267 and V269 were replaced by an alanine residue (Fig. 4). The effect of these mutated DAX-1
proteins on transcription driven by two different basal promoters
[herpes simplex virus (HSV) thymidine kinase (tk) and rabbit
ß-globin promoters] was measured in two cell lines, mouse
L tk- fibroblasts and Y-1 adrenal tumor cells.
All GAL4/DAX-1 fusion proteins are expressed at similar levels in
transfected cells and bind to the cognate 17 mer sequence with
comparable affinities (data not shown).
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). Conversely, the tk promoter is
silenced less efficiently (
10-fold) by G4D 207–470 in L
tk- cells and poorly (3-fold) in Y-1 cells (Fig. 5).
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).
When N-terminal deletions of G4D 207–470 were examined, we observed
that deletion of aa 207–244, corresponding to the predicted H1 and to
part of the loop between H1 and H3, significantly reduces silencing of
the ß-globin promoter in Y-1, but not in L tk- cells.
Considering the poor repression activity of G4D 207–470 on the tk
promoter in Y-1 cells, it is difficult to evaluate the effect of G4D
245–470 in this context. Conversely, no loss of silencing activity of
the tk promoter by G4D 245–470 was detected in L tk-
cells. G4D 272–470 and mutants with deletions spanning further in the
N terminus display loss of silencing (Fig. 5).
Introduction of the R267P and V269 mutations into G4D 245–470
results in complete loss of silencing of both the tk and the ß-globin
promoters in L tk- cells and of the ß-globin promoter in
Y-1 cells. It was not possible to assess the effect that these
mutations have on silencing of the tk promoter in Y-1 cells since, as
already mentioned, G4D 245–470 has negligible effect on the activity
of this promoter in this cell type. We have also generated additional
mutations at positions 267 and 269. While alanine substitution of R267
has no effect on silencing activity, mutation of V269 into alanine
results in complete loss of silencing (Fig. 5).
Recruitment of Corepressors
The ligand-independent silencing effect of TR and RAR has been
shown to be mediated by the interaction of their LBDs with corepressor
molecules termed TRACs (9, 10, 11). Cotransfection of expression vectors
encoding either TR and RAR causes the recovery of basal promoter
expression silenced by unliganded GAL4/TR and GAL4/RAR (19). This
phenomenon is believed to be produced by titration of cellular
corepressors.
When full-length DAX-1 is cotransfected together with G4D 245–470,
attenuation of tk promoter silencing is observed (Fig. 6, a and b). This result implies that the
mechanism of transcriptional repression by DAX-1 involves interaction
with a corepressor molecule or a component of the basal transcriptional
machinery. Significantly, R267P and V269 DAX-1 mutants are unable to
relieve silencing by G4D 245–470 (Fig. 6b), suggesting that the
impaired repression activity of these mutants can be accounted for by a
less efficient interaction with corepressor molecules than the DAX-1
wild type protein.
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does not relieve silencing by G4D 245–470 (Fig. 6, a and b). This result suggests that transcriptional repression
caused by the DAX-1 C terminus may involve interaction with different
molecules than the TRAC corepressors that have been described to
interact with TR and RAR in the absence of ligand. |
DISCUSSION |
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TOPABSTRACTINTRODUCTIONRESULTSDISCUSSIONMATERIALS AND METHODSREFERENCES |
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V269, located in the predicted
H3, abolish DAX-1-silencing function, either in the context of the
natural protein (Fig. 3) or when the C terminus is fused to a
heterologous DNA-binding domain (Fig. 4). Remarkably, substitution of
R267 with alanine has no effect, while alanine replacement of V269
causes loss of silencing (Fig. 4). While deletion or mutation of V269
is likely to affect the stability of the conserved hydrophobic core
(12, 13, 14, 15), R267 is predicted to be exposed on H3 surface (Fig. 2). Here
we show that residues of different nature (charged vs.
hydrophobic) can occupy this position without producing loss of
transcriptional silencing, indicating that the effect of the R267P
mutation is probably due to distortion in the spatial arrangement of
the final portion of H3. Unliganded RAR and TR, as well as the orphan receptor COUP-TF, act as transcriptional repressors (7, 8); the domain responsible for their silencing function resides in the C terminus, corresponding to the LBD (7, 8). v-erbA and kindred S TR are variants of TR harboring mutations in their C terminus that impair hormone binding but that do not affect silencing activity (7, 20). Constitutive silencing by v-erbA and kindred S TR is believed to be important in the pathogenesis of erythroid transformation and generalized thyroid hormone resistance, respectively (21, 20). Remarkably, all mutations in DAX-1 causing AHC/HHG reported to date have, as a common feature, the production of C-terminally modified proteins (2, 3, 4, 5). Based on our deletion analysis, the result is invariably the impairment of transcriptional silencing by DAX-1. This represents a novel example of loss of transcriptional repression by a member of the nuclear receptor superfamily associated with a pathological situation.
Our analysis shows that DAX-1 contains a transferable silencing domain that is able to repress the activity of various promoters, when appropriately tethered in their vicinity. This finding may be relevant to the understanding of the pathogenetic mechanism of AHC/HHG. Indeed, it is likely that DAX-1 modulates the expression of a set of genes involved in adrenal gland development. Some of these genes may be distinct from those whose expression is characteristic of the differentiated steroidogenic function of the adrenal cortex (i.e. StAR). Our data show that promoters containing a diverse array of elements supporting basal transcription can be a target for regulation by DAX-1. Several studies in Drosophila demonstrated the importance of transcriptional repressors in regulating developmental cascades. For example, even-skipped is a homeodomain protein genetically defined as a repressor of segmentation-controlling genes (22), and the ecdysone-induced orphan receptor E75B regulates metamorphosis by repressing the function of another orphan receptor, DHR3 (23). DAX-1 provides one of the rare known examples of mammalian transcriptional repressors whose loss of function is associated with a congenital disease. Another case is represented by the WT1 tumor suppressor gene. A point mutation in a WT1 allele still present in a patient affected by WAGR (Wilms’ tumor, aniridia, genitourinary malformations and mental retardation) syndrome has been described (24), which converts glycine 201 into aspartic acid. The consequence is the transformation of the product encoded by the mutated WT1 allele from a transcriptional repressor into an activator (24).
The variable degree of silencing by the DAX-1 C terminus, depending on
the promoter and cell type, represents functional evidence that
additional factors are needed to mediate repression by DAX-1. These
might belong to the family of corepressor factors (TRACs) that are able
to form a complex with unliganded TR/RXR and RAR/RXR heterodimers
(9, 10, 11). Corepressors are released when specific ligands bind to the
receptors, allowing recruitment of coactivators (11). Multiple modes of
interaction of unliganded nuclear receptors with TRAC corepressors
exist (9, 10, 25). DAX-1, however, lacks sequence similarity with
motifs that have been shown to be required for interaction of TR/RAR
(9, 10) and RevErb (25) with corepressors. In addition, repression by
G4D 245–470 can be relieved by cotransfected DAX-1, but not RAR
(Fig. 6), suggesting that distinct factors are required to mediate
silencing by DAX-1. The abundance of these mediating factors might
possibly vary according to the cell type. The particular promoter
structure might also influence the efficiency of their recruitment,
depending on the specific set of transcription factors bound to the
promoter. This could explain the difference in silencing efficacy of
the tk promoter by G4D 207–470 in L tk- as compared with
Y-1 cells. In addition, our data suggest that H1 sequences, which are
absent in G4D 245–470, can significantly increase the availability of
mediating factors to the DAX-1-silencing domain when they are either
present in limiting amounts or inefficiently recruited to the
promoter.
Recent results indicate a direct and specific in vitro interaction between the transactivator SF-1 and DAX-1 (26). While analogous in vitro results have been obtained in our laboratory, we have not been able, by using several experimental approaches, to demonstrate an in vivo interaction between SF-1 and DAX-1 (Ref. 6 and our unpublished results). On the other hand, we have shown that DAX-1-mediated repression of both the dax-1 and the StAR promoters is dependent on specific binding of DAX-1 to DNA hairpin structures (6). It is conceivable that SF-1 and DAX-1 association may be possible in vitro under some experimental conditions that do not exist in physiological situations. It is also possible that tissue-specific bridging factors may exist that could facilitate SF-1 and DAX-1 association.
In conclusion, one mechanism by which DAX-1 exerts transcriptional repression is the recruitment of a powerful silencing domain to target promoters via binding to hairpin DNA structures (6). Due to the presence and conservation in the DAX-1 C terminus of a potential AF-2 domain, it is still possible that a ligand may induce a switch in DAX-1 function from a repressor to an activator.
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MATERIALS AND METHODS |
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TOPABSTRACTINTRODUCTIONRESULTSDISCUSSIONMATERIALS AND METHODSREFERENCES |
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(hRXR) and liganded human
RAR (hRAR) crystal structures, combined with sequence analysis.
In this respect DAX-1 exhibits about 20% and 16% sequence identity
and 35% and 29% sequence similarity with hRXR and hRAR,
respectively. In DAX-1 the conserved regions (from helix H3 to H5 and
from helices H7 to H11) are clearly identified, and, in addition, DAX-1
also has a conserved C-terminal amphipathic -helical domain (helix
H12). We could clearly identify the conserved regions among nuclear
receptors, which constitute the anchoring points on which the model
relies. The conserved regions identified suggest that the fold is
conserved and that a good starting model can be obtained, except
for the loop 6–7 region. The loop 6–7 in DAX-1 is a rather long loop
(30 amino acids) that cannot be modeled reliably. The importance of the
loop 6–7 for DAX-1 structure and function requires further
investigation. In the absence of any three-dimensional (3D)
experimental data, we preferred not to include the loop in the model,
as it brings no further information concerning the mutants discussed.
Structural modeling was performed according to the sequence alignment
shown in Fig. 1 and taking the liganded hRAR crystal structure (13)
as a landmark. To obtain the final model, we first minimized the
structure obtained from Modeller with the CHARMM package (MSI Inc., San
Diego, CA). The minimization is conducted in two steps, each consisting
of 1000 steps of the Powell algorithm. The C atoms were first
restrained by a harmonic potential of 30 kcal/Å2 and then
released to give the final structure. The united atom force field was
used. The final structure was then analyzed with PROCHECK (29), which
shows that more than 90% of the residues in the Ramachandran plot are
in the most favored regions and that main-chain and side-chain
parameter statistics are inside the range of or better than the
statistics derived from crystal structures solved at a resolution of
2Å (data not shown). The quality/validity of the 3D model can also be
assessed by how well the DAX-1 sequence fits the native fold of the
hRAR crystal structure. The program PROSAII (version 3.0) (30) gives
a Z-score for Cß potentials of -4.2, which is in the range observed
for crystal structures of the same size (range from -4 to -9; hRAR
Z-score equal to -8.4 and hRXR Z-score equal to -6.9).
Plasmids
Construction of the pSG5-based human DAX-1 expression vector
(pSG.DAX-1) has been described (2). The DAX-1-coding sequence (from
position 3 to 1197 with respect to the translation start site) was
PCR-amplified from genomic DNA of patients 2115 (V269) and 2687
(R267P) (3). To insert each mutation into the wild type-coding
sequence, generating pSG.V269 DAX-1 and pSG.R267P DAX-1, the
amplified DNA was excised with BspEI-PvuII and cloned into
BspEI-PvuII-digested pSG.DAX-1.
The vector pG4MpolyII (31) was used to generate fusion constructs
between the sequence encoding for the yeast GAL4 (aa 1–147)
DNA-binding domain and various portions of the DAX-1 C terminus. DAX-1
sequences were PCR-amplified from plasmid pSG.DAX-1 using the
appropriate primers and cloned into the
KpnI-BamHI sites of pG4MpolyII. pG4D R267P and
pG4D V269 were constructed by PCR amplification of the sequence
encoding for aa 245–470 from pSG.R267P DAX-1 and pSG.V269 DAX-1,
respectively, and subsequent insertion into the
KpnI-BamHI sites of pG4MpolyII. PCR mutagenesis
was used to introduce the mutations R267A and V269A into pG4D 207–470.
Each plasmid was verified by sequencing.
DAX-1-, R267P DAX-1-, and V269 DAX-1-coding sequences were PCR
amplified from pSG.DAX-1, pSG.R267P DAX-1, and pSG.V269 DAX-1,
respectively, and cloned into pGEX 4T-3 (Pharmacia, Piscataway, NJ),
for glutathione-S-transferase (GST) fusion protein
expression. Each plasmid was verified by sequencing.
pGL1.3 kb StAR (32), 2x17mer-tk-chloramphenicol acetyltransferase (CAT) (33) (which has two GAL4 sites cloned upstream the -105/+51 HSV tk promoter), and 5x17mer-globin-luc (which has five GAL4 sites cloned upstream from the -109/+10 rabbit ß-globin promoter) were used as reporter plasmids in transient transfection assays.
DAX-1 Protein Expression in Escherichia coli and
Electrophoretic Mobility Shift Assay
These were performed according to the described methods (6, 25).
In the electrophoretic mobility shift assay, the labeled
oligonucleotide
5'-TTGCACAGTGAGTGATGGCGTTTTTAT-C-TCCTGATGATGATGCACAGCCTTCAGCGGGGGACAT-TTAAGACGCAGAA
-3', encompassing StAR promoter hairpin -67/-21 (6) was used as a
probe.
Protein Analysis
Western blotting was performed as described in Ref. 6, using the
anti-DAX-1 monoclonal antibody 2F4 raised in our laboratory for DAX-1
protein detection (6).
Transient Transfection Assays
Y-1 mouse adrenal cells were transfected by the calcium
phosphate method, as described previously (2, 6). L tk-
mouse fibroblast cells were transfected by the
diethylaminoethyl-dextran method (34). CAT and luciferase assays were
performed as described (6, 31).
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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E. L. was supported by a Telethon Italy Fellowship. B. B. was supported by an EMBO short term fellowship. This study was supported by grants from CNRS, INSERM, CHUR, Rhône-Poulenc Rorer (Bioavenir), and Association pour la Recherche sur le Cancer to P. S.-C.
Received for publication August 7, 1997. Revision received September 22, 1997. Accepted for publication September 25, 1997.
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A. SPAT and L. HUNYADY Control of Aldosterone Secretion: A Model for Convergence in Cellular Signaling Pathways Physiol Rev, April 1, 2004; 84(2): 489 - 539. [Abstract] [Full Text] [PDF]
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E. Lalli and P. Sassone-Corsi DAX-1, an Unusual Orphan Receptor at the Crossroads of Steroidogenic Function and Sexual Differentiation Mol. Endocrinol., August 1, 2003; 17(8): 1445 - 1453. [Abstract] [Full Text] [PDF]
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K. Kawajiri, T. Ikuta, T. Suzuki, M. Kusaka, M. Muramatsu, K. Fujieda, M. Tachibana, and K.-i. Morohashi Role of the LXXLL-Motif and Activation Function 2 Domain in Subcellular Localization of Dax-1 (Dosage-Sensitive Sex Reversal-Adrenal Hypoplasia Congenita Critical Region on the X Chromosome, Gene 1) Mol. Endocrinol., June 1, 2003; 17(6): 994 - 1004. [Abstract] [Full Text] [PDF]
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 S. G. Lehmann, J.-M. Wurtz, J.-P. Renaud, P. Sassone-Corsi, and E. Lalli Structure-function analysis reveals the molecular determinants of the impaired biological function of DAX-1 mutants in AHC patients Hum. Mol. Genet., May 1, 2003; 12(9): 1063 - 1072. [Abstract] [Full Text] [PDF]
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K. Tajima, A. Dantes, Z. Yao, K. Sorokina, F. Kotsuji, R. Seger, and A. Amsterdam Down-Regulation of Steroidogenic Response to Gonadotropins in Human and Rat Preovulatory Granulosa Cells Involves Mitogen-Activated Protein Kinase Activation and Modulation of DAX-1 and Steroidogenic Factor-1 J. Clin. Endocrinol. Metab., May 1, 2003; 88(5): 2288 - 2299. [Abstract] [Full Text] [PDF]
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P. Brown, G. A. Scobie, J. Townsend, R. A. L. Bayne, J. R. Seckl, P. T. K. Saunders, and R. A. Anderson Identification of a Novel Missense Mutation That Is as Damaging to DAX-1 Repressor Function as a Nonsense Mutation J. Clin. Endocrinol. Metab., March 1, 2003; 88(3): 1341 - 1349. [Abstract] [Full Text] [PDF]
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