FASEB J. Integrated DNA Technologies
HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
QUICK SEARCH:   [advanced]


     

This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF) Free
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow reprints & permissions
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by BURKE, L. J.
Right arrow Articles by BANIAHMAD, A.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by BURKE, L. J.
Right arrow Articles by BANIAHMAD, A.
(The FASEB Journal. 2000;14:1876-1888.)
© 2000 FASEB

Co-repressors 2000

LES J. BURKE and ARIA BANIAHMAD1

Genetic Institute, Justus Liebig University, Heinrich Buff Ring 58–62, D-35392 Giessen, Germany

1Correspondence: Genetic Institute, Justus Liebig University, Heinrich Buff Ring 58–62, D-35392 Giessen, Germany. E-mail: Aria.Baniahmad{at}gen.bio.uni-giessen.de


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 BIOLOGICAL ROLE OF CO-REPRESSORS
 CO-REPRESSORS AND DISEASES
 CO-REPRESSOR ACTION
 MECHANISMS OF SILENCER-CO...
 OUTLOOK
 REFERENCES
 
In the last 5 years, many co-repressors have been identified in eukaryotes that function in a wide range of species, from yeast to Drosophila and humans. Co-repressors are coregulators that are recruited by DNA-bound transcriptional silencers and play essential roles in many pathways including differentiation, proliferation, programmed cell death, and cell cycle. Accordingly, it has been shown that aberrant interactions of co-repressors with transcriptional silencers provide the molecular basis of a variety of human diseases. Co-repressors mediate transcriptional silencing by mechanisms that include direct inhibition of the basal transcription machinery and recruitment of chromatin-modifying enzymes. Chromatin modification includes histone deacetylation, which is thought to lead to a compact chromatin structure to which the accessibility of transcriptional activators is impaired. In a general mechanistic view, the overall picture suggests that transcriptional silencers and co-repressors act in analogy to transcriptional activators and coactivators, but with the opposite effect leading to gene silencing. We provide a comprehensive overview of the currently known higher eukaryotic co-repressors, their mechanism of action, and their involvement in biological and pathophysiological pathways. We also show the different pathways that lead to the regulation of co-repressor–silencer complex formation.—Burke, L. J., Baniahmad, A. Co-repressors 2000.


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
BIOLOGICAL ROLE OF CO-REPRESSORS
 CO-REPRESSORS AND DISEASES
 CO-REPRESSOR ACTION
 MECHANISMS OF SILENCER-CO...
 OUTLOOK
 REFERENCES
 
GENE EXPRESSION IN eukaryotes in response to environmental and developmental stimuli is a complex phenomenon involving the coordinated silencing and activation of gene expression by the action of transcriptional repressors and activators. Recently, coregulators have been identified that interact with DNA-bound transcription factors and play essential roles in the action of these transcription factors. Moreover, these coregulator proteins can recruit multiprotein complexes that also function to modulate transcription. Transcriptional coregulators can be subdivided into coactivators, which mediate gene activation, and co-repressors, which mediate gene silencing. We will focus on the action of co-repressors of higher eukaryotes. Co-repressors harbor intrinsic silencing ability and actively repress transcription but do not bind DNA directly. Rather, they are recruited by transcription factors bound to the regulatory regions of target genes and contribute to the silencing ability of transcriptional silencers or repress the transcriptional activity of gene activators.

A large number of co-repressors have been identified (Table 1 ). Co-repressors are not just recruited by a small selection of transcriptional silencers. Rather, they bind to and mediate the function of a wide range of transcriptional regulators. Specific co-repressors are used for a particular transcriptional silencer. Furthermore, specific interactions of particular co-repressors with silencers can lead to additional recruitment of protein complexes that also contain intrinsic repression function, thus increasing the complexity of transcriptional silencing.


View this table:
[in this window]
[in a new window]
  		Table 1. No caption available.

This is perhaps best illustrated by the various mechanisms used to recruit histone deacetylase (HDAC) enzymes, which are often associated with co-repressor function. Indirect recruitment of HDAC activity involves different interaction partners depending on the transcriptional regulator. One such targeting complex is the SIN3-protein complex, which includes HDAC1 and 2. The SIN3 proteins SIN3A and SIN3B bind directly to various silencers and target the HDAC activity to these repressors (1 2 3 4 5 6 7 8 9 10 11 12 13 14) . The SIN3 complex and the associated HDAC activity can also be recruited by the nuclear receptor co-repressor (NCoR)/silencing mediator for retinoic acid and thyroid hormone receptor (SMRT) and Alien classes of co-repressors to different silencers (5 , 6 , 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30) .

On the other hand, some transcriptional silencers are able to bind directly to HDACs or use both direct and indirect recruitment of HDAC to silence transcription. The retinoblastoma protein (RB) can directly bind to HDACs independently of SIN3 proteins (31 32 33) . In addition, RB binds directly to Ski that associates with the SIN3 complex, thus indirectly recruiting HDAC activity (50) . Similarly, the NCoR and SMRT co-repressors bind directly to SIN3 and to HDAC4, 5, and 7, whereas HDAC7 can then recruit the SIN3 proteins (93 94 95) . Furthermore, complexes containing HDAC activity are not restricted to SIN3-containing complexes. Another co-repressor complex, the Mi-2/NuRD (nucleosome remodeling and deacetylase) complex, also contains HDAC activity, which is mediated by HDAC1 and 2 but is not associated with the SIN3 proteins (reviewed in refs 96 , 97 ). Thus, as seen in Table 1 , the same co-repressor can associate specifically with different transcription factors and transcriptional silencers can use multiple co-repressors to exert their effect.


   BIOLOGICAL ROLE OF CO-REPRESSORS
TOP
 ABSTRACT
 INTRODUCTION
 BIOLOGICAL ROLE OF CO-REPRESSORS
CO-REPRESSORS AND DISEASES
 CO-REPRESSOR ACTION
 MECHANISMS OF SILENCER-CO...
 OUTLOOK
 REFERENCES
 
Co-repressors have been shown to be essential for a wide range of biological pathways and homeostatic mechanisms, including differentiation, development, cell proliferation, and apoptosis. The critical nature of the co-repressor–repressor interaction is also exemplified by the fact that the binding of co-repressors and their function are critical for action by tumor suppressors, cell cycle regulators, and proteins involved in the regulation by the methylation status of DNA.

Essential functions of co-repressors in development have been revealed through knockout or mutant alleles in Drosophila and vertebrates (98) . Mutants of groucho, a co-repressor for many of the repressor proteins in the Drosophila embryo, including hairy and dorsal, exhibit severe defects in neurogenesis, segmentation, and initiation of sex determination (63 , 68) . Reduction of the levels of Drosophila CtBP (carboxy-terminal binding protein) co-repressor results in severe segmentation and dorsoventral patterning defects, which can be attributed to loss of repression activity of Krüppel, Knirps, and Snail (77) . The ecdysone receptor/ultraspiracle heterodimer, a critical regulator of molting and metamorphic processes, silences transcription by recruitment of the co-repressors Alien and SMRTER (SMRT-related ecdysone receptor interacting protein) (30 , 57) . A mutation in the ecdysone receptor that results in loss of co-repressor interaction and silencing is characterized by developmental abnormalities and lethality (57) . In Xenopus the homologue of dCtBP, XCtBP, is a co-repressor for XTcf-3 that mediates dorsal ventral axis formation. Expression of a mutant XCtBP that has activation rather than silencing function indicates a critical role for XCtBP in the regulation of head and notochord development (80) .

In vertebrates, the SIN3 proteins and the associated HDAC activity have been shown to associate directly with a number of transcriptional repressors involved in essential cell functions. The Myc/Mad family of basic helix-loop-helix (bHLH) proteins are transcription factors that mediate diverse cellular functions including proliferation, differentiation and apoptosis (reviewed in ref 99 ). Mad-Max heterodimers silence genes that are activated by Myc-Max and thus antagonize Myc action. The Mad/Max-silencer binds to the SIN3 co-repressor complex, which also includes the co-repressors NCoR, Ski, and HDACs (1 , 2 , 100 101 102) . The essential role of the two SIN3 proteins, SIN3A and SIN3B, in cellular transformation by the Mad transcription factor is underlined by the observation that deletion of the carboxyl terminus of SIN3B results in loss of transforming potential of the Mad family (100) .

SIN3A itself and the SIN3 co-repressor complex are also associated with the Ikaros family of proteins, which regulate B and T cell differentiation and proliferation of differentiated thymocytes and mature T cells (reviewed in ref 103 ). The Ikaros family of proteins have been shown to be associated with two types of HDAC complexes, the SIN3 co-repressor complex and the Mi-2/NuRD complex; Ikaros can recruit the Mi-2/NuRD complex to the heterochromatic regions (11 , 52) . The role of these complexes in the functions of the Ikaros family of proteins, however, is at present unclear.

The two co-repressor complexes SIN3 and Mi-2/NuRD are also involved in transcriptional silencing mediated by methylated DNA. The presence of methyl-cytosines in CpG groups has long been associated with tissue and developmental specific gene regulation. Recently, factors containing a methyl binding domain (MBD) have been shown to recruit HDAC activity and chromatin remodeling activities to methyl-CpGs (reviewed in ref 104 ). MeCP2, which specifically binds methyl-CpGs, mediates transcriptional repression by a carboxyl-terminal repression domain through interaction with the co-repressor SIN3A and recruits HDACs (7 , 8) . This provided the first functional link between the presence of methyl-CpGs and transcriptional repression. Since then, other repressing complexes involving MBD-containing proteins have been identified. The MeCP1 complex that binds to methylated DNA contains the methyl binding protein MBD2 along with HDAC activity (105) , whereas MBD3 is part of the Mi-2/NuRD complex (54 , 106) . The de novo DNA methyltransferase, Dnmt1, has also been shown to contain a repression domain that associates with HDACs (42) .

The two tumor suppressor proteins, p53 and RB, which are involved in cell cycle control and apoptosis, also rely on the SIN3 co-repressor complex for their action. Both tumor suppressor proteins are targets of viral oncoproteins. RB is a major regulator of the cell cycle at the G1/S phase boundary. RB forms a complex with c-Ski, Sin3A, and HDACs via direct binding to c-Ski and HDACs (31 32 33 , 50) . Furthermore, RB and the related protein, p130, also recruit the CtBP/CtIP complex (82) , indicating that there are multiple mechanisms operating at the level of RB-mediated transcriptional repression (Table 1) . The p53 protein is often mutated in tumors and has the dual function to activate and repress genes. The activity of p53 is stimulated by a variety of agents to induce apoptosis or programmed cell death (reviewed in ref 107 ). This p53-dependent apoptosis is specifically inhibited by the HDAC inhibitor trichostatin A (TSA) (10) , indicating a critical role of HDACs in the apoptotic process. During apoptosis, p53 silences the expression of various genes, including the microtubule-associated protein Map4 (108) . This silencing of Map4 expression involves the recruitment of SIN3 proteins and the associated HDAC activity that leads to a p53-dependent deacetylation of nucleosomes of the Map4 promoter (10) .

The SIN3 co-repressor complex is also associated with gene silencing by nuclear hormone receptors (NHRs). NHRs are ligand-regulated transcription factors that control key processes in development, differentiation, and homeostasis. Some members of this superfamily have the dual role to silence gene expression in the absence of ligand and to activate gene transcription in the presence of their cognate hormone (109) . Silencing is mediated, at least in part, by the hormone-sensitive interaction with the co-repressor proteins NCoR (16) , SMRT (15 , 110 , 111) , and with Alien (30) , which bind to the SIN3 proteins and recruit HDAC activity.

The SMRT/NCoR co-repressor class is not specific for the NHR superfamily (Table 1) . SMRT is also a co-repressor for POZ domain-containing transcriptional silencers such as PLZF, which is involved in leukemia-associated translocations, and BCL6, which is involved in germinal center formation (5 , 19 20 21 22 23 24) . The homeo domain-containing protein Rpx, which plays a role in pituitary determination, requires NCoR, the SIN3 proteins, and HDAC2 for repression activity (27) . NCoR is also necessary for the activity of the Mad protein/SIN3 complex (100 , 101) . In addition, NCoR interacts with the myogenic factor MyoD and represses MyoD-mediated trans-activation by an HDAC-dependent mechanism (25) . Moreover, specific functions of MyoD, including differentiation of C2C12 cells and MyoD-mediated myogenic conversion of pluripotent precursor cells, can be blocked by NCoR.

Co-repressors are also a major determinant for cell-specific gene expression. Changes in the relative abundance of co-repressors or the cell-specific expression of co-repressors may determine the relative contribution of co-repressors to transcriptional repression mediated by specific receptors. It has been demonstrated that limiting amounts of the SMRT co-repressor compromises RAR-mediated but not TR-mediated silencing (112) . Thus, the level of certain cellular co-repressors can control the hormonal response, and therefore modulating target gene expression. Furthermore, cell-specific expression of mSiah2 that promotes NCoR degradation also determines the ability of NHRs to function as repressors in specific cell types (113) .

Thus, co-repressors are essential factors in gene regulation at all levels of biological pathways.


   CO-REPRESSORS AND DISEASES
TOP
 ABSTRACT
 INTRODUCTION
 BIOLOGICAL ROLE OF CO-REPRESSORS
 CO-REPRESSORS AND DISEASES
CO-REPRESSOR ACTION
 MECHANISMS OF SILENCER-CO...
 OUTLOOK
 REFERENCES
 
Regulation of co-repressor interaction with the DNA-bound transcriptional silencer partner is an important and critical parameter for normal biological function. Aberrant interaction of co-repressors can lead to severe pathophysiological manifestations. Several human diseases are a consequence of either enhanced or reduced co-repressor–silencer interactions.

An enhanced co-repressor–transcription factor interaction has been associated with many forms of leukemia. Several types of leukemia result from translocations involving fusions to transcriptional silencers (for review, see ref 114 ). Increased co-repressor binding to these fusion proteins leads to inappropriate repression of target genes important for normal cellular differentiation.

The AML-1 gene is the target of chromosomal translocations that have been associated with leukemia. Acute myelogenic leukemia (AML) has been shown to involve the chromosomal translocation t(8;21), which fuses the DNA binding domain of the AML protein to the transcriptional repressor ETO/MTG8. Similarly, B cell acute lymphoblastic leukemia (ALL) involves the chromosomal translocation t(12;21), which results in the fusion of the repression domain of the ets-leukemia protein TEL to the large form of AML, AML-1B. AML-1 normally activates and represses target gene expression when bound to DNA. However, fusion proteins of AML-1 display abnormal transcriptional properties and act mainly as repressors on promoters. This function arises from the recruitment of NCoR and the SIN3–HDAC complex by ETO (6 , 17 , 18) and TEL (9 , 115) . An inhibitor of HDAC1, phenylbutyrate, partially reverses this ETO-mediated transcriptional repression and is also able to induce partial differentiation of an AML1-ETO cell line (116) . This highlights the importance of the transcriptional repression by HDACs in the development of leukemia.

The three chromosomal translocations t(11;17), t(15;17), and t(5;17) involved in acute promyelocytic leukemia (APL) result in fusion of the promyelocytic leukemia zinc finger protein PLZF, the promyelocytic leukemia protein PML, or nucleophosmin, respectively (117) , to RAR (reviewed in ref 118 ). All of the resulting fusion proteins have been shown to play important roles in leukemogenesis. These fusion proteins are able to bind to RAR target sequences and repress transcription. The wild-type, unfused RAR represses genes in the absence of its cognate ligand due to recruitment of co-repressors, whereas in the presence of its ligand, all-trans retinoic acid (t-RA), RAR activates target genes by recruitment of coactivators. As expected, both the RAR-PML and RAR-PLZF fusion proteins recruit the NCoR/SMRT co-repressors and the associated HDACs via the SIN3 co-repressor in the absence of ligand (24 , 119 , 120) . However, the fusion receptors exhibit a reduced responsiveness to retinoic acid and thus target genes remain repressed (Fig. 1 ) even in the presence of endogenous blood levels of t-RA. After treatments with pharmacological levels of t-RA, patients with the PML-RAR{alpha} fusion protein have complete, if somewhat transient, remission of leukemia. This correlates with co-repressor dissociation from RAR{alpha} at higher concentrations of t-RA. However, patients with the PLZF-RAR{alpha} translocation are unresponsive to higher doses of t-RA (24 , 120 , 121) . This is related to the ability of the PLZF moiety to retain co-repressors. Upon treatment with t-RA, co-repressors dissociate from the RAR{alpha} part of the fusion protein, whereas the PLZF part remains attached to the co-repressor SMRT (23) .



View larger version (19K):
[in this window]
[in a new window]
  		Figure 1. Abnormal development and cancer result from aberrant co-repressor–silencer interaction. Several human diseases are based on aberrant co-repressor (dark circles) interaction with transcriptional silencers. Loss of co-repressor association has been found to be associated with the Rett syndrome and adrenal hypoplasia. Target genes are unrepressed due to lack of functional transcriptional silencers and co-repressor recruitment. On the other hand, loss of co-repressor dissociation is associated with the thyroid hormone resistance (THR) syndrome and leukemia. Genes that are normally expressed thereby remain constitutively silenced.

Furthermore, HDAC inhibitors, in combination with t-RA, can overcome the transcriptional repressor activity as well as the unresponsiveness of PLZF-RAR{alpha}-expressing leukemic cells to t-RA (24 , 119 , 120) . After a period of time, patients with PML-RAR{alpha} fusions become refractive to t-RA treatment. This refractiveness can be overcome with sodium phenylbutyrate, an inhibitor of HDACs, which results in clinical and cytogenetic remission shortly after treatment (122) . This points to the potential of a combined treatment of APL patients with t-RA and HDAC inhibitors for more successful therapy.

Increased stability of a co-repressor–silencer complex is also involved in the thyroid hormone resistance syndrome (THR). This syndrome is inherited in an autosomal dominant manner and is due to mutations of the thyroid hormone receptor (TR) ß, a member of the NHR superfamily (118 , 123 124 125) . Patients with this syndrome have a short physical stature due to a delay in bone growth and exhibit hearing defects, learning disabilities, and mental retardation. Furthermore, patients have higher levels of thyroid hormone, although symptoms of hypothyroidism are manifested. Point mutations in TRß reduce or completely abolish thyroid hormone binding capability, whereby the receptor remains in the repressive state (126) and remains attached to co-repressors (127 , 128) despite higher levels of blood thyroid hormone (Fig. 1) . It is thought that important genes required for normal development and cellular differentiation remain abnormally silenced. Similarly, the oncogene v-ErbA, which is a mutated form of TR{alpha}, induces erythroblastosis and sarcomas through repression of genes that are essential for normal differentiation. The oncogene exhibits constitutive and dysregulated binding to co-repressors, which leads to constitutive silencing function (reviewed in ref 129 ).

Examples of human diseases based on loss of co-repressor interaction are represented by mutations of MeCP2, RB, and DAX-1. The latter is an unusual member of the NHR superfamily in that it has a conserved carboxyl-terminal domain, whereas the DNA binding domain differs from other members. Mutations of the DAX-1 gene are associated with adrenal hypoplasia and hypogonadism (130 131 132 133) . DAX-1 is a potent transcriptional silencer of the orphan nuclear receptor steroidogenic factor 1, SF-1, and recruits the nuclear receptor co-repressors NCoR and Alien, but not SMRT. Naturally occurring DAX-1 mutants have lost silencing function, which correlates with loss of interaction with the co-repressors NCoR and Alien (134 , 135) (Fig. 1) .

The Rett syndrome is an X-linked progressive neurodevelopmental disorder. The genetic basis of this syndrome are mutations in the X-linked methyl-CpG binding protein 2, MeCP2, that affect either the methyl binding domain or the trans-repression domain (136) . These mutations result in loss of silencing function and loss of recruitment of the SIN3 co-repressor to target promoters. In these cases, transcriptional silencing of important genes is lost (Fig. 1) .

Naturally occurring mutants of the tumor suppressor protein RB from patients who have developed cancer show that the ability of these mutant RB proteins to repress E2F trans-activation is lost. This results in loss of cell cycle regulation. Accordingly, mutant RBs have been shown to lack interaction with HDACs and have lost silencing function (reviewed in ref 137 ). Thus, one mechanism of generating cancer by mutation of the RB gene is the loss of co-repressor interaction and loss of gene silencing.

Other viral oncoproteins also recruit co-repressors and this association is important for disease formation. The oncoprotein E7 is the main transforming protein of human papillomavirus 16, which plays a major role in cervical cancer. E7 has been shown to bind to Mi-2 and HDACs, and this HDAC association is necessary for the growth-promoting effects mediated by the E7 protein (53) .

Thus, co-repressors play an important role in human diseases and the co-repressor–silencer complex formation must be controlled in a stringent fashion.


   CO-REPRESSOR ACTION
TOP
 ABSTRACT
 INTRODUCTION
 BIOLOGICAL ROLE OF CO-REPRESSORS
 CO-REPRESSORS AND DISEASES
 CO-REPRESSOR ACTION
MECHANISMS OF SILENCER-CO...
 OUTLOOK
 REFERENCES
 
Mechanisms of co-repressor action on chromatin
A general correlation between histone acetylation status and gene activity has been established (reviewed in ref 138 ). It is generally accepted that the acetylation of the lysine residues of the core histone tails is associated with transcriptionally active DNA whereas the deacetylation of these lysine residues is associated with transcriptional repression. The most widely accepted proposal surrounding this observation is that the acetylation of the lysine residues in the core histone tails results in a more open structure of the chromatin. Thereby, chromatin is more readily accessible to transcription factors. Deacetylation results in a more compact chromatin structure and thus decreases accessibility of the chromatin for transcription factors (for review, see ref 139 ) (Fig. 2 ).



View larger version (33K):
[in this window]
[in a new window]
  		Figure 2. Mechanism of co-repressor action. Transcriptional silencers are able to recruit co-repressors through their silencing domain. Co-repressors repress genes by recruiting histone deacetylase (HDAC) activity and/or interaction with the basal transcription machinery. The model indicates that histone deacetylation (arrows) of the lysine residues of histone tails (open circles) leads to a more compact chromatin structure with lower accessibility to transcriptional activators.

Many enzymes that catalyze either histone acetylation (HATs) or histone deacetylation (HDACs) have been identified. The importance of HDAC activity in mediating gene silencing is shown in cases of HDAC1 and HDAC2/mRPD3 for which the HDAC activity is essential for the full functional repression (140 , 141) . In higher eukaryotes, seven proteins have been identified so far that possess HDAC activity (37 , 38 , 94 , 142 , 143) . These can be divided into two classes based on their sequence homology to yeast proteins and the observation that the homologous proteins in yeast form distinct complexes (144) . Class I HDACs, consisting of HDAC 1–3, share homologies to the yeast RPD3 whereas class II HDACs, consisting of HDAC 4 to 7, share homologies to yeast Hda1 (94) .

HDAC1 and 2 exist as core components of the two deacetylase complexes characterized in eukaryotes: the SIN3 complex and the Mi-2/NuRD complex (reviewed in refs 96 , 97 ). These complexes both contain the four core proteins HDAC1, HDAC2, which possess deacetylase activity (37 , 142) , and the retinoblastoma-associated proteins RbAp46 and RbAp48, which appear to target the complex by binding to the histones (145) . The SIN3 complex is composed of the four core proteins and a number of other factors, including the SIN-associated proteins SAP18 and SAP30. The mechanism of action and the biological role of these associated factors in the context of the complex are largely unknown.

The Mi-2/NuRD complex, apart from the core proteins, contains MTA2, a protein that is similar to the metastasis-associated protein MTA-1, the methyl binding domain proteins MBD3a/b, and a protein with chromatin remodeling activities, Mi-2ß/CHD4 (106 , 146 147 148 149) . The Mi-2ß protein is a member of the SWI/SNF family of proteins, which are known to change DNA-histone interactions in an ATP-dependent manner. Traditionally, these ATP-dependent chromatin remodeling activities have been associated with transcriptional activation, but have recently been shown to facilitate transcriptional repression by a yet unknown mechanism. The ability of the NuRD complex to remodel nucleosomes is necessary for deacetylation of oligonucleosomal histone in vitro (149) , suggesting that the remodeling activity in some way influences the access of the deacetylating components of the Mi-2/NuRD complex. Therefore, it has been postulated that the remodeling activities of the Mi-2/NuRD components make the DNA more accessible to the deacetylase and thus promote deacetylation. Thus, co-repressors that recruit these HDACs mediate gene silencing by targeting and modifying chromatin (for review, see ref (150) .

Mechanisms of co-repressor action on the basal transcription machinery
The use of the HDAC inhibitors sodium butyrate and (more recently) the specific inhibitor TSA have been instrumental in the identification of proteins that have an associated HDAC activity. However, it has also been revealed that in some cases not all of the silencing ability of co-repressors could be relieved by these inhibitors (30 , 93 , 101 , 140 , 151) . Accordingly, some co-repressors have been shown to use multiple mechanisms to repress gene expression. This includes interaction of co-repressors with factors of the basal transcriptional machinery (Fig. 2) .

RevErbß, a member of the NHR superfamily, can bind a complex containing the co-repressor NcoR and the basal transcription factors TAFII32, TAFII70, TFIIB, SIN3, and HDAC1. It has been shown that multiple and distinct domains of NCoR are required for the interaction with different members of the basal transcriptional apparatus (152) . Furthermore, the amino-terminal repression domain of NCoR, which can bind to both TFIIB and TAFII32, can disrupt the functional interaction between TAFII32 and TFIIB that is required for transcriptional activation. Similarly, SMRT also harbors multiple repression domains and can interact with both the SIN3 co-repressor and the basal factor TFIIB. This TFIIB interaction correlates with the repression ability of SMRT (153) .

Members of the basal transcriptional machinery, including TFIIE and TFIIF, can also be acetylated by histone acetyltransferases (154) . The action of HDACs on the acetylation status of these proteins during transcriptional repression is unknown, although it is conceivable that these proteins may also be targets of HDACs.

Thus, co-repressors act via multiple mechanisms with multiple interaction partners, including the transcriptional apparatus. This implies that a large complex that involves both histone deacetylation and repression of the basal transcriptional machinery (Fig. 2) is very potent for full transcriptional repression.

Repression of transcriptional activators
Not only can co-repressors mediate the silencing effects of DNA-bound silencers, but more and more examples are being presented where co-repressors also associate with previously described transcriptional activators. This association may result in the masking of the activation domain and the displacement of coactivators. In these cases, not only is the activation of the transcription factor reduced, but active gene silencing also results. Thus, under certain conditions a transcription factor can act as a repressor or an activator.

One such example is the modulation of E2F activity by the RB tumor suppressor. In the absence of RB binding, E2F acts as a transcriptional activator. Binding of RB to E2F renders E2F response elements from an activating to a repressive sequence. RB has a dual role in this regulation in that the activation domain of E2F is blocked by RB binding and RB also actively represses transcription (155 , 156) by direct recruitment of HDAC1 (31 32 33) , c-Ski (50) and CtBP (82) .


   MECHANISMS OF SILENCER-CO-REPRESSOR FORMATION
TOP
 ABSTRACT
 INTRODUCTION
 BIOLOGICAL ROLE OF CO-REPRESSORS
 CO-REPRESSORS AND DISEASES
 CO-REPRESSOR ACTION
 MECHANISMS OF SILENCER-CO...
OUTLOOK
 REFERENCES
 
The stringent regulation of the silencer–co-repressor complexes is essential for various important biological functions. The formation or the dissociation of a particular silencer–co-repressor complex is proving to be the next level of complexity in the regulation of transcription factor function. The multiple mechanisms understood so far include ligand binding, DNA-induced specificity, posttranslational modification, proteosomal degradation, competition for cellular factors, and subcellular localization (Fig. 3 ).



View larger version (25K):
[in this window]
[in a new window]
  		Figure 3. Mechanisms of regulation of co-repressor–silencer complexes. Several mechanisms have been shown to regulate co-repressor–silencer complexes, including A) ligand binding by nuclear hormone receptors (NHR), B) DNA sequence-induced specificity, C) posttranslational modification, D) proteosomal degradation, E) competition for cellular factors, and F) subcellular localization. For a detailed description, see text.

NHRs that bind ligands recruit co-repressors in a ligand-sensitive manner (reviewed in ref 157 ). In the absence of ligand, these NHRs are bound to response elements in the regulatory regions of target genes in association with co-repressors (NCoR, SMRT, and Alien) and actively repress transcription. After ligand binding, the receptors undergo conformational changes that lead to the dissociation of these co-repressors (15 , 16 , 158) .

Co-repressor–silencer complex formation can also depend on the architecture of the specific DNA sequence, which is exemplified in case of NHRs (39 , 159 , 160) . When RAR is bound to a DR5 response element, a direct repeat with five base pair spacing, co-repressors dissociate on ligand binding. On this element RAR is a silencer and a hormone-dependent transcriptional activator. However, on a DR1 element, a direct repeat with one base pair spacing, co-repressors remain bound to the receptor even after binding to ligand. Since coactivators are recruited and co-repressors are not dissociated upon hormone binding, this leads to a transcriptionally inert receptor (159) . Also, on negative TREs, which are named for their ability to repress genes in the presence of thyroid hormone, liganded TR recruits HDAC2 in the presence of ligand (39) . Opposite to that, on classical elements ligand binding to TR leads to dissociation of the co-repressor complex (15 , 16 , 158) .

Phosphorylation of the silencer proteins can lead to changes in the recruitment of the co-repressors. In early G1 phase, hypophosphorylated RB represses E2F gene activation by recruitment of HDAC activity (31 32 33 ; reviewed in ref 137 ). Activation of cdk4/6 cyclin-dependent kinases in late G1 phase results in hyperphosphorylation of RB and dissociation of the HDAC activity resulting in inactivation of transcriptional repression mediated by RB bound to E2F (161) . NHR co-repressor interactions are also influenced by kinases. Activation of the epidermal growth factor receptor signal transduction pathway inhibits the ability of TR and v-ErbA to repress transcription and to interact with SMRT (162) . Furthermore, this tyrosine kinase activation also inhibits the ability of PLZF to repress transcription and to interact with SMRT, implying that the involvement of tyrosine phosphorylation in regulation of SMRT recruitment is more widespread than just by NHRs.

Proteolysis of co-repressors is also a mechanism that regulates the duration of the co-repressor–silencer complex at the promoter region of the targeted gene. The NH2 terminus of NCoR can be targeted by mSiah2 for degradation (113) . This mechanism of co-repressor removal, therefore, operates like an antirepressor mechanism. Since the expression of mSiah2 is cell specific, this regulates the ability of NCoR specific receptors such as RevErb to function as repressors in specific cell types. Similarly, the Ski family of proteins are regulated by proteolysis. This family are co-repressors for the SMAD proteins that are involved in tumor growth factor ß (TGFß) -mediated cell signaling (reviewed in ref 163 ). TGFß can induce the rapid degradation of the two Ski family proteins c-Ski and SnoN probably by the proteosomal pathway, thus allowing activation of SMAD responsive target genes (49) .

Competition for cellular components also regulates the ability of silencers to associate with co-repressors. The proteins encoded by the Ski proto-oncogene family have been shown to be part of a histone deacetylase complex and bind to mSin3A and NCoR/SMRT (102) . Transcriptional silencing by RB and the Mad family requires a complex containing c-Ski, which binds directly to RB and the Mad proteins (50 , 102) . The viral counterpart of c-Ski, v-Ski, lacks the SIN3 binding region but can still bind to RB and Mad. After v-Ski expression, RB and Mad proteins will bind v-Ski but fail to recruit the SIN3 factor, leading to abrogation of the silencing mediated by RB or Mad.

Cellular localization of the repressor also regulates the binding of co-repressors. TGFß receptor activation induces the phosphorylation of SMAD2. This results in the heterodimerization with SMAD4 and the nuclear localization of the SMAD2/4 complex. Once in the nucleus, the SMAD2/4 complex forms a complex with FAST2 on DNA and recruits the homeodomain protein TGIF and histone deacetylase activity to repress SMAD2/4-responsive genes (92) .

Thus, nature has generated multiple mechanisms to regulate the protein complex formation of transcriptional silencers with co-repressors on DNA response elements.


   OUTLOOK
TOP
 ABSTRACT
 INTRODUCTION
 BIOLOGICAL ROLE OF CO-REPRESSORS
 CO-REPRESSORS AND DISEASES
 CO-REPRESSOR ACTION
 MECHANISMS OF SILENCER-CO...
 OUTLOOK
REFERENCES
 
Meanwhile, it is generally agreed that transcriptional silencing is as important as transcriptional activation for gene control. This includes not only protein encoding genes, but also RNA polymerase I- and III-regulated genes, which have been shown to be repressed by RB (164 , 165) . In general, co-repressors play a major part in gene repression mechanisms. An important insight was gained by revealing that co-repressors harbor or recruit HDAC activity as one major player of gene repression. At this stage, the contribution of either the HDAC activity or the interaction with the basal transcription machinery is still unclear. Using the in vitro transcription system with naked DNA or chromatin templates, the detailed influence of each HDAC activity or the inhibition of basal transcription factors on gene silencing will be able to be determined. Also, silencing mediated by heterochromatic areas, telomeric regions, and other aspects of higher order chromosome structure are presumably based on the involvement of co-repressors. The fact that HDACs are expressed in a tissue and stage-specific manner raises questions of the specificity of HDACs in gene control and the role of each HDAC in development. Future experiments including mice model systems will reveal the biological role of each co-repressor. These findings are also important for cancer therapy by using inhibitors of HDACs. It will be important to develop drugs specific for a particular HDAC and/or peptides to effectively inhibit a specific co-repressor–silencer interaction.


   ACKNOWLEDGMENTS
 
Due to space limitations we apologize to all authors in this area for not citing their contributions. We are grateful to O. Ammerpohl, U. Dressel, D. Thormeyer and H. Dotzlaw for critically reading this manuscript. This work was supported by grants from the Sonderforschungsbereich SFB 397 of the Deutsche Forschungsgemeinschaft.


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 BIOLOGICAL ROLE OF CO-REPRESSORS
 CO-REPRESSORS AND DISEASES
 CO-REPRESSOR ACTION
 MECHANISMS OF SILENCER-CO...
 OUTLOOK
 REFERENCES
 

  1. Ayer, D. E., Lawrence, Q. A., Eisenman, R. N. (1995) Mad-Max transcriptional repression is mediated by ternary complex formation with mammalian homologs of yeast repressor Sin3. Cell 80,767-776[Medline]
  2. Schreiber-Agus, N., Chin, L., Chen, K., Torres, R., Rao, G., Guida, P., Skoultchi, A. I., DePinho, R. A. (1995) An amino-terminal domain of Mxi1 mediates anti-Myc oncogenic activity and interacts with a homolog of the yeast transcriptional repressor SIN3. Cell 80,777-786[Medline]
  3. Rao, G., Alland, L., Guida, P., Schreiber-Agus, N., Chen, K., Chin, L., Rochelle, J. M., Seldin, M. F., Skoultchi, A. I., DePinho, R. A. (1996) Mouse Sin3A interacts with and can functionally substitute for the amino-terminal repression of the Myc antagonist Mxi1. Oncogene 12,1165-1172[Medline]
  4. Hurlin, P. J., Queva, C., Eisenman, R. N. (1997) Mnt, a novel Max-interacting protein is coexpressed with Myc in proliferating cells and mediates repression at Myc binding sites. Genes Dev 11,44-58[Abstract/Free Full Text]
  5. David, G., Alland, L., Hong, S. H., Wong, C. W., DePinho, R. A., Dejean, A. (1998) Histone deacetylase associated with mSin3A mediates repression by the acute promyelocytic leukemia-associated PLZF protein. Oncogene 16,2549-2556[Medline]
  6. Lutterbach, B., Westendorf, J. J., Linggi, B., Patten, A., Moniwa, M., Davie, J. R., Huynh, K. D., Bardwell, V. J., Lavinsky, R. M., Rosenfeld, M. G., Glass, C., Seto, E., Hiebert, S. W. (1998) ETO, a target of t(8;21) in acute leukemia, interacts with the N-CoR and mSin3 co-repressors. Mol. Cell. Biol. 18,7176-7184[Abstract/Free Full Text]
  7. Nan, X., Ng, H. H., Johnson, C. A., Laherty, C. D., Turner, B. M., Eisenman, R. N., Bird, A. (1998) Transcriptional repression by the methyl-CpG-binding protein MeCP2 involves a histone deacetylase complex. Nature (London) 393,386-389[Medline]
  8. Jones, P. L., Veenstra, G. J., Wade, P. A., Vermaak, D., Kass, S. U., Landsberger, N., Strouboulis, J., Wolffe, A. P. (1998) Methylated DNA and MeCP2 recruit histone deacetylase to repress transcription. Nat. Genet. 19,187-191[Medline]
  9. Fenrick, R., Amann, J. M., Lutterbach, B., Wang, L., Westendorf, J. J., Downing, J. R., Hiebert, S. W. (1999) Both TEL and AML-1 contribute repression domains to the t(12;21) fusion protein. Mol. Cell. Biol. 19,6566-6574[Abstract/Free Full Text]
  10. Murphy, M., Ahn, J., Walker, K. K., Hoffman, W. H., Evans, R. M., Levine, A. J., George, D. L. (1999) Transcriptional repression by wild-type p53 utilizes histone deacetylases, mediated by interaction with mSin3a. Genes Dev 13,2490-2501[Abstract/Free Full Text]
  11. Koipally, J., Renold, A., Kim, J., Georgopoulos, K. (1999) Repression by Ikaros and Aiolos is mediated through histone deacetylase complexes. EMBO J 18,3090-3100[Medline]
  12. Huang, Y., Myers, S. J., Dingledine, R. (1999) Transcriptional repression by REST: recruitment of Sin3A and histone deacetylase to neuronal genes. Nat. Neurosci 2,867-872[Medline]
  13. Naruse, Y., Aoki, T., Kojima, T., Mori, N. (1999) Neural restrictive silencer factor recruits mSin3 and histone deacetylase complex to repress neuron-specific target genes. Proc. Natl. Acad. Sci. USA 96,13691-13696[Abstract/Free Full Text]
  14. Yang, Q., Kong, Y., Rothermel, B., Garry, D. J., Bassel-Duby, R., Williams, R. S. (2000) The winged-helix/forkhead protein myocyte nuclear factor beta (MNF-beta) forms a co-repressor complex with mammalian Sin3B. Biochem. J. 345,335-343
  15. Hörlein, A. J., Naar, A. M., Heinzel, T., Torchia, J., Gloss, B., Kurokawa, R., Ryan, A., Kamei, Y., Soderstrom, M., Glass, C. K., et al (1995) Ligand-independent repression by the thyroid hormone receptor mediated by a nuclear receptor co-repressor. Nature (London) 377,397-404[Medline]
  16. Chen, J. D., Evans, R. M. (1995) A transcriptional co-repressor that interacts with nuclear hormone receptors. Nature (London) 377,454-457[Medline]
  17. Wang, J., Hoshino, T., Redner, R. L., Kajigaya, S., Liu, J. M. (1998) ETO, fusion partner in t(8;21) acute myeloid leukemia, represses transcription by interaction with the human N-CoR/mSin3/HDAC1 complex. Proc. Natl. Acad. Sci. USA 95,10860-10865[Abstract/Free Full Text]
  18. Gelmetti, V., Zhang, J., Fanelli, M., Minucci, S., Pelicci, P. G., Lazar, M. A. (1998) Aberrant recruitment of the nuclear receptor co-repressor-histone deacetylase complex by the acute myeloid leukemia fusion partner ETO. Mol. Cell. Biol. 18,7185-7191[Abstract/Free Full Text]
  19. Wong, C. W., Privalsky, M. L. (1998) Components of the SMRT co-repressor complex exhibit distinctive interactions with the POZ domain oncoproteins PLZF. PLZF-RARalpha, and BCL-6. J. Biol. Chem. 273,27695-27702[Abstract/Free Full Text]
  20. Huynh, K. D., Bardwell, V. J. (1998) The BCL-6 POZ domain and other POZ domains interact with the co-repressors N-CoR and SMRT. Oncogene 17,2473-2484[Medline]
  21. Dhordain, P., Albagli, O., Lin, R. J., Ansieau, S., Quief, S., Leutz, A., Kerckaert, J. P., Evans, R. M., Leprince, D. (1997) Co-repressor SMRT binds the BTB/POZ repressing domain of the LAZ3/BCL6 oncoprotein. Proc. Natl. Acad. Sci. USA 94,10762-10767[Abstract/Free Full Text]
  22. Dhordain, P., Lin, R. J., Quief, S., Lantoine, D., Kerckaert, J. P., Evans, R. M., Albagli, O. (1998) The LAZ3(BCL-6) oncoprotein recruits a SMRT/mSIN3A/histone deacetylase containing complex to mediate transcriptional repression. Nucleic Acids Res 26,4645-4651[Abstract/Free Full Text]
  23. Hong, S. H., David, G., Wong, C. W., Dejean, A., Privalsky, M. L. (1997) SMRT co-repressor interacts with PLZF and with the PML-retinoic acid receptor alpha (RARalpha) and PLZF-RARalpha oncoproteins associated with acute promyelocytic leukemia. Proc. Natl. Acad. Sci. USA 94,9028-9033[Abstract/Free Full Text]
  24. Grignani, F., De Matteis, S., Nervi, C., Tomassoni, L., Gelmetti, V., Cioce, M., Fanelli, M., Ruthardt, M., Ferrara, F. F., Zamir, I., Seiser, C., Lazar, M. A., Minucci, S., Pelicci, P. G. (1998) Fusion proteins of the retinoic acid receptor-alpha recruit histone deacetylase in promyelocytic leukaemia. Nature (London) 391,815-818[Medline]
  25. Bailey, P., Downes, M., Lau, P., Harris, J., Chen, S. L., Hamamori, Y., Sartorelli, V., Muscat, G. E. (1999) The nuclear receptor co-repressor N-CoR regulates differentiation: N-CoR directly interacts with MyoD. Mol. Endocrinol. 13,1155-1168[Abstract/Free Full Text]
  26. Kao, H. Y., Ordentlich, P., Koyano-Nakagawa, N., Tang, Z., Downes, M., Kintner, C. R., Evans, R. M., Kadesch, T. (1998) A histone deacetylase co-repressor complex regulates the Notch signal transduction pathway. Genes Dev 12,2269-2277[Abstract/Free Full Text]
  27. Xu, L., Lavinsky, R. M., Dasen, J. S., Flynn, S. E., McInerney, E. M., Mullen, T. M., Heinzel, T., Szeto, D., Korzus, E., Kurokawa, R., Aggarwal, A. K., Rose, D. W., Glass, C. K., Rosenfeld, M. G. (1998) Signal-specific co-activator domain requirements for Pit-1 activation. Nature (London) 395,301-306[Medline]
  28. Muto, A., Hoshino, H., Madisen, L., Yanai, N., Obinata, M., Karasuyama, H., Hayashi, N., Nakauchi, H., Yamamoto, M., Groudine, M., Igarashi, K. (1998) Identification of Bach2 as a B-cell-specific partner for small maf proteins that negatively regulate the immunoglobulin heavy chain gene 3' enhancer. EMBO J 17,5734-5743[Medline]
  29. Asahara, H., Dutta, S., Kao, H. Y., Evans, R. M., Montminy, M. (1999) Pbx-Hox heterodimers recruit coactivator–co-repressor complexes in an isoform-specific manner. Mol. Cell. Biol. 19,8219-8225[Abstract/Free Full Text]
  30. Dressel, U., Thormeyer, D., Altincicek, B., Paululat, A., Eggert, M., Schneider, S., Tenbaum, S. P., Renkawitz, R., Baniahmad, A. (1999) Alien, a highly conserved protein with characteristics of a co-repressor for members of the nuclear hormone receptor superfamily. Mol. Cell. Biol. 19,3383-3394[Abstract/Free Full Text]
  31. Brehm, A., Miska, E. A., McCance, D. J., Reid, J. L., Bannister, A. J., Kouzarides, T. (1998) Retinoblastoma protein recruits histone deacetylase to repress transcription. Nature (London) 391,597-601[Medline]
  32. Luo, R. X., Postigo, A. A., Dean, D. C. (1998) Rb interacts with histone deacetylase to repress transcription. Cell 92,463-473[Medline]
  33. Magnaghi-Jaulin, L., Groisman, R., Naguibneva, I., Robin, P., Lorain, S., Le Villain, J. P., Troalen, F., Trouche, D., Harel-Bellan, A. (1998) Retinoblastoma protein represses transcription by recruiting a histone deacetylase. Nature (London) 391,601-605[Medline]
  34. Ferreira, R., Magnaghi-Jaulin, L., Robin, P., Harel-Bellan, A., Trouche, D. (1998) The three members of the pocket proteins family share the ability to repress E2F activity through recruitment of a histone deacetylase. Proc. Natl. Acad. Sci. USA 95,10493-10498[Abstract/Free Full Text]
  35. Stiegler, P., De Luca, A., Bagella, L., Giordano, A. (1998) The COOH-terminal region of pRb2/p130 binds to histone deacetylase 1 (HDAC1), enhancing transcriptional repression of the E2F-dependent cyclin A promoter. Cancer Res 58,5049-5052[Abstract/Free Full Text]
  36. Doetzlhofer, A., Rotheneder, H., Lagger, G., Koranda, M., Kurtev, V., Brosch, G., Wintersberger, E., Seiser, C. (1999) Histone deacetylase 1 can repress transcription by binding to Sp1. Mol. Cell. Biol. 19,5504-5511[Abstract/Free Full Text]
  37. Yang, W. M., Inouye, C., Zeng, Y., Bearss, D., Seto, E. (1996) Transcriptional repression by YY1 is mediated by interaction with a mammalian homolog of the yeast global regulator RPD3. Proc. Natl. Acad. Sci. USA 93,12845-12850[Abstract/Free Full Text]
  38. Yang, W. M., Yao, Y. L., Sun, J. M., Davie, J. R., Seto, E. (1997) Isolation and characterization of cDNAs corresponding to an additional member of the human histone deacetylase gene family. J. Biol. Chem. 272,28001-28007[Abstract/Free Full Text]
  39. Sasaki, S., Lesoon-Wood, L. A., Dey, A., Kuwata, T., Weintraub, B. D., Humphrey, G., Yang, W. M., Seto, E., Yen, P. M., Howard, B. H., Ozato, K. (1999) Ligand-induced recruitment of a histone deacetylase in the negative-feedback regulation of the thyrotropin beta gene. EMBO J 18,5389-5398[Medline]
  40. Ghosh, A. K., Steele, R., Ray, R. B. (1999) MBP-1 physically associates with histone deacetylase for transcriptional repression. Biochem. Biophys. Res. Commun. 260,405-409[Medline]
  41. van der Vlag, J., Otte, A. P. (1999) Transcriptional repression mediated by the human polycomb-group protein EED involves histone deacetylation. Nat. Genet. 23,474-478[Medline]
  42. Fuks, F., Burgers, W. A., Brehm, A., Hughes-Davies, L., Kouzarides, T. (2000) DNA methyltransferase dnmt1 associates with histone deacetylase activity. Nat. Genet. 24,88-91[Medline]
  43. Miska, E. A., Karlsson, C., Langley, E., Nielsen, S. J., Pines, J., Kouzarides, T. (1999) HDAC4 deacetylase associates with and represses the MEF2 transcription factor. EMBO J 18,5099-5107[Medline]
  44. Wang, A. H., Bertos, N. R., Vezmar, M., Pelletier, N., Crosato, M., Heng, H. H., Th’ng, J., Han, J., Yang, X. J. (1999) HDAC4, a human histone deacetylase related to yeast HDA1, is a transcriptional co-repressor. Mol. Cell. Biol. 19,7816-7827[Abstract/Free Full Text]
  45. Yarden, R. I., Brody, L. C. (1999) BRCA1 interacts with components of the histone deacetylase complex. Proc. Natl. Acad. Sci. USA 96,4983-4988[Abstract/Free Full Text]
  46. Akiyoshi, S., Inoue, H., Hanai, J., Kusanagi, K., Nemoto, N., Miyazono, K., Kawabata, M. (1999) c-Ski acts as a transcriptional Co-repressor in transforming growth factor-beta signaling through interaction with Smads. J. Biol. Chem. 274,35269-35277[Abstract/Free Full Text]
  47. Luo, K., Stroschein, S. L., Wang, W., Chen, D., Martens, E., Zhou, S., Zhou, Q. (1999) The Ski oncoprotein interacts with the Smad proteins to repress TGFbeta signaling. Genes Dev 13,2196-2206[Abstract/Free Full Text]
  48. Sun, Y., Liu, X., Eaton, E. N., Lane, W. S., Lodish, H. F., Weinberg, R. A. (1999) Interaction of the Ski oncoprotein with Smad3 regulates TGF-beta signaling. Mol. Cell 4,499-509[Medline]
  49. Sun, Y., Liu, X., Ng-Eaton, E., Lodish, H. F., Weinberg, R. A. (1999) SnoN and Ski protooncoproteins are rapidly degraded in response to transforming growth factor beta signaling. Proc. Natl. Acad. Sci. USA 96,12442-12447[Abstract/Free Full Text]
  50. Tokitou, F., Nomura, T., Khan, M. M., Kaul, S. C., Wadhwa, R., Yasukawa, T., Kohno, I., Ishii, S. (1999) Viral ski inhibits retinoblastoma protein (Rb)-mediated transcriptional repression in a dominant negative fashion. J. Biol. Chem. 274,4485-4488[Abstract/Free Full Text]
  51. Stroschein, S. L., Wang, W., Zhou, S., Zhou, Q., Luo, K. (1999) Negative feedback regulation of TGF-beta signaling by the SnoN oncoprotein. Science 286,771-774[Abstract/Free Full Text]
  52. Kim, J., Sif, S., Jones, B., Jackson, A., Koipally, J., Heller, E., Winandy, S., Viel, A., Sawyer, A., Ikeda, T., Kingston, R., Georgopoulos, K. (1999) Ikaros DNA-binding proteins direct formation of chromatin remodeling complexes in lymphocytes. Immunity 10,345-355[Medline]
  53. Brehm, A., Nielsen, S. J., Miska, E. A., McCance, D. J., Reid, J. L., Bannister, A. J., Kouzarides, T. (1999) The E7 oncoprotein associates with Mi2 and histone deacetylase activity to promote cell growth. EMBO J 18,2449-2458[Medline]
  54. Zhang, Y., Ng, H. H., Erdjument-Bromage, H., Tempst, P., Bird, A., Reinberg, D. (1999) Analysis of the NuRD subunits reveals a histone deacetylase core complex and a connection with DNA methylation. Genes Dev 13,1924-1935[Abstract/Free Full Text]
  55. Kehle, J., Beuchle, D., Treuheit, S., Christen, B., Kennison, J. A., Bienz, M., Muller, J. (1998) dMi-2, a hunchback-interacting protein that functions in polycomb repression. Science 282,1897-1900[Abstract/Free Full Text]
  56. Zamir, I., Dawson, J., Lavinsky, R. M., Glass, C. K., Rosenfeld, M. G., Lazar, M. A. (1997) Cloning and characterization of a co-repressor and potential component of the nuclear hormone receptor repression complex. Proc. Natl. Acad. Sci. USA 94,14400-14405[Abstract/Free Full Text]
  57. Tsai, C. C., Kao, H. Y., Yao, T. P., McKeown, M., Evans, R. M. (1999) SMRTER, a Drosophila nuclear receptor coregulator, reveals that EcR-mediated repression is critical for development. Mol Cell 4,175-186[Medline]
  58. Sparrow, D. B., Miska, E. A., Langley, E., Reynaud-Deonauth, S., Kotecha, S., Towers, N., Spohr, G., Kouzarides, T., Mohun, T. J. (1999) MEF-2 function is modified by a novel co-repressor. MITR. EMBO J. 18,5085-5098[Medline]
  59. Friedman, J. R., Fredericks, W. J., Jensen, D. E., Speicher, D. W., Huang, X. P., Neilson, E. G., Rauscher, F. J., 3rd (1996) KAP-1, a novel co-repressor for the highly conserved KRAB repression domain. Genes Dev. 10,2067-2078[Abstract/Free Full Text]
  60. Kim, S. S., Chen, Y. M., O’Leary, E., Witzgall, R., Vidal, M., Bonventre, J. V. (1996) A novel member of the RING finger family, KRIP-1, associates with the KRAB-A transcriptional repressor domain of zinc finger proteins. Proc. Natl. Acad. Sci. USA 93,15299-15304[Abstract/Free Full Text]
  61. Moosmann, P., Georgiev, O., Le Douarin, B., Bourquin, J. P., Schaffner, W. (1996) Transcriptional repression by RING finger protein TIF1 beta that interacts with the KRAB repressor domain of KOX1. Nucleic Acids Res 24,4859-4867[Abstract/Free Full Text]
  62. Agata, Y., Matsuda, E., Shimizu, A. (1999) Two novel Kruppel-associated box-containing zinc-finger proteins, KRAZ1 and KRAZ2, repress transcription through functional interaction with the co-repressor KAP-1 (TIF1beta/KRIP-1). J. Biol. Chem. 274,16412-16422[Abstract/Free Full Text]
  63. Paroush, Z., Finley, R. L., Jr, Kidd, T., Wainwright, S. M., Ingham, P. W., Brent, R., Ish-Horowicz, D. (1994) Groucho is required for Drosophila neurogenesis, segmentation, and sex determination and interacts directly with hairy-related bHLH proteins. Cell 79,805-815[Medline]
  64. Aronson, B. D., Fisher, A. L., Blechman, K., Caudy, M., Gergen, J. P. (1997) Groucho-dependent and -independent repression activities of Runt domain proteins. Mol. Cell. Biol. 17,5581-5587[Abstract/Free Full Text]
  65. Imai, Y., Kurokawa, M., Tanaka, K., Friedman, A. D., Ogawa, S., Mitani, K., Yazaki, Y., Hirai, H. (1998) TLE, the human homolog of groucho, interacts with AML1 and acts as a repressor of AML1-induced transactivation. Biochem. Biophys. Res. Commun. 252,582-589[Medline]
  66. Levanon, D., Goldstein, R. E., Bernstein, Y., Tang, H., Goldenberg, D., Stifani, S., Paroush, Z., Groner, Y. (1998) Transcriptional repression by AML1 and LEF-1 is mediated by the TLE/Groucho co-repressors. Proc. Natl. Acad. Sci. USA 95,11590-11595[Abstract/Free Full Text]
  67. Jimenez, G., Paroush, Z., Ish-Horowicz, D. (1997) Groucho acts as a co-repressor for a subset of negative regulators, including Hairy and Engrailed. Genes Dev 11,3072-3082[Abstract/Free Full Text]
  68. Dubnicoff, T., Valentine, S. A., Chen, G., Shi, T., Lengyel, J. A., Paroush, Z., Courey, A. J. (1997) Conversion of dorsal from an activator to a repressor by the global co-repressor Groucho. Genes Dev 11,2952-2957[Abstract/Free Full Text]
  69. Cavallo, R. A., Cox, R. T., Moline, M. M., Roose, J., Polevoy, G. A., Clevers, H., Peifer, M., Bejsovec, A. (1998) Drosophila Tcf and Groucho interact to repress Wingless signalling activity. Nature (London) 395,604-608[Medline]
  70. Choi, C. Y., Kim, Y. H., Kwon, H. J., Kim, Y. (1999) The homeodomain protein NK-3 recruits Groucho and a histone deacetylase complex to repress transcription. J. Biol. Chem. 274,33194-33197[Abstract/Free Full Text]
  71. Choi, C. Y., Lee, Y. M., Kim, Y. H., Park, T., Jeon, B. H., Schulz, R. A., Kim, Y. (1999) The homeodomain transcription factor NK-4 acts as either a transcriptional activator or repressor and interacts with the p300 coactivator and the Groucho co-repressor. J. Biol. Chem. 274,31543-31552[Abstract/Free Full Text]
  72. Valentine, S. A., Chen, G., Shandala, T., Fernandez, J., Mische, S., Saint, R., Courey, A. J. (1998) Dorsal-mediated repression requires the formation of a multiprotein repression complex at the ventral silencer. Mol. Cell. Biol. 18,6584-6594[Abstract/Free Full Text]
  73. Roose, J., Molenaar, M., Peterson, J., Hurenkamp, J., Brantjes, H., Moerer, P., van de Wetering, M., Destree, O., Clevers, H. (1998) The Xenopus Wnt effector XTcf-3 interacts with Groucho-related transcriptional repressors. Nature (London) 395,608-612[Medline]
  74. Ren, B., Chee, K. J., Kim, T. H., Maniatis, T. (1999) PRDI-BF1/Blimp-1 repression is mediated by co-repressors of the Groucho family of proteins. Genes Dev 13,125-137[Abstract/Free Full Text]
  75. Turner, J., Crossley, M. (1998) Cloning and characterization of mCtBP2, a co-repressor that associates with basic Kruppel-like factor and other mammalian transcriptional regulators. EMBO J 17,5129-5140[Medline]
  76. Postigo, A. A., Dean, D. C. (1999) ZEB represses transcription through interaction with the co-repressor CtBP. Proc. Natl. Acad. Sci. USA 96,6683-6688[Abstract/Free Full Text]
  77. Nibu, Y., Zhang, H., Bajor, E., Barolo, S., Small, S., Levine, M. (1998) dCtBP mediates transcriptional repression by Knirps. Kruppel and Snail in the Drosophila embryo. EMBO J. 17,7009-7020[Medline]
  78. Poortinga, G., Watanabe, M., Parkhurst, S. M. (1998) Drosophila CtBP: a Hairy-interacting protein required for embryonic segmentation and hairy-mediated transcriptional repression. EMBO J 17,2067-2078[Medline]
  79. Furusawa, T., Moribe, H., Kondoh, H., Higashi, Y. (1999) Identification of CtBP1 and CtBP2 as co-repressors of zinc finger-homeodomain factor deltaEF1. Mol. Cell. Biol. 19,8581-8590[Abstract/Free Full Text]
  80. Brannon, M., Brown, J. D., Bates, R., Kimelman, D., Moon, R. T. (1999) XCtBP is a XTcf-3 co-repressor with roles throughout Xenopus development. Development 126,3159-3170[Abstract]
  81. Sewalt, R. G., Gunster, M. J., van der Vlag, J., Satijn, D. P., Otte, A. P. (1999) C-Terminal binding protein is a transcriptional repressor that interacts with a specific class of vertebrate Polycomb proteins. Mol. Cell. Biol. 19,777-787[Abstract/Free Full Text]
  82. Meloni, A. R., Smith, E. J., Nevins, J. R. (1999) A mechanism for Rb/p130-mediated transcription repression involving recruitment of the CtBP co-repressor. Proc. Natl. Acad. Sci. USA 96,9574-9579[Abstract/Free Full Text]
  83. Li, S., Chen, P. L., Subramanian, T., Chinnadurai, G., Tomlinson, G., Osborne, C. K., Sharp, Z. D., Lee, W. H. (1999) Binding of CtIP to the BRCT repeats of BRCA1 involved in the transcription regulation of p21 is disrupted upon DNA damage. J. Biol. Chem. 274,11334-11338[Abstract/Free Full Text]
  84. Lai, A., Lee, J. M., Yang, W. M., DeCaprio, J. A., Kaelin, W. G., Jr, Seto, E., Branton, P. E. (1999) RBP1 recruits both histone deacetylase-dependent and -independent repression activities to retinoblastoma family proteins. Mol. Cell. Biol. 19,6632-6641[Abstract/Free Full Text]
  85. Tsang, A. P., Visvader, J. E., Turner, C. A., Fujiwara, Y., Yu, C., Weiss, M. J., Crossley, M., Orkin, S. H. (1997) FOG, a multitype zinc finger protein, acts as a cofactor for transcription factor GATA-1 in erythroid and megakaryocytic differentiation. Cell 90,109-119[Medline]
  86. Holmes, M., Turner, J., Fox, A., Chisholm, O., Crossley, M., Chong, B. (1999) hFOG-2, a novel zinc finger protein, binds the co-repressor mCtBP2 and modulates GATA-mediated activation. J. Biol. Chem. 274,23491-23498[Abstract/Free Full Text]
  87. Andres, M. E., Burger, C., Peral-Rubio, M. J., Battaglioli, E., Anderson, M. E., Grimes, J., Dallman, J., Ballas, N., Mandel, G. (1999) CoREST: a functional co-repressor required for regulation of neural-specific gene expression. Proc. Natl. Acad. Sci. USA 96,9873-9878[Abstract/Free Full Text]
  88. Russo, M. W., Sevetson, B. R., Milbrandt, J. (1995) Identification of NAB1, a repressor of NGFI-A- and Krox20-mediated transcription. Proc. Natl. Acad. Sci. USA 92,6873-6877[Abstract/Free Full Text]
  89. Svaren, J., Sevetson, B. R., Apel, E. D., Zimonjic, D. B., Popescu, N. C., Milbrandt, J. (1996) NAB2, a co-repressor of NGFI-A (Egr-1) and Krox20, is induced by proliferative and differentiative stimuli. Mol. Cell. Biol. 16,3545-3553[Abstract/Free Full Text]
  90. Bach, I., Rodriguez-Esteban, C., Carriere, C., Bhushan, A., Krones, A., Rose, D. W., Glass, C. K., Andersen, B., Izpisua Belmonte, J. C., Rosenfeld, M. G. (1999) RLIM inhibits functional activity of LIM homeodomain transcription factors via recruitment of the histone deacetylase complex. Nat. Genet. 22,394-399[Medline]
  91. Hsieh, J. J., Zhou, S., Chen, L., Young, D. B., Hayward, S. D. (1999) CIR, a co-repressor linking the DNA binding factor CBF1 to the histone deacetylase complex. Proc. Natl. Acad. Sci. USA 96,23-28[Abstract/Free Full Text]
  92. Wotton, D., Lo, R. S., Lee, S., Massague, J. (1999) A Smad transcriptional co-repressor. Cell 97,29-39[Medline]
  93. Nagy, L., Kao, H. Y., Chakravarti, D., Lin, R. J., Hassig, C. A., Ayer, D. E., Schreiber, S. L., Evans, R. M. (1997) Nuclear receptor repression mediated by a complex containing SMRT, mSin3A, and histone deacetylase. Cell 89,373-380[Medline]
  94. Kao, H. Y., Downes, M., Ordentlich, P., Evans, R. M. (2000) Isolation of a novel histone deacetylase reveals that class I and class II deacetylases promote SMRT-mediated repression. Genes Dev 14,55-66[Abstract/Free Full Text]
  95. Huang, E. Y., Zhang, J., Miska, E. A., Guenther, M. G., Kouzarides, T., Lazar, M. A. (2000) Nuclear receptor co-repressors partner with class II histone deacetylases in a Sin3-independent repression pathway. Genes Dev 14,45-54[Abstract/Free Full Text]
  96. Ayer, D. E. (1999) Histone deacetylases: transcriptional repression with SINers and NuRDs. Trends Cell Biol 9,193-198[Medline]
  97. Knoepfler, P. S., Eisenman, R. N. (1999) Sin meets NuRD and other tails of repression. Cell 99,447-450[Medline]
  98. Mannervik, M., Nibu, Y., Zhang, H., Levine, M. (1999) Transcriptional coregulators in development. Science 284,606-609[Abstract/Free Full Text]
  99. Dang, C. V., Resar, L. M., Emison, E., Kim, S., Li, Q., Prescott, J. E., Wonsey, D., Zeller, K. (1999) Function of the c-Myc oncogenic transcription factor. Exp. Cell Res. 253,63-77[Medline]
  100. Alland, L., Muhle, R., Hou, H., Jr, Potes, J., Chin, L., Schreiber-Agus, N., DePinho, R. A. (1997) Role for N-CoR and histone deacetylase in Sin3-mediated transcriptional repression. Nature (London) 387,49-55[Medline]
  101. Heinzel, T., Lavinsky, R. M., Mullen, T. M., Soderstrom, M., Laherty, C. D., Torchia, J., Yang, W. M., Brard, G., Ngo, S. D., Davie, J. R., Seto, E., Eisenman, R. N., Rose, D. W., Glass, C. K., Rosenfeld, M. G. (1997) A complex containing N-CoR, mSin3 and histone deacetylase mediates transcriptional repression. Nature (London) 387,43-48[Medline]
  102. Nomura, T., Khan, M. M., Kaul, S. C., Dong, H. D., Wadhwa, R., Colmenares, C., Kohno, I., Ishii, S. (1999) Ski is a component of the histone deacetylase complex required for transcriptional repression by Mad and thyroid hormone receptor. Genes Dev 13,412-423[Abstract/Free Full Text]
  103. Georgopoulos, K. (1997) Transcription factors required for lymphoid lineage commitment. Curr. Opin. Immunol. 9,222-227[Medline]
  104. Bird, A. P., Wolffe, A. P. (1999) Methylation-induced repression—belts, braces, and chromatin. Cell 99,451-454[Medline]
  105. Ng, H. H., Zhang, Y., Hendrich, B., Johnson, C. A., Turner, B. M., Erdjument-Bromage, H., Tempst, P., Reinberg, D., Bird, A. (1999) MBD2 is a transcriptional repressor belonging to the MeCP1 histone deacetylase complex. Nat. Genet. 23,58-61[Medline]
  106. Wade, P. A., Gegonne, A., Jones, P. L., Ballestar, E., Aubry, F., Wolffe, A. P. (1999) Mi-2 complex couples DNA methylation to chromatin remodelling and histone deacetylation. Nat. Genet. 23,62-66[Medline]
  107. Levine, A. J. (1997) p53, the cellular gatekeeper for growth and division. Cell 88,323-331[Medline]
  108. Murphy, M., Hinman, A., Levine, A. J. (1996) Wild-type p53 negatively regulates the expression of a microtubule-associated protein. Genes Dev 10,2971-2980[Abstract/Free Full Text]
  109. Mangelsdorf, D. J., Thummel, C., Beato, M., Herrlich, P., Schutz, G., Umesono, K., Blumberg, B., Kastner, P., Mark, M., Chambon, P., et al (1995) The nuclear receptor superfamily: the second decade. Cell 83,835-839[Medline]
  110. Ordentlich, P., Downes, M., Xie, W., Genin, A., Spinner, N. B., Evans, R. M. (1999) Unique forms of human and mouse nuclear receptor co-repressor SMRT. Proc. Natl. Acad. Sci. USA 96,2639-2644[Abstract/Free Full Text]
  111. Park, E. J., Schroen, D. J., Yang, M., Li, H., Li, L., Chen, J. D. (1999) SMRTe, a silencing mediator for retinoid and thyroid hormone receptor-extended isoform that is more related to the nuclear receptor co-repressor. Proc. Natl. Acad. Sci. USA 96,3519-3524[Abstract/Free Full Text]
  112. Baniahmad, A., Dressel, U., Renkawitz, R. (1998) Cell-specific inhibition of retinoic acid receptor-alpha silencing by the AF2/tau c activation domain can be overcome by the co-repressor SMRT, but not by N-CoR. Mol. Endocrinol. 12,504-5012[Abstract/Free Full Text]
  113. Zhang, J., Guenther, M. G., Carthew, R. W., Lazar, M. A. (1998) Proteasomal regulation of nuclear receptor co-repressor-mediated repression. Genes Dev 12,1775-1780[Abstract/Free Full Text]
  114. Look, A. T. (1997) Oncogenic transcription factors in the human acute leukemias. Science 278,1059-1064[Abstract/Free Full Text]
  115. Chakrabarti, S. R., Nucifora, G. (1999) The leukemia-associated gene TEL encodes a transcription repressor that associates with SMRT and mSin3A. Biochem. Biophys. Res. Commun. 264,871-877[Medline]
  116. Wang, J., Saunthararajah, Y., Redner, R. L., Liu, J. M. (1999) Inhibitors of histone deacetylase relieve ETO-mediated repression and induce differentiation of AML1-ETO leukemia cells. Cancer Res 59,2766-2769[Abstract/Free Full Text]
  117. Redner, R. L., Rush, E. A., Faas, S., Rudert, W. A., Corey, S. J. (1996) The t(5;17) variant of acute promyelocytic leukemia expresses a nucleophosmin-retinoic acid receptor fusion. Blood 87,882-886[Abstract/Free Full Text]
  118. Tenbaum, S., Baniahmad, A. (1997) Nuclear receptors: structure, function and involvement in disease. Int J. Biochem. Cell Biol. 29,1325-1341[Medline]
  119. He, L. Z., Guidez, F., Tribioli, C., Peruzzi, D., Ruthardt, M., Zelent, A., Pandolfi, P. P. (1998) Distinct interactions of PML-RARalpha and PLZF-RARalpha with co-repressors determine differential responses to RA in APL. Nat. Genet. 18,126-135[Medline]
  120. Lin, R. J., Nagy, L., Inoue, S., Shao, W., Miller, W. H., Jr, Evans, R. M. (1998) Role of the histone deacetylase complex in acute promyelocytic leukaemia. Nature (London) 391,811-814[Medline]
  121. Guidez, F., Ivins, S., Zhu, J., Soderstrom, M., Waxman, S., Zelent, A. (1998) Reduced retinoic acid-sensitivities of nuclear receptor co-repressor binding to PML- and PLZF-RARalpha underlie molecular pathogenesis and treatment of acute promyelocytic leukemia. Blood 91,2634-2642[Abstract/Free Full Text]
  122. Warrell, R. P., Jr, He, L. Z., Richon, V., Calleja, E., Pandolfi, P. P. (1998) Therapeutic targeting of transcription in acute promyelocytic leukemia by use of an inhibitor of histone deacetylase. J. Natl. Cancer Inst. 90,1621-1625[Abstract/Free Full Text]
  123. Beck-Peccoz, P., Chatterjee, V. K. (1994) The variable clinical phenotype in thyroid hormone resistance syndrome. Thyroid 4,225-232[Medline]
  124. Refetoff, S. (1994) Resistance to thyroid hormone. Curr. Ther. Endocrinol. Metab. 5,117-119[Medline]
  125. Refetoff, S. (1994) Resistance to thyroid hormone and its molecular basis. Acta Paediatr. Jpn. 36,1-15[Medline]
  126. Baniahmad, A., Tsai, S. Y., O’Malley, B. W., Tsai, M. J. (1992) Kindred S thyroid hormone receptor is an active and constitutive silencer and a repressor for thyroid hormone and retinoic acid responses. Proc. Natl. Acad. Sci. USA 89,10633-10637[Abstract/Free Full Text]
  127. Yoh, S. M., Chatterjee, V. K., Privalsky, M. L. (1997) Thyroid hormone resistance syndrome manifests as an aberrant interaction between mutant T3 receptors and transcriptional co-repressors. Mol. Endocrinol. 11,470-480[Abstract/Free Full Text]
  128. Tagami, T., Jameson, J. L. (1998) Nuclear co-repressors enhance the dominant negative activity of mutant receptors that cause resistance to thyroid hormone. Endocrinology 139,640-650[Abstract/Free Full Text]
  129. Thormeyer, D., Baniahmad, A. (1999) The v-erbA oncogene (review). Int. J. Mol. Med. 4,351-358[Medline]
  130. Guo, W., Burris, T. P., Zhang, Y. H., Huang, B. L., Mason, J., Copeland, K. C., Kupfer, S. R., Pagon, R. A., McCabe, E. R. (1996) Genomic sequence of the DAX1 gene: an orphan nuclear receptor responsible for X-linked adrenal hypoplasia congenita and hypogonadotropic hypogonadism. J. Clin. Endocrinol. Metab. 81,2481-2486[Abstract]
  131. Habiby, R. L., Boepple, P., Nachtigall, L., Sluss, P. M., Crowley, W. F., Jr, Jameson, J. L. (1996) Adrenal hypoplasia congenita with hypogonadotropic hypogonadism: evidence that DAX-1 mutations lead to combined hypothalmic and pituitary defects in gonadotropin production. J. Clin. Invest. 98,1055-1062[Medline]
  132. Muscatelli, F., Strom, T. M., Walker, A. P., Zanaria, E., Recan, D., Meindl, A., Bardoni, B., Guioli, S., Zehetner, G., Rabl, W., et al (1994) Mutations in the DAX-1 gene give rise to both X-linked adrenal hypoplasia congenita and hypogonadotropic hypogonadism. Nature (London) 372,672-676[Medline]
  133. Zhang, Y. H., Guo, W., Wagner, R. L., Huang, B. L., McCabe, L., Vilain, E., Burris, T. P., Anyane-Yeboa, K., Burghes, A. H., Chitayat, D., Chudley, A. E., Genel, M., Gertner, J. M., Klingensmith, G. J., Levine, S. N., Nakamoto, J., New, M. I., Pagon, R. A., Pappas, J. G., Quigley, C. A., Rosenthal, I. M., Baxter, J. D., Fletterick, R. J., McCabe, E. R. (1998) DAX1 mutations map to putative structural domains in a deduced three-dimensional model. Am. J. Hum. Genet. 62,855-864[Medline]
  134. Crawford, P. A., Dorn, C., Sadovsky, Y., Milbrandt, J. (1998) Nuclear receptor DAX-1 recruits nuclear receptor co-repressor N-CoR to steroidogenic factor 1. Mol. Cell. Biol. 18,2949-2956[Abstract/Free Full Text]
  135. Altincicek, B., Tenbaum, S. P., Dressel, U., Thormeyer, D., Renkawitz, R., Baniahmad, A. (2000) Interaction of the co-repressor Alien with DAX-1 is abrogated by mutations in DAX-1 involved in adrenal hypoplasia congenita. J. Biol. Chem. 275,7662-7667[Abstract/Free Full Text]
  136. Amir, R. E., Van den Veyver, I. B., Wan, M., Tran, C. Q., Francke, U., Zoghbi, H. Y. (1999) Rett syndrome is caused by mutations in X-linked MECP2, encoding methyl-CpG-binding protein 2. Nat. Genet. 23,185-188[Medline]
  137. Kouzarides, T. (1999) Histone acetylases and deacetylases in cell proliferation. Curr. Opin. Genet. Dev. 9,40-48[Medline]
  138. Hebbes, T. R., Thorne, A. W., Crane-Robinson, C. (1988) A direct link between core histone acetylation and transcriptionally active chromatin. EMBO J 7,1395-1402[Medline]
  139. Kornberg, R. D., Lorch, Y. (1999) Twenty-five years of the nucleosome, fundamental particle of the eukaryote chromosome. Cell 98,285-294[Medline]
  140. Hassig, C. A., Fleischer, T. C., Billin, A. N., Schreiber, S. L., Ayer, D. E. (1997) Histone deacetylase activity is required for full transcriptional repression by mSin3A. Cell 89,341-347[Medline]
  141. Kadosh, D., Struhl, K. (1998) Histone deacetylase activity of Rpd3 is important for transcriptional repression in vivo. Genes Dev 12,797-805[Abstract/Free Full Text]
  142. Taunton, J., Hassig, C. A., Schreiber, S. L. (1996) A mammalian histone deacetylase related to the yeast transcriptional regulator Rpd3p. Science 272,408-411[Abstract]
  143. Grozinger, C. M., Hassig, C. A., Schreiber, S. L. (1999) Three proteins define a class of human histone deacetylases related to yeast Hda1p. Proc. Natl. Acad. Sci. USA 96,4868-4873[Abstract/Free Full Text]
  144. Rundlett, S. E., Carmen, A. A., Kobayashi, R., Bavykin, S., Turner, B. M., Grunstein, M. (1996) HDA1 and RPD3 are members of distinct yeast histone deacetylase complexes that regulate silencing and transcription. Proc. Natl. Acad. Sci. USA 93,14503-14508[Abstract/Free Full Text]
  145. Roth, S. Y., Allis, C. D. (1996) Histone acetylation and chromatin assembly: a single escort, multiple dances?. Cell 87,5-8[Medline]
  146. Zhang, Y., LeRoy, G., Seelig, H. P., Lane, W. S., Reinberg, D. (1998) The dermatomyositis-specific autoantigen Mi2 is a component of a complex containing histone deacetylase and nucleosome remodeling activities. Cell 95,279-289[Medline]
  147. Xue, Y., Wong, J., Moreno, G. T., Young, M. K., Cote, J., Wang, W. (1998) NURD, a novel complex with both ATP-dependent chromatin-remodeling and histone deacetylase activities. Mol Cell 2,851-861[Medline]
  148. Wade, P. A., Jones, P. L., Vermaak, D., Wolffe, A. P. (1998) A multiple subunit Mi-2 histone deacetylase from Xenopus laevis cofractionates with an associated Snf2 superfamily ATPase. Curr. Biol. 8,843-846[Medline]
  149. Tong, J. K., Hassig, C. A., Schnitzler, G. R., Kingston, R. E., Schreiber, S. L. (1998) Chromatin deacetylation by an ATP-dependent nucleosome remodelling complex. Nature (London) 395,917-921[Medline]
  150. Tyler, J. K., Kadonaga, J. T. (1999) The ‘dark side’ of chromatin remodeling: repressive effects on transcription. Cell 99,443-446[Medline]
  151. Laherty, C. D., Yang, W. M., Sun, J. M., Davie, J. R., Seto, E., Eisenman, R. N. (1997) Histone deacetylases associated with the mSin3 co-repressor mediate mad transcriptional repression. Cell 89,349-356[Medline]
  152. Muscat, G. E., Burke, L. J., Downes, M. (1998) The co-repressor N-CoR and its variants RIP13a and RIP13Delta1 directly interact with the basal transcription factors TFIIB, TAFII32 and TAFII70. Nucleic Acids Res 26,2899-2907[Abstract/Free Full Text]
  153. Wong, C. W., Privalsky, M. L. (1998) Transcriptional repression by the SMRT-mSin3 co-repressor: multiple interactions, multiple mechanisms, and a potential role for TFIIB. Mol. Cell. Biol. 18,5500-1550[Abstract/Free Full Text]
  154. Imhof, A., Yang, X. J., Ogryzko, V. V., Nakatani, Y., Wolffe, A. P., Ge, H. (1997) Acetylation of general transcription factors by histone acetyltransferases. Curr. Biol. 7,689-692[Medline]
  155. Flemington, E. K., Speck, S. H., Kaelin, W. G., Jr (1993) E2F-1-mediated transactivation is inhibited by complex formation with the retinoblastoma susceptibility gene product. Proc. Natl. Acad. Sci. USA 90,6914-6918[Abstract/Free Full Text]
  156. Weintraub, S. J., Chow, K. N., Luo, R. X., Zhang, S. H., He, S., Dean, D. C. (1995) Mechanism of active transcriptional repression by the retinoblastoma protein. Nature (London) 375,812-815[Medline]
  157. Glass, C. K., Rosenfeld, M. G. (2000) The coregulator exchange in transcriptional functions of nuclear receptors. Genes Dev 14,121-141[Free Full Text]
  158. Baniahmad, A., Leng, X., Burris, T. P., Tsai, S. Y., Tsai, M. J., O’Malley, B. W. (1995) The tau 4 activation domain of the thyroid hormone receptor is required for release of a putative co-repressor(s) necessary for transcriptional silencing. Mol. Cell. Biol. 15,76-86[Abstract/Free Full Text]
  159. Kurokawa, R., Soderstrom, M., Horlein, A., Halachmi, S., Brown, M., Rosenfeld, M. G., Glass, C. K. (1995) Polarity-specific activities of retinoic acid receptors determined by a co-repressor. Nature (London) 377,451-454[Medline]
  160. Olson, D. P., Sun, B., Koenig, R. J. (1998) Thyroid hormone response element architecture affects co-repressor release from thyroid hormone receptor dimers. J. Biol. Chem. 273,3375-3380[Abstract/Free Full Text]
  161. Harbour, J. W., Luo, R. X., Dei Santi, A., Postigo, A. A., Dean, D. C. (1999) Cdk phosphorylation triggers sequential intramolecular interactions that progressively block Rb functions as cells move through G1. Cell 98,859-869[Medline]
  162. Hong, S. H., Wong, C. W., Privalsky, M. L. (1998) Signaling by tyrosine kinases negatively regulates the interaction between transcription factors and SMRT (silencing mediator of retinoic acid and thyroid hormone receptor) co-repressor. Mol. Endocrinol. 12,1161-1171[Abstract/Free Full Text]
  163. Vogel, G. (1999) A new blocker for the TGF-beta pathway. Science 286,665[Free Full Text]
  164. Cavanaugh, A. H., Hempel, W. M., Taylor, L. J., Rogalsky, V., Todorov, G., Rothblum, L. I. (1995) Activity of RNA polymerase I transcription factor UBF blocked by Rb gene product. Nature (London) 374,177-180[Medline]
  165. White, R. J., Trouche, D., Martin, K., Jackson, S. P., Kouzarides, T. (1996) Repression of RNA polymerase III transcription by the retinoblastoma protein. Nature (London) 382,88-90[Medline]



This article has been cited by other articles:


Home page
 Anticancer ResHome page
C. CARLBERG and S. SEUTER
A Genomic Perspective on Vitamin D Signaling
Anticancer Res, September 1, 2009; 29(9): 3485 - 3493.
[Abstract] [Full Text] [PDF]

Home page
 J. Biol. Chem.Home page
K. M. Makkonen, S. Pasonen-Seppanen, K. Torronen, M. I. Tammi, and C. Carlberg
Regulation of the Hyaluronan Synthase 2 Gene by Convergence in Cyclic AMP Response Element-binding Protein and Retinoid Acid Receptor Signaling
J. Biol. Chem., July 3, 2009; 284(27): 18270 - 18281.
[Abstract] [Full Text] [PDF]

Home page
 EndocrinologyHome page
R. A. Heimeier, B. Das, D. R. Buchholz, and Y.-B. Shi
The Xenoestrogen Bisphenol A Inhibits Postembryonic Vertebrate Development by Antagonizing Gene Regulation by Thyroid Hormone
Endocrinology, June 1, 2009; 150(6): 2964 - 2973.
[Abstract] [Full Text] [PDF]

Home page
 J Mol EndocrinolHome page
M. Eisold, M. Asim, H. Eskelinen, T. Linke, and A. Baniahmad
Inhibition of MAPK-signaling pathway promotes the interaction of the corepressor SMRT with the human androgen receptor and mediates repression of prostate cancer cell growth in the presence of antiandrogens
J. Mol. Endocrinol., May 1, 2009; 42(5): 429 - 435.
[Abstract] [Full Text] [PDF]

Home page
 Mol. Cell. Biol.Home page
H. Matsuda, B. D. Paul, C. Y. Choi, T. Hasebe, and Y.-B. Shi
Novel Functions of Protein Arginine Methyltransferase 1 in Thyroid Hormone Receptor-Mediated Transcription and in the Regulation of Metamorphic Rate in Xenopus laevis
Mol. Cell. Biol., February 1, 2009; 29(3): 745 - 757.
[Abstract] [Full Text] [PDF]

Home page
 Mol. Endocrinol.Home page
R. A. Heimeier, V. S. Hsia, and Y.-B. Shi
Participation of Brahma-Related Gene 1 (BRG1)-Associated Factor 57 and BRG1-Containing Chromatin Remodeling Complexes in Thyroid Hormone-Dependent Gene Activation during Vertebrate Development
Mol. Endocrinol., May 1, 2008; 22(5): 1065 - 1077.
[Abstract] [Full Text] [PDF]

Home page
 Molecular Cancer TherapeuticsHome page
H. Su, L. Altucci, and Q. You
Competitive or noncompetitive, that's the question: research toward histone deacetylase inhibitors
Mol. Cancer Ther., May 1, 2008; 7(5): 1007 - 1012.
[Abstract] [Full Text] [PDF]

Home page
 Mol. Endocrinol.Home page
H. Matsuda, B. D. Paul, C. Y. Choi, and Y.-B. Shi
Contrasting Effects of Two Alternative Splicing Forms of Coactivator-Associated Arginine Methyltransferase 1 on Thyroid Hormone Receptor-Mediated Transcription in Xenopus laevis
Mol. Endocrinol., May 1, 2007; 21(5): 1082 - 1094.
[Abstract] [Full Text] [PDF]

Home page
 Mol. Endocrinol.Home page
U. Moehren, M. Papaioannou, C. A. Reeb, W. Hong, and A. Baniahmad
Alien Interacts with the Human Androgen Receptor and Inhibits Prostate Cancer Cell Growth
Mol. Endocrinol., May 1, 2007; 21(5): 1039 - 1048.
[Abstract] [Full Text] [PDF]

Home page
 Nucleic Acids ResHome page
M. Nair, V. Bilanchone, K. Ortt, S. Sinha, and X. Dai
Ovol1 represses its own transcription by competing with transcription activator c-Myb and by recruiting histone deacetylase activity
Nucleic Acids Res., March 12, 2007; 35(5): 1687 - 1697.
[Abstract] [Full Text] [PDF]

Home page
 J. Biol. Chem.Home page
K. Narayanan, S. Gajjeraman, A. Ramachandran, J. Hao, and A. George
Dentin Matrix Protein 1 Regulates Dentin Sialophosphoprotein Gene Transcription during Early Odontoblast Differentiation
J. Biol. Chem., July 14, 2006; 281(28): 19064 - 19071.
[Abstract] [Full Text] [PDF]

Home page
 BioinformaticsHome page
K. Missal, M. A. Cross, and D. Drasdo
Gene network inference from incomplete expression data: transcriptional control of hematopoietic commitment
Bioinformatics, March 15, 2006; 22(6): 731 - 738.
[Abstract] [Full Text] [PDF]

Home page
 BloodHome page
R. Gupta, S. Karpatkin, and R. S. Basch
Hematopoiesis and stem cell renewal in long-term bone marrow cultures containing catalase
Blood, March 1, 2006; 107(5): 1837 - 1846.
[Abstract] [Full Text] [PDF]

Home page
 Nucleic Acids ResHome page
M. Matilainen, M. Malinen, K. Saavalainen, and C. Carlberg
Regulation of multiple insulin-like growth factor binding protein genes by 1{alpha},25-dihydroxyvitamin D3
Nucleic Acids Res., September 26, 2005; 33(17): 5521 - 5532.
[Abstract] [Full Text] [PDF]

Home page
 J. Biol. Chem.Home page
B. D. Paul, D. R. Buchholz, L. Fu, and Y.-B. Shi
Tissue- and Gene-specific Recruitment of Steroid Receptor Coactivator-3 by Thyroid Hormone Receptor during Development
J. Biol. Chem., July 22, 2005; 280(29): 27165 - 27172.
[Abstract] [Full Text] [PDF]

Home page
 Nucleic Acids ResHome page
L. Sinkkonen, M. Malinen, K. Saavalainen, S. Vaisanen, and C. Carlberg
Regulation of the human cyclin C gene via multiple vitamin D3-responsive regions in its promoter
Nucleic Acids Res., April 29, 2005; 33(8): 2440 - 2451.
[Abstract] [Full Text] [PDF]

Home page
 Mol. Cell. Biol.Home page
R. Alpatov, G. C. Munguba, P. Caton, J. H. Joo, Y. Shi, Y. Shi, M. E. Hunt, and S. P. Sugrue
Nuclear Speckle-Associated Protein Pnn/DRS Binds to the Transcriptional Corepressor CtBP and Relieves CtBP- Mediated Repression of the E-Cadherin Gene
Mol. Cell. Biol., December 1, 2004; 24(23): 10223 - 10235.
[Abstract] [Full Text] [PDF]

Home page
 J. Biol. Chem.Home page
K. Narayanan, A. Ramachandran, M. C. Peterson, J. Hao, A.-B. Kolsto, A. D. Friedman, and A. George
The CCAAT Enhancer-binding Protein (C/EBP){beta} and Nrf1 Interact to Regulate Dentin Sialophosphoprotein (DSPP) Gene Expression during Odontoblast Differentiation
J. Biol. Chem., October 29, 2004; 279(44): 45423 - 45432.
[Abstract] [Full Text] [PDF]

Home page
 J BiochemHome page
J.-F. Li, L.-D. Liu, S.-H. Ma, Y.-C. Che, L.-C. Wang, C.-H. Dong, H.-L. Zhao, Y. Liao, and Q.-H. Li
HTRP--An Immediate-Early Gene Product Induced by HSV1 Infection in Human Embryo Fibroblasts, Is Involved in Cellular Co-Repressors
J. Biochem., August 1, 2004; 136(2): 169 - 176.
[Abstract] [Full Text] [PDF]

Home page
 Nucleic Acids ResHome page
U. Moehren, U. Dressel, C. A. Reeb, S. Vaisanen, T. W. Dunlop, C. Carlberg, and A. Baniahmad
The highly conserved region of the co-repressor Sin3A functionally interacts with the co-repressor Alien
Nucleic Acids Res., June 1, 2004; 32(10): 2995 - 3004.
[Abstract] [Full Text] [PDF]

Home page
 Mol. Cell. Biol.Home page
A. Tomita, D. R. Buchholz, and Y.-B. Shi
Recruitment of N-CoR/SMRT-TBLR1 Corepressor Complex by Unliganded Thyroid Hormone Receptor for Gene Repression during Frog Development
Mol. Cell. Biol., April 15, 2004; 24(8): 3337 - 3346.
[Abstract] [Full Text] [PDF]

Home page
 J. Biol. Chem.Home page
C. Zhao, D. Fu, V. Dave, and J. Ma
A Composite Motif of the Drosophila Morphogenetic Protein Bicoid Critical to Transcription Control
J. Biol. Chem., November 7, 2003; 278(45): 43901 - 43909.
[Abstract] [Full Text] [PDF]

Home page
 Mol. Cell. Biol.Home page
D. R. Buchholz, S.-C. V. Hsia, L. Fu, and Y.-B. Shi
A Dominant-Negative Thyroid Hormone Receptor Blocks Amphibian Metamorphosis by Retaining Corepressors at Target Genes
Mol. Cell. Biol., October 1, 2003; 23(19): 6750 - 6758.
[Abstract] [Full Text] [PDF]

Home page
 Mol. Endocrinol.Home page
M. M. Gonzalez, P. Samenfeld, M. Perakyla, and C. Carlberg
Corepressor Excess Shifts the Two-Side Chain Vitamin D Analog Gemini from an Agonist to an Inverse Agonist of the Vitamin D Receptor
Mol. Endocrinol., October 1, 2003; 17(10): 2028 - 2038.
[Abstract] [Full Text] [PDF]

Home page
 J. Biol. Chem.Home page
A. Tomita, D. R. Buchholz, K. Obata, and Y.-B. Shi
Fusion Protein of Retinoic Acid Receptor {alpha} with Promyelocytic Leukemia Protein or Promyelocytic Leukemia Zinc Finger Protein Recruits N-CoR-TBLR1 Corepressor Complex to Repress Transcription in Vivo
J. Biol. Chem., August 15, 2003; 278(33): 30788 - 30795.
[Abstract] [Full Text] [PDF]

Home page
 Endocr. Rev.Home page
K. De Bosscher, W. Vanden Berghe, and G. Haegeman
The Interplay between the Glucocorticoid Receptor and Nuclear Factor-{kappa}B or Activator Protein-1: Molecular Mechanisms for Gene Repression
Endocr. Rev., August 1, 2003; 24(4): 488 - 522.
[Abstract] [Full Text] [PDF]

Home page
 Nucleic Acids ResHome page
K. S. Childs and S. Goodbourn
Identification of novel co-repressor molecules for Interferon Regulatory Factor-2
Nucleic Acids Res., June 15, 2003; 31(12): 3016 - 3026.
[Abstract] [Full Text] [PDF]

Home page
 J. Biol. Chem.Home page
Y. Xie, R. Zhong, C. Chen, and S. K. Calderwood
Heat Shock Factor 1 Contains Two Functional Domains That Mediate Transcriptional Repression of the c-fos and c-fms Genes
J. Biol. Chem., February 7, 2003; 278(7): 4687 - 4698.
[Abstract] [Full Text] [PDF]

Home page
 Mol. Cell. Biol.Home page
L. M. Sachs, P. L. Jones, E. Havis, N. Rouse, B. A. Demeneix, and Y.-B. Shi
Nuclear Receptor Corepressor Recruitment by Unliganded Thyroid Hormone Receptor in Gene Repression during Xenopus laevis Development
Mol. Cell. Biol., December 15, 2002; 22(24): 8527 - 8538.
[Abstract] [Full Text] [PDF]

Home page
 J. Biol. Chem.Home page
J. Koipally and K. Georgopoulos
A Molecular Dissection of the Repression Circuitry of Ikaros
J. Biol. Chem., July 26, 2002; 277(31): 27697 - 27705.
[Abstract] [Full Text] [PDF]

Home page
 J. Biol. Chem.Home page
M. Schulz, M. Eggert, A. Baniahmad, A. Dostert, T. Heinzel, and R. Renkawitz
RU486-induced Glucocorticoid Receptor Agonism Is Controlled by the Receptor N Terminus and by Corepressor Binding
J. Biol. Chem., July 12, 2002; 277(29): 26238 - 26243.
[Abstract] [Full Text] [PDF]

Home page
 Endocr. Rev.Home page
C. P. Leo, S. Y. Hsu, and A. J. W. Hsueh
Hormonal Genomics
Endocr. Rev., June 1, 2002; 23(3): 369 - 381.
[Abstract] [Full Text] [PDF]

Home page
 J. Biol. Chem.Home page
M. M. Gonzalez and C. Carlberg
Cross-repression, a Functional Consequence of the Physical Interaction of Non-liganded Nuclear Receptors and POU Domain Transcription Factors
J. Biol. Chem., May 17, 2002; 277(21): 18501 - 18509.
[Abstract] [Full Text] [PDF]

Home page
 Mol. Cell. Biol.Home page
M. Fu, C. Wang, J. Wang, X. Zhang, T. Sakamaki, Y. G. Yeung, C. Chang, T. Hopp, S. A. W. Fuqua, E. Jaffray, et al.
Androgen Receptor Acetylation Governs trans Activation and MEKK1-Induced Apoptosis without Affecting In Vitro Sumoylation and trans-Repression Function
Mol. Cell. Biol., May 15, 2002; 22(10): 3373 - 3388.
[Abstract] [Full Text] [PDF]

Home page
 BloodHome page
Y. Peng and N. Jahroudi
The NFY transcription factor functions as a repressor and activator of the von Willebrand factor promoter
Blood, April 1, 2002; 99(7): 2408 - 2417.
[Abstract] [Full Text] [PDF]

Home page
 J. Biol. Chem.Home page
S. Bai and X. Cao
A Nuclear Antagonistic Mechanism of Inhibitory Smads in Transforming Growth Factor-beta Signaling
J. Biol. Chem., February 1, 2002; 277(6): 4176 - 4182.
[Abstract] [Full Text] [PDF]

Home page
 Genes Dev.Home page
G. B. Potter, G. M.J. Beaudoin III, C. L. DeRenzo, J. M. Zarach, S. H. Chen, and C. C. Thompson
The hairless gene mutated in congenital hair loss disorders encodes a novel nuclear receptor corepressor
Genes & Dev., October 15, 2001; 15(20): 2687 - 2701.
[Abstract] [Full Text] [PDF]

Home page
 J. Biol. Chem.Home page
G. M. Leong, N. Subramaniam, J. Figueroa, J. L. Flanagan, M. J. Hayman, J. A. Eisman, and A. P. Kouzmenko
Ski-interacting Protein Interacts with Smad Proteins to Augment Transforming Growth Factor-beta -dependent Transcription
J. Biol. Chem., May 18, 2001; 276(21): 18243 - 18248.
[Abstract] [Full Text] [PDF]

Home page
 J. Biol. Chem.Home page
U. Dressel, P. J. Bailey, S-C. M. Wang, M. Downes, R. M. Evans, and G. E. O. Muscat
A Dynamic Role for HDAC7 in MEF2-mediated Muscle Differentiation
J. Biol. Chem., May 11, 2001; 276(20): 17007 - 17013.
[Abstract] [Full Text] [PDF]

This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF) Free
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow reprints & permissions
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by BURKE, L. J.
Right arrow Articles by BANIAHMAD, A.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by BURKE, L. J.
Right arrow Articles by BANIAHMAD, A.

HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS