Download Structure and Function of the Groucho Gene Family and Encoded

Proc. Natl. Sci. Counc. ROC(B)
Vol. 24, No. 2, 2000. pp. 47-55
(Invited Review Paper)
Structure and Function of the Groucho Gene Family and
Encoded Transcriptional Corepressor Proteins from Human,
Mouse, Rat, Xenopus, Drosophila and Nematode
STEVEN SHOEI-LUNG LI
Institute of Biomedical Sciences
National Sun Yat-Sen University
Kaohsiung, Taiwan, R.O.C.
(Received March 29, 1999; Accepted June 7, 1999)
ABSTRACT
A gene family of the Groucho, TLE, ESG and AES proteins has been characterized from Drosophila,
nematode, Xenopus, mouse, rat and human, and their structural relationships have been analyzed. The genomic
organization of nematode ESG, human and mouse AES genes has been determined, and the expression of ESG
and AES genes from Xenopus and human has been analyzed. The Groucho, TLE and ESG proteins all share a
similar structure, consisting of a conserved amino-terminal domain, a variable middle region, and highly conserved carboxyl-terminal WD-40 repeats. The Drosophila Groucho transcriptional corepressor protein has been
shown to interact with the DNA-binding bHLH domain of Enhancer of split, Hairy and Deadpan proteins, which
proteins are involved in neurogenesis, segmentation and sex-determination, respectively. Human TLE1 protein
has been demonstrated to interact with mammalian AML1 protein, which regulates hematopoiesis and osteoblast
differentiation. The AES proteins from human, mouse, rat and Xenopus exhibit strong similarity to the amino-terminal domain of Groucho proteins; however, the biological function remains to be elucidated.
Key Words: groucho, Enhancer of split, corepressor, human, mouse, rat, Xenopus, Drosophila, nematode
I. Introduction
The expression of eukaryotic genes may be regulated by transcriptional activation and repression. Although
activation has been studied and is now better understood,
recent work has shown that repression is as important as
activation in regulating the expression of many eukaryotic
genes (Gray and Levine, 1996). The transcriptional repression system utilizes a sequence-specific DNA-binding
protein that also contains a protein domain required for
repression. While it has been proposed that many repressor domains interact directly with the general transcriptional machinery or with activators, some of the repressors
appear to act indirectly by recruiting corepressor proteins
that bring about repression. A corepressor is defined as a
protein that is required for the repressor activity of a specific transcription factor but does not have the ability to
bind DNA alone. A family of transcriptional corepres-
sors, known as Groucho proteins, has been reported from
Drosophila, nematode, Xenopus, mouse, rat and human.
The Groucho gene was identified initially as a viable
mutation that affects the development of the Drosophila
nervous system, with an allele resulting in thick tufts of
sensory bristles over the eyes, resembling the bushy eyebrows of the comedian Groucho Marx. The Drosophila
Groucho gene, the founding member of the Groucho gene
family, encodes a transcriptional corepressor protein of
719 amino acids. This protein sequence includes the
repeat of approximately 40 amino acids demarcated by
Trp-Asp (WD-40 repeat) present in a guanine nucleotide
binding protein (G-protein) β-subunit (Fong et al., 1986;
Hartley et al., 1988). Stifani et al. (1992) reported human
homologs, Transducin-Like Enhancer of split (TLE)l,
TLE2, TLE3 and TLE4, of the Drosophila Groucho protein. My associates and I described a mouse homolog,
Enhancer of split Groucho (ESG), of the Drosophila
Abbreviations used: AES, Amino Enhancer of split; AML1, acute myeloid leukemia transcriptional activator 1; bHLH, basic helix-loop-helix; CKII,
casein kinase II; cdc2K, cdc2 kinase; ESG, Enhancer of split groucho; G-protein, guanine nucleotide binding protein; Grg, Groucho related gene;
NLS, nuclear localization sequence; TLE, transducin-like Enhancer of split; WD-40 repeat, the repeat of approximately 40 amino acids demarcated by
Trp-Asp (WD); WRPW, Trp-Arg-Pro-Trp.
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Fig. 1. Amino acid sequence comparison of the Groucho, TLE, ESG and AES proteins from Drosophila, nematode, Xenopus, mouse, rat and human.
The amino acid sequences were aligned using the Wisconsin GCG package. Human TLE4 is a partial sequence. Identical residues among all the
sequences are shown in boldface, and gaps are shown using hyphens. The NLS, CKII and cdc2K sites are indicated, and the WD-sequences
demarcating WD-40 repeats are underlined. The translation stop codon is indicated by a star.
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Groucho Transcriptional Corepressor Proteins
Groucho protein (Miyasaka et al., 1993). In addition, we
first reported human and mouse Amino Enhancer of split
(AES) proteins, which exhibit strong similarity to the
amino-terminal domain of Drosophila Groucho, human
TLE and mouse ESG proteins, but lack WD-40 repeats
(Miyasaka et al., 1993). Mallo et al. (1993) also identified mouse AES (Groucho related gene, Grg) protein.
Schmidt and Sladek (1993) described rat homologs, Resp1 and R-esp2 of mouse AES and ESG proteins, respectively. In 1997 my laboratory reported Xenopus AES,
ESG1 and ESG2 as well as nematode ESG proteins
(Choudhury et al., 1997; Sharief et al., 1997). Pflugrad et
al. (1997) independently identified the nematode UNC-37
(ESG) protein. This review will briefly describe the structure and function of the Groucho gene family and encoded
transcriptional corepressor proteins.
II. Primary Structure of Groucho and
Related Proteins
The amino acid sequences of the Groucho, TLE,
ESG and AES proteins from Drosophila, nematode, Xenopus, mouse, rat and human are compared in Fig. 1, and
their structural/evolutionary relationships are indicated in
the diagram in Fig. 2 (Sharief et al., 1997). The AES proteins of 197 amino acids from human, mouse, rat and
Xenopus are homologous with the amino-terminal domain
of the Groucho, TLE and ESG proteins. There is 13%
identity at the 221 positions when the amino-terminal
domains of Groucho and AES proteins are compared. The
middle region of the Groucho proteins exhibits only 5%
identity for the 234 positions compared. The carboxyl-terminal WD-40 repeats of the Groucho proteins exhibit 47%
identity at the 369 positions compared among the different
proteins from human to nematode. The Groucho, TLE
and ESG proteins are clustered into a group while the four
AES proteins are clustered into a separate group. The
nematode ESG (UNC-37) protein of 612 amino acids has
been found to be the smallest of the Groucho proteins that
are known, and it appears to be the ancestor of both the
Groucho and AES proteins. Human TLE2 is structurally
Fig. 2. The structural and evolutionary relationships among the Groucho,
TLE, ESG and AES proteins. These relationships were constructed using the UPGMA method included in the Wisconsin GCG
package. [Reprinted, by permission, from Sharief et al. (1997)]
closer to Drosophila Groucho and Xenopus ESG1. The
mouse ESG protein appears to be most similar to human
TLE3 protein while the rat R-esp2 protein is more similar
to the human TLE1 protein.
III. Genomic Organization of Groucho
Gene Family
The nematode ESG (UNC-37) gene is located on
chromosome 1, and its protein-coding sequence is interrupted by five introns (Fig. 3). The sizes of exons 1 to 6
are 81, 144, 511, 198, 849 and 156 basepairs, respectively,
Fig. 3. The exon organization and protein domains of the nematode ESG (UNC-37) gene. The six exons are indicated by hatched bars. The Groucho
protein consists of the conserved NH2 domain, the variable middle region and highly conserved WD-40 repeats. [Redrawed, by permission,
from Sharief et al. (1997)]
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Fig. 4. The exon-intron organization of the human AES gene. The deduced amino acids (single letter code) are shown below individual codons. The
intron sequence is shown in lower case. The polyadenylation signal AATAAA is underlined. [Summarized, by permission, from Hou and Li
(1998)]
while introns 1 to 5 contain 52, 252, 87, 53 and 518 basepairs, respectively (Sharief et al., 1997; Pflugrad et al.,
1997). The UNC-37 gene transcripts have been shown to
be transpliced to either SL1 or SL2 leaders at a position
five nucleotides upstream of the ATG start. This finding
is consistent with the location of a consenses 3’ splice site
TTTCAG in the genomic sequence abutting the short 5’
untranslated region TAAAA (Pflugrad et al., 1997).
In humans, there are four Groucho (TLE1, TLE2,
TLE3 and TLE4) genes and one AES gene. We previously reported that human TLE3 and AES genes are located
on human chromosomes 15 and 19, respectively (Miyasaka et al., 1993). Liu et al. (1996) showed that the human
TLE3 gene is located at chromosome band 15q22 while
both the TLE1 and TLE2 genes have been mapped to
chromosome band 19p13.3. It is very interesting that we
have also localized the human AES gene to the same chromosome band 19p13.3 (Hou and Li, 1998). As indicated
in Fig. 4, the protein-coding sequence of the human AES
gene is interrupted by six introns (Hou and Li, 1998), and
the exon-intron junction sites have been found to be identical to those of the mouse AES (Grg) gene (Mallo et al.,
1994). The first six exons of the human and mouse AES
genes are rather small, ranging from 45 to 98 basepairs,
while exon 7 contains 219 nucleotides of coding sequence
and a 3’ untranslated region.
IV. Expression of Groucho and AES
Genes
The embryogenesis of the African frog Xenopus laevis has been extensively studied, and it is an excellent
model for investigating vertebrate development. We have
previously described the tissue-specific and developmental expression of the Xenopus ESG1, EGS2, and AES
genes (Choudhury et al., 1997). Northern blot analysis
using the ESG1 coding-probe revealed two transcripts of
3.6 kb and 2.8 kb in all the adult tissues examined, except
in muscle, where the 2.8 kb species was apparently undetectable (Fig. 5(a)). However, only the 3.6 kb band was
detected from the same Northern blot using the ESG2-specific 3’ noncoding-probe. These results of Northern blot
and sequence analyses suggest that the Xenopus ESG1 and
ESG2 transcripts may derive from either two different
genes or may be spliced variants using different exons as
3’-terminal sequences of the same gene. The ESG1
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Groucho Transcriptional Corepressor Proteins
cDNA, presumably derived from the 2.8 kb transcript, is
abundantly expressed in the brain, lung, testis and ovary
whereas the 3.6 kb ESG2 transcript is abundantly expressed in the spleen and ovary. Differences in mRNA level
among these adult tissues suggest that Xenopus ESG
mRNAs are subjected to tissue-specific regulation. Northern blot analysis of AES mRNA from adult tissues using
the AES specific coding-probe showed that the AES transcript of 2.2 kb is widespread and is predominantly present in the brain, testis and ovary (Fig. 5(a)).
The Xenopus ESG1 and AES transcripts of 2.8 kb
and 2.2 kb, respectively, have been found to be ubiquitously expressed in developing embryos (Fig. 5(b)).
These two transcripts are also expressed in both unfertilized and fertilized eggs, suggesting the ESG1 and AES
genes are expressed maternally. Unlike the results obtained from adult tissues, the ESG1 probe detected only a 2.8
kb transcript in all embryonic stages, and the 2.8 kb transcript appeared to disappear after stage 9, fine cell blastula. Sequential hybridization of the same blot with the
ESG2 specific probe detected none of the 3.6 kb tran-
script, suggesting that the ESG2 gene is not expressed in
the early developmental stages.
In Drosophila, embryogenesis has also been shown
to require maternally deposited Groucho proteins (Paroush
et al., 1994) whereas postembryonic development relies
on zygotic Groucho expression (Delidakis et al., 1991).
In nematode, some of UNC-37 mutations have been
shown to be maternal effect lethals (Pflugrad et al., 1997).
Northern blot analysis of mouse poly(A)-RNAs indicated that the AES transcripts of 1.5 kb and 1.3 kb are
more abundant in the muscle, heart and brain than in the
spleen, liver, kidney and testis (Miyasaka et al., 1993).
The mouse AES-1 and AES-2 cDNAs, containing different 5’ untranslated regions, and their first 14 and 9 amino
acids, respectively, presumably derive from these two different transcripts. Furthermore, the mouse AES-2 cDNA,
transcribed from the proximal promoter, was identified by
Mallo et al. (1994) while the AES-1 cDNA presumably
derives from the distal promoter of the same AES gene.
The rat R-esp2 protein have been found to contain a deletion of 25 amino acids in positions 110-144 (Fig. 1)
(a)
(b)
Fig. 5. Northern blot analyses of the Xenopus ESG1, ESG2 and AES genes. (a) Adult tissues. (b) Unfertilized and fertilized eggs, and embryos at different developmental stages: stage 6, late morula (~1,000 cells); stage 9, fine cell blastula (~6,000 cells); stage 11, mid gastrula (~30,000 cells);
stage 20, late neurula; stage 24, early tailbud; stage 32, late tailbud. [Reprinted, by permission, from Choudhury et al. (1997)]
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Fig. 6. The structural domains of the Groucho, TLE, ESG and AES proteins. The hatched area indicates similarity among the amino-terminal domains
of the Groucho, TLE and ESG, and AES proteins. The variable middle region contains NLS, CKII and cdc2K sites. The C-terminal region of the
Groucho, TLE and ESG proteins contains highly conserved WD-40 repeats (dotted area). [Redrawed, by permission, from Choudhury et al.
(1997)]
(Schmidt and Sladek, 1993). The corresponding amino
acids of the mouse AES protein are encoded by exon 6 of
the mouse AES gene (Mallo et al., 1994), suggesting that
the deletion of 25 amino acids might be due to alternative
splicing of rat R-esp2 gene.
Northern blot analysis of human poly(A)-RNAs
from adult tissues indicated that the AES transcripts of
both 1.6 kb and 1.4 kb are predominantly present in the
muscle, heart and placenta (Miyasaka et al., 1993). The
transcript of 1.4 kb is expressed in the lung, liver, kidney
and pancreas while the transcript of 1.6 kb appears to be
present in the brain. This size difference of human AES
transcripts may be due to alternative splicing in the 5’
region, as is the case for mouse AES transcripts. It should
also be noted that three CAG repeats are present at the
acceptor site of intron 6 of the human AES gene. Alternative use of the first two AG dinucleotides as acceptor sites
may explain our earlier finding of either the presence or
absence of G1n at amino acid 125 in two different human
AES cDNA clones (Miyasaka et al., 1993).
V. Biological Functions of Groucho-Related Proteins
The Drosophila Groucho gene was first found to
interact genetically with members of the Enhancer of split
gene complex. Molecular studies showed that most of the
transcripts from this gene complex encode basic helixloop-helix (bHLH) DNA-binding proteins, which play a
critical role by repressing target genes during neurogenesis. More recent data has demonstrated that the Drosophila Groucho protein also interacts with Hairy and Deadpan
regulatory proteins in segmentation and sex determination,
respectively (Delidakis and Artavanis-Tsakonas, 1992;
Knust et al., 1992). The role of Groucho proteins in
repression by Hairy-related proteins has been studied both
biochemically and genetically. Initially, a yeast twohybrid screening performed using the Drosophila Hairy
protein identified the Drosophila Groucho protein. Subsequently, both the Drosophila Groucho and human TLE1
proteins were shown to bind several Hairy-related proteins. The Trp-Arg-Pro-Trp (WRPW) motif found at the
carboxyl terminus of the Hairy-related proteins has been
shown to be both necessary and sufficient for interaction
with Groucho proteins. This interaction between the
WRPW motif and Groucho protein is required for transcriptional repression by these proteins in Drosophila
embryos and cultured cells. Embryos lacking Groucho
proteins exhibit mutant phenotypes consistent with functional roles for Groucho proteins as corepressors for the
Hairy, Enhancer of split, and Deadpan proteins involved
in segmentation, neurogenesis, and sex-determination,
respectively. Studies using in vitro biochemistry, transcriptional repression assays in cells, and Drosophila genetics found that the Groucho proteins are essential corepressors for the Hairy-related proteins (Paroush et al.,
1994; Fisher et al., 1996; Grbavec and Stifani, 1996;
Jimenez et al., 1997; Fisher and Caudy, 1998). Together,
these results have led to the prevailing view that the Hairy
protein functions as a promoter-bound repressor; specifically, an intact bHLH region is required for the Hairy protein to bind to specific DNA sites, where it then uses its
WRPW motif to recruit the Groucho corepressor protein.
The Groucho protein, once recruited as a non-DNA binding corepressor, can repress both basal and activated transcription for specific subsets of DNA-binding transcription factors.
Using a yeast two-hybrid assay, in vitro association
and pull-down experiments, human TLE1 protein was
demonstrated to interact specifically with mammalian
AML1 protein, which regulates hematopoiesis and osteoblast differentiation. The TLE1 protein was also shown to
inhibit AML1-dependent transactivation of the T cell receptor in transfected Jurkat T cells (Levanon et al., 1998).
The biological function of AES proteins resembling
the amino-terminal domain of the Groucho proteins is not
yet understood. Although they may act as corepressors,
these AES proteins could also act as antagonists of the
Groucho proteins by titrating an effector or by binding to
the targets of repression and acting as dominant-negative
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Groucho Transcriptional Corepressor Proteins
inhibitors of the Groucho proteins (Fisher and Caudy,
1998).
VI. Structure-Function Relationship of
Groucho-related Proteins
The overall structural domains of the Groucho, TLE,
ESG and AES proteins are illustrated in Fig. 6 (Choudhury et al., 1997). The Groucho, TLE and ESG proteins
all share a similar structure, consisting of a conserved
amino-terminal domain, a variable middle region, and a
series of highly conserved carboxyl-terminal WD-40 repeats. It should be noted that the amino-terminal domain of
the nematode Groucho protein is encoded by exon 1, exon
2 and a portion of exon 3. The middle region is encoded
by a portion of exon 3 and a portion of exon 4. The carboxyl-terminal WD-40 repeats are encoded by portions of
exon 4, exon 5 and exon 6 (Fig. 3).
The conserved amino-terminal domain of the Groucho proteins has been shown to be able to repress both
basal and activated transcription, and to act as a dimerization domain (Fisher et al., 1996). We previously noted
that the amino-terminal domain of the Groucho and AES
proteins contains a potential leucine zipper, which may
provide a basis for direct interaction between proteins
(Miyasaka et al., 1993). The variable middle region contains potential phosphorylation sites for cdc2 kinase
(cdc2K) and casein kinase II (CKII) in close proximity
with a nuclear localization sequence (NLS). Moreover,
the phosphorylated forms of Drosophila Groucho and
human TLE proteins have been shown to be present in the
nucleus (Hartley et al., 1988; Stifani et al., 1992). Based
on the results of studies on other WD-40 repeat proteins
(Neer et al., 1994; Sondek et al., 1996), the WD-40
repeats found at the carboxyl terminus of the Groucho
proteins most likely are involved in protein-protein interaction. The WD-40 repeats have been found to form a
beta-propeller structure, in which each repeat projects outwards radially and is available for interaction with other
proteins. Recently, the WD-40 repeats of the nematode
Groucho (UNC-37) protein have been found to interact
genetically with the homeodomain of the UNC-4 protein
in such a way as to control neuronal development (Pflugrad et al., 1997). Interestingly, a chimera containing the
amino terminus of the nematode UNC-37 protein and the
WD-40 repeats of human TLE1 is able to rescue the
UNC-37 mutant phenotype, which suggests that the structure and function of the WD-40 repeats are highly conserved among different Groucho proteins from human to
nematode.
The conserved carboxyl-terminal WD-40 repeats of
Groucho proteins have also been found in an expanding
group of proteins, including TUP1 (a mediator of glucose
repression), SLF2 (suppressor gene for floculation),
AAR1 (al-a2 repression and cell control) and AER2 (control of heme-regulated and catabolite-repressed gene). The
TUP1, SLF2, AAR1 and AER2 genes have been identified
on the basis of different phenotypes, but all the genes have
been found to be identical (Yochem and Byers, 1987; Fujita et al., 1990; Williams and Trumbly, 1990; Mukai et al.,
1991; Zhang et al., 1991). It is interesting that both the
Groucho and yeast TUP1 proteins containing the carboxyl-terminal WD-40 repeats have common a function as
transcriptional corepressors; however, there are major
structural and mechanistic differences between them
(Fisher and Caudy, 1998).
VII. Conclusion
A gene family of the Groucho, TLE, ESG and AES
proteins has been characterized from Drosophila, nematode, Xenopus, mouse, rat and human. In humans, there
are four TLE genes, TLE1, TLE2, TLE3, and TLE4, and
one AES gene. Human TLE2 is structurally closer to
Drosophila Groucho and Xenopus ESG1. The mouse
ESG protein appears to be most similar to the human
TLE3 protein, and the rat R-esp2 protein is similar to the
human TLE1 protein. The Groucho transcriptional corepressor protein has been found to interact with the DNAbinding bHLH domain of the Enhancer of split, Hairy and
Deadpan proteins, which are involved in neurogenesis,
segmentation and sex-determination, respectively. The
human TLE1 protein has been found to interact with the
mammalian AML1 protein, which regulates hematopoiesis and osteoblast differentiation. These genetic and biochemical studies have provided new insight into mechanisms of transcriptional repression as well as greater
understanding of the significance of transcriptional repression during development. The AES proteins, which exhibit a strong similarity to the amino-terminal domain of the
Groucho proteins, have been identified in Xenopus,
mouse, rat and human, but their biological functions are
not yet understood.
Acknowledgment
This investigation was supported in part by grants NSC 86-2313B-110-002 and NSC 87-2313-B-110-002 from the National Science
Council, R.O.C., as well as the Intramural Research Program of NIEHS,
NIH, U.S.A.
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of G proteins is involved in control of heme-regulated and catabolite-repressed genes. Gene, 91:153- 161.
–54–
Groucho Transcriptional Corepressor Proteins
Groucho
ESG
ESG
Groucho
AES
TLE
TLE
ESG
AES
ESG
WD-40
DNA
Deadpan
AML1
bHLH
TLE1
AES
AES
–55–
AES
Groucho
Hairy
Groucho