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• W2028274324 abstract "Cell-cell communication plays a key role in organ formation and patterning in multicellular animals and is carried out by a few evolutionarily conserved signaling pathways. The modes of action of these pathways share a number of general properties, or habits, that allow them to strongly activate target genes in a ligand-dependent manner in the proper cellular contexts. Recent studies have revealed that some developmental signaling pathways can also strongly repress genes in a ligand-dependent manner. These new findings raise the interesting possibility that this repressive mode of action is shared by many or most developmental signaling pathways. Cell-cell communication plays a key role in organ formation and patterning in multicellular animals and is carried out by a few evolutionarily conserved signaling pathways. The modes of action of these pathways share a number of general properties, or habits, that allow them to strongly activate target genes in a ligand-dependent manner in the proper cellular contexts. Recent studies have revealed that some developmental signaling pathways can also strongly repress genes in a ligand-dependent manner. These new findings raise the interesting possibility that this repressive mode of action is shared by many or most developmental signaling pathways. Patterning and cell specification events during the development of multicellular animals are wrought by a few evolutionary conserved signaling pathways. Signaling via these pathways is used reiteratively throughout development, both in time and space. The signals are interpreted in a tissue- and context-dependent manner, resulting in rapid changes in gene transcription in nuclei of the responding cells. Although the mechanistic details may differ, the pathways share a number of conserved properties or “habits,” which include “default repression,” “activator insufficiency,” and “cooperative activation” (Barolo and Posakony, 2002Barolo S. Posakony J.W. Three habits of highly effective signaling pathways: principles of transcriptional control by developmental cell signaling.Genes Dev. 2002; 16: 1167-1181Crossref PubMed Scopus (315) Google Scholar; reviewed below, and see Figure 1 and Figure 2). The combination of these three habits allows the pathways to robustly activate target genes in response to the signal, in a context-dependent manner, while preventing target gene expression in the absence of the signal.Figure 2General Outline of Wnt, Hh, Notch, and Nuclear Receptor SignalingShow full captionThe major developmental signaling pathways (Notch, Wnt, Hedgehog, and nuclear receptor signaling) have evolved different mechanisms that share the same function: switching on target gene expression by changing transcriptional repression to activation following binding of the ligands to their respective receptors. Figure adapted from Barolo and Posakony, 2002Barolo S. Posakony J.W. Three habits of highly effective signaling pathways: principles of transcriptional control by developmental cell signaling.Genes Dev. 2002; 16: 1167-1181Crossref PubMed Scopus (315) Google Scholar.View Large Image Figure ViewerDownload Hi-res image Download (PPT) The major developmental signaling pathways (Notch, Wnt, Hedgehog, and nuclear receptor signaling) have evolved different mechanisms that share the same function: switching on target gene expression by changing transcriptional repression to activation following binding of the ligands to their respective receptors. Figure adapted from Barolo and Posakony, 2002Barolo S. Posakony J.W. Three habits of highly effective signaling pathways: principles of transcriptional control by developmental cell signaling.Genes Dev. 2002; 16: 1167-1181Crossref PubMed Scopus (315) Google Scholar. More recently, it has become clear that the transcription of target genes is not only activated by developmental signals, but that target genes can also be directly repressed. By “directly” we mean that a gene's transcription is repressed, upon signaling, without prior transcriptional induction of a nuclear repressor, i.e., in the absence of de novo protein synthesis. Conceptually this appears to conflict with one of the three habits of developmental signaling pathways, namely that signal-regulated genes are under default repression. If the genes are actively kept off in the absence of the signal, then there would be no opportunity to shut down their transcription upon signaling. In this review, we first briefly describe the three habits of developmental signaling pathways. Before describing well-studied cases from such signaling pathways, in which genes have been shown to be repressed in a ligand-induced manner, we outline a few theoretical scenarios explaining how signals could actively repress genes. We then describe the defined molecular events leading to gene repression and discuss them in the light of the three habits shared by these signaling pathways. Based on the well-characterized cases of signal-induced repression, we propose possible scenarios of how default repression could be overridden and how active repression could be brought about in other developmental signaling pathways. The Barolo and Posakony review (Barolo and Posakony, 2002Barolo S. Posakony J.W. Three habits of highly effective signaling pathways: principles of transcriptional control by developmental cell signaling.Genes Dev. 2002; 16: 1167-1181Crossref PubMed Scopus (315) Google Scholar) provides a useful framework for thinking about some of the common features of signaling pathways. As described in this review, the development of multicellular animals is controlled by seven major cell-cell signaling pathways (TGFβ, Wnt, Hedgehog [Hh], Notch, receptor tyrosine kinases (RTK), nuclear receptors, and Jak/STAT). Each of these pathways acts repetitively during development, regulating the expression of largely different sets of target genes in distinct tissues and cell types. Although these seven pathways use rather different molecular mechanisms to regulate target genes (see Figure 1, Figure 2, and below), the major consequence of triggering all pathways is the transcriptional activation of specific target genes by signal-regulated transcription factors. These signal-regulated transcription factors bind to specific DNA sequences, called signaling pathway response elements (SPREs), in the promoters or enhancers of the target genes. A pivotal role in signal-induced transcriptional regulation is attributed to these pathway-specific SPREs and the corresponding DNA binding proteins. To achieve a high degree of temporal and spatial specificity of signal responses, the major developmental signaling pathways utilize a number of common habits. These habits have been discussed extensively by Barolo and Posakony, 2002Barolo S. Posakony J.W. Three habits of highly effective signaling pathways: principles of transcriptional control by developmental cell signaling.Genes Dev. 2002; 16: 1167-1181Crossref PubMed Scopus (315) Google Scholar and are only briefly outlined here. Most developmental signaling pathways appear to regulate gene transcription by a switch mechanism: genes are actively repressed in the absence of the signal and turned on in the presence of the signal. Given the later focus on direct repression, the most relevant habit, for the purposes of this review, is repression of target genes in the absence of ligand, which has been termed default repression. Somewhat surprisingly, default repression in the case of the Wnt, Hh, Notch, and nuclear receptor signaling pathways is exerted on a given gene not only via the same SPRE as signal-induced activation, but also by the same DNA binding protein, the signal-regulated transcription factors of these pathways. These transcription factors [Lef/T Cell factor (Tcf) in the Wnt pathway, Ci/Gli in the Hh pathway, Su(H)/CBF1 in the Notch pathway, and nuclear receptors themselves] bind to the SPREs in many target genes in the absence of signaling, recruit corepressor complexes (including histone deacetylases [HDACs]), and thus help to keep these target genes repressed prior to signaling (Figure 2). These pathway-specific transcriptional regulators use different mechanisms to become converted from repressors to activators upon signaling (such as protein cleavage, interaction with signal-regulated cofactors, or signal-induced conformational changes). Some of these mechanisms will be outlined below. The two other habits shared by developmental signaling pathways are referred to as activator insufficiency and cooperative activation. If the binding of signal-activated transcription factors to the corresponding SPRE were sufficient to activate the transcription of target genes, a given signal would activate the same set (and the full set) of target genes in all tissues. However, in different tissue contexts in vivo, the subsets of target genes that are activated overlap only partially or not at all. Indeed, experimental approaches have shown that the simple binding of signal-regulated transcription factors to SPREs does not generally lead to transcriptional activation, a phenomenon referred to as activator insufficiency. Transcription is only significantly increased when these transcription factors join forces with other transcriptional regulators, which often bind in a tissue-specific manner to sequences close to the SPREs. The coordinated action with additional coregulators in signal-induced activation has generally been referred to as cooperative activation. Together with default repression, activator insufficiency and cooperative activation allow genes to be switched from the “off” state in the absence of signals to the “on” state in the presence of the signal in a temporally and spatially coordinated manner (Figure 2; see Barolo and Posakony, 2002Barolo S. Posakony J.W. Three habits of highly effective signaling pathways: principles of transcriptional control by developmental cell signaling.Genes Dev. 2002; 16: 1167-1181Crossref PubMed Scopus (315) Google Scholar, for an extensive discussion of this subject). Although studies carried out in the last few years have further strengthened the idea of the commonality of the three habits in developmental signaling, it has been shown that certain signaling pathways not only activate gene transcription in a signal-induced manner, but that signaling can also directly repress genes that are transcribed in cells before they respond to the signal. At first sight, signal-induced gene repression conflicts with the principle of default repression. Default repression keeps genes silent in cells prior to signaling via direct binding of default repressors to SPREs. Thus, if genes are kept silent before the signaling events are triggered, there is no apparent need or possibility to repress such genes upon signaling. Indeed, for a signaling pathway to downregulate or repress a previously active gene, default repression of this particular gene would have to be circumvented or overruled, allowing the gene to be transcriptionally active prior to signaling. We will first consider theoretically how the habits outlined above could serve as a roadmap for constructing a signaling system that would allow tissue-specific gene repression (instead of gene activation) upon signaling. The simplest way to obtain signal-induced repression would be to reverse the three habits. Instead of genes being repressed prior to signaling by default repression, genes could be kept active prior to signaling by “default activation.” In the simplest case, default activation would be exerted by the same kind of protein species that is used for the signal-induced repression. Upon signaling, the signal-controlled transcription factors would act as repressors. To regulate the repression in a tissue-dependent context, these repressors should be insufficient to inhibit transcription by themselves (“repressor insufficiency”) but would rather require other transcription factors to mediate repression at specific target sites (“cooperative repression”). Together, these three conceptual habits would allow signaling pathways to strongly repress target genes in a context- and signal-dependent manner, while activating their expression in the absence of the signal. Since all major developmental signaling pathways directly activate the transcription of many genes upon signaling, repression of target genes must involve ways to circumvent habits in specific cases. Alternatively, some or all of the habits could be context dependent; for example, default repression could be functional only in some cases, releasing certain genes from default repression and making them available for signal-induced repression. Allosteric effects, at the DNA and protein levels, could contribute to such variation, with slightly different binding sites producing opposing effects with regard to transcriptional outcome. Below we outline in detail the molecular twists allowing several of the developmental signaling pathways to both activate and repress target genes directly in a signal-regulated manner. The developmental signaling pathway for which the capability to repress target gene transcription in a signal-dependent manner is best understood is the TGFβ pathway (reviewed in Affolter and Basler, 2007Affolter M. Basler K. The Decapentaplegic morphogen gradient: from pattern formation to growth regulation.Nat. Rev. Genet. 2007; 8: 663-674Crossref PubMed Scopus (293) Google Scholar, Feng and Derynck, 2005Feng X.H. Derynck R. Specificity and versatility in tgf-β signaling through Smads.Annu. Rev. Cell Dev. Biol. 2005; 21: 659-693Crossref PubMed Scopus (1456) Google Scholar, Massague and Gomis, 2006Massague J. Gomis R.R. The logic of TGFβ signaling.FEBS Lett. 2006; 580: 2811-2820Abstract Full Text Full Text PDF PubMed Scopus (615) Google Scholar, Parker et al., 2004Parker L. Stathakis D.G. Arora K. Regulation of BMP and activin signaling in Drosophila.Prog. Mol. Subcell. Biol. 2004; 34: 73-101Crossref PubMed Google Scholar, Raftery et al., 2006Raftery L.A. Korochkina S. Cao J. Smads.in: ten Dijke P. Heldin C.-H. Drosophila – Interpretation Of Graded Signals In Vivo. In Proteins And Cell Regulation. Volume 5. Springer Netherlands, Dordrecht, The Netherlands2006: 55-73Google Scholar, Schmierer and Hill, 2007Schmierer B. Hill C.S. TGFβ-SMAD signal transduction: molecular specificity and functional flexibility.Nat. Rev. Mol. Cell Biol. 2007; 8: 970-982Crossref PubMed Scopus (880) Google Scholar). Signaling is elicited by the binding of TGFβ ligands to two transmembrane receptor serine-threonine kinases, referred to as type I and type II receptors. Upon oligomerization of the ligand-receptor complex, the type II receptors phosphorylate and thereby activate the type I receptors. In turn the latter recruit and phosphorylate receptor-regulated Smads or R-Smads. Subsequently, phosphorylated R-Smads form complexes with a common mediator Smad (Smad4 in vertebrates and Medea in Drosophila). These newly formed heteromeric Smad complexes accumulate in the nucleus, where they are directly involved in regulating the transcription of target genes. In agreement with two of the habits of developmental signaling pathways, activator insufficiency and cooperative activation, TGFβ target genes are activated by signaling only when DNA-bound Smad complexes interact with additional transcriptional regulators on native enhancer and/or promoter elements. Smad complexes can interact with a wide variety of other transcription regulators, including DNA binding and non-DNA binding proteins, in order to activate transcription in a signal-dependent manner (Feng and Derynck, 2005Feng X.H. Derynck R. Specificity and versatility in tgf-β signaling through Smads.Annu. Rev. Cell Dev. Biol. 2005; 21: 659-693Crossref PubMed Scopus (1456) Google Scholar, Massague et al., 2005Massague J. Seoane J. Wotton D. Smad transcription factors.Genes Dev. 2005; 19: 2783-2810Crossref PubMed Scopus (1801) Google Scholar). While a distinct default repressor has not been identified thus far in TGFβ signaling in vertebrates (see also below), genetic studies have led to the isolation and characterization of a default repressor in the Drosophila TGFβ (Decapentaplegic [Dpp]/Bmp) signaling pathway, Brinker (Brk). Most target genes activated by Dpp signaling in different developmental contexts are directly repressed in the absence of signaling by a DNA binding protein encoded by the brk gene (Campbell and Tomlinson, 1999Campbell G. Tomlinson A. Transducing the Dpp morphogen gradient in the wing of Drosophila: regulation of Dpp targets by brinker.Cell. 1999; 96: 553-562Abstract Full Text Full Text PDF PubMed Scopus (226) Google Scholar, Jazwinska et al., 1999Jazwinska A. Kirov N. Wieschaus E. Roth S. Rushlow C. The Drosophila gene brinker reveals a novel mechanism of Dpp target gene regulation.Cell. 1999; 96: 563-573Abstract Full Text Full Text PDF PubMed Scopus (219) Google Scholar, Minami et al., 1999Minami M. Kinoshita N. Kamoshida Y. Tanimoto H. Tabata T. brinker is a target of Dpp in Drosophila that negatively regulates Dpp-dependent genes.Nature. 1999; 398: 242-246Crossref PubMed Scopus (185) Google Scholar). Brk recruits corepressors such as Groucho (Gro) and Carboxy-terminal binding proteins (CtBP) to target gene enhancers and represses their activity (Hasson et al., 2001Hasson P. Muller B. Basler K. Paroush Z. Brinker requires two corepressors for maximal and versatile repression in Dpp signalling.EMBO J. 2001; 20: 5725-5736Crossref PubMed Scopus (68) Google Scholar, Winter and Campbell, 2004Winter S.E. Campbell G. Repression of Dpp targets in the Drosophila wing by Brinker.Development. 2004; 131: 6071-6081Crossref PubMed Scopus (33) Google Scholar). Therefore, in order for target genes to be transcriptionally activated by Smad complexes, Brk first has to be removed, and this occurs through transcriptional repression of brk via Dpp signaling. A combination of genetic and molecular analyses has unraveled a molecular mechanism leading to Dpp-induced transcriptional repression of the brk gene. Since these studies represent the most detailed molecular characterization of a signal-induced repression mechanism built into a developmental signaling pathway, our consideration of the Dpp pathway will be further outlined in detail. To understand how activated Dpp signaling leads to the observed transcriptional repression of brk, a comprehensive dissection of the cis-regulatory region of the brk gene was undertaken (Müller et al., 2003Müller B. Hartmann B. Pyrowolakis G. Affolter M. Basler K. Conversion of an extracellular Dpp/BMP morphogen gradient into an inverse transcriptional gradient.Cell. 2003; 113: 221-233Abstract Full Text Full Text PDF PubMed Scopus (138) Google Scholar). This analysis resulted in the identification of short (16 base pairs) sequence elements referred to as silencer elements (SEs), which are able to produce Dpp-dependent repression when fused to a broadly active enhancer of brk or to widely activated regulatory elements of unrelated genes. The SE was shown to bind a complex consisting of two molecules of Mothers Against Dpp (Mad)—the Drosophila R-Smad—and one molecule of Medea—the common mediator Smad (Müller et al., 2003Müller B. Hartmann B. Pyrowolakis G. Affolter M. Basler K. Conversion of an extracellular Dpp/BMP morphogen gradient into an inverse transcriptional gradient.Cell. 2003; 113: 221-233Abstract Full Text Full Text PDF PubMed Scopus (138) Google Scholar, Pyrowolakis et al., 2004Pyrowolakis G. Hartmann B. Muller B. Basler K. Affolter M. A simple molecular complex mediates widespread BMP-induced repression during Drosophila development.Dev. Cell. 2004; 7: 229-240Abstract Full Text Full Text PDF PubMed Scopus (105) Google Scholar, Gao et al., 2005Gao S. Steffen J. Laughon A. Dpp-responsive silencers are bound by a trimeric Mad-Medea complex.J. Biol. Chem. 2005; 280: 36158-36164Crossref PubMed Scopus (45) Google Scholar). While the two Mad molecules bind to a GRCGNC sequence motif, Medea binds to a conserved GTCT sequence. At the SE, the Mad/Medea complex recruits the large zinc finger protein Schnurri (Shn); Shn recruitment requires that the distance between the two Smad binding motifs is exactly five nucleotides, and that the fourth nucleotide in the GTCT motif is a T (see Figure 3). Shn is required for the protein complex to repress gene transcription, thus turning the Mad/Medea complex into a transcriptional repressor. Whether the Shn protein recognizes the GTCT motif, or whether the second T in the GTCT motif induces an allosteric change in the Mad/Medea complex that results in the recruitment of Shn, remains to be determined. Further studies have shown that a number of other genes (e.g., gooseberry, bag of marbles) repressed by Dpp signaling also use SE elements for transcriptional downregulation, and it appears that signal-induced repression via a Mad/Medea/Shn complex is an integral and widely used feature of the Dpp signaling pathway (Pyrowolakis et al., 2004Pyrowolakis G. Hartmann B. Muller B. Basler K. Affolter M. A simple molecular complex mediates widespread BMP-induced repression during Drosophila development.Dev. Cell. 2004; 7: 229-240Abstract Full Text Full Text PDF PubMed Scopus (105) Google Scholar, Pyrowolakis et al., 2007Pyrowolakis G. Hartmann B. Affolter M. TGF-β family signaling in Drosophila.in: Derynck R. Miyazono K. The TGF-β Family. Cold Spring Harbor Laboratory Press, Cold Spring Harbor, NY2007: 493-526Google Scholar). Given the apparent incompatibility of signal-induced repression and default repression, it is interesting to consider how default repression is regulated in the Dpp signaling pathway. Clearly, the Brk protein has to be considered the default repressor of the pathway. Brk binds to the consensus sequence GGCGYY, and such sites have been found in the regulatory regions of most (or all) Dpp target genes. Consistent with the function of these sites in default repression, most or all Dpp target genes can be repressed by ectopic Brk expression in Dpp responding cells (and cannot be activated in shn mutants, which also display ectopic Brk expression); several of these genes also show expanded expression in the absence of brk. Many of the Brk sites identified in the fly genome overlap with Mad binding sites (GRCGNC); this means that, somewhat similarly to several of the other developmental signaling pathways (Wingless [Wg]/Wnt, Hh, and Notch pathways, as well as nuclear receptor signaling), the binding sites of the default repressor and the sites to which the signal-induced transcriptional activators bind overlap; however, unlike the case in many of the other signaling pathways, the sequence elements to which the two transcriptional regulators bind are not identical. Importantly, Brk does not bind directly to the Mad/Medea-binding SEs described above (unpublished data); if it did, brk transcription would be off in most or all cells of the organism: brk would turn off its own expression in the absence of Dpp signaling, and brk transcription would be turned off by the Mad/Medea/Shn complex in those cells that experience Dpp signaling. When all this is taken together, it appears that the default repressor of the Dpp signaling pathway has a unique property—it can bind to many of the Mad sites in the genome (the SPRE of the Dpp pathway), but does not recognize all sites that are recognized by Mad/Medea. This differential binding probably arises from the fact that Brk has a homeodomain-like DNA binding domain (Cordier et al., 2006Cordier F. Hartmann B. Rogowski M. Affolter M. Grzesiek S. DNA recognition by the brinker repressor–an extreme case of coupling between binding and folding.J. Mol. Biol. 2006; 361: 659-672Crossref PubMed Scopus (21) Google Scholar) that has a very different 3D fold compared with the DNA binding domains present in the signal-induced transcriptional regulators (Mad and Medea; see Shi et al., 1998Shi Y. Wang Y.F. Jayaraman L. Yang H. Massagué J. Pavletich N.P. Crystal structure of a Smad MH1 domain bound to DNA: insights on DNA binding in TGF-beta signaling.Cell. 1998; 94: 585-594Abstract Full Text Full Text PDF PubMed Scopus (593) Google Scholar). Therefore, default repression and signal-induced transcriptional repression are exerted via subtle differences in the sequence elements, allowing the exemption of certain genes from default repression and making them available for signal-induced repression via Mad/Medea/Shn. Consequently, despite the presence of a default repressor in the Dpp pathway, there are a number of genes that carry cis-regulatory elements that avoid such repression because of the absence of binding sites for the default repressor. Signal-induced repression is a key event in Dpp signaling and a prerequisite for the subsequent activation of genes upon signaling, because it is responsible for the transcriptional downregulation and thus the removal of the default repressor. The existence of distinct DNA binding species involved either in default repression (Brk) or in signal-induced activation/repression (Mad/Medea) has also allowed an interesting twist in how Dpp signaling regulates gene transcription. For a number of genes (one of the best-characterized examples being optomotor blind), it has been shown that their activation in response to signaling is the result of the removal of repression via Brk; these genes do not require direct binding of Mad/Medea complexes to their cis-regulatory regions to become expressed (Jazwinska et al., 1999Jazwinska A. Kirov N. Wieschaus E. Roth S. Rushlow C. The Drosophila gene brinker reveals a novel mechanism of Dpp target gene regulation.Cell. 1999; 96: 563-573Abstract Full Text Full Text PDF PubMed Scopus (219) Google Scholar, Campbell and Tomlinson, 1999Campbell G. Tomlinson A. Transducing the Dpp morphogen gradient in the wing of Drosophila: regulation of Dpp targets by brinker.Cell. 1999; 96: 553-562Abstract Full Text Full Text PDF PubMed Scopus (226) Google Scholar, Sivasankaran et al., 2000Sivasankaran R. Vigano A.M. Müller B. Affolter M. Basler K. Direct transcriptional control of the Dpp target omb by the DNA binding protein Brinker.EMBO J. 2000; 19: 6162-6172Crossref PubMed Scopus (71) Google Scholar). The activation of these genes upon signaling can thus be best described as a process of “derepression,” leading to the definition of different classes of genes positively regulated by Dpp signaling (class I and class II genes; see Figure 3). What about activation and repression of target genes via TGFβ signaling in vertebrates? Although the core molecular players, such as the Smad proteins, are the same in vertebrates and in invertebrates, a clear default repressor has not been identified thus far in vertebrates. However, a number of studies have identified genes that are directly repressed by TGFβ signaling, and molecular scenarios accounting for repression have been described. In epithelial cells, Smad3 associates with E2F4/5, DP1, and p107; this complex moves into the nucleus upon TGFβ signaling and recruitment of Smad4. In the nucleus, the complex recognizes a composite Smad-E2F binding site in the c-myc regulatory region and represses c-myc transcription (Chen et al., 2002Chen C.R. Kang Y. Siegel P.M. Massague J. E2F4/5 and p107 as Smad cofactors linking the TGFβ receptor to c-myc repression.Cell. 2002; 110: 19-32Abstract Full Text Full Text PDF PubMed Scopus (369) Google Scholar, Frederick et al., 2004Frederick J.P. Liberati N.T. Waddell D.S. Shi Y. Wang X.F. Transforming growth factor β-mediated transcriptional repression of c-myc is dependent on direct binding of Smad3 to a novel repressive Smad binding element.Mol. Cell. Biol. 2004; 24: 2546-2559Crossref PubMed Scopus (176) Google Scholar). Smad3 can also physically cooperate with ATF3 and repress transcription of the Id1 gene, which encodes an inhibitor of differentiation in epithelial cells (Kang et al., 2003Kang Y. Chen C.R. Massague J. A self-enabling TGFβ response coupled to stress signaling: Smad engages stress response factor ATF3 for Id1 repression in epithelial cells.Mol. Cell. 2003; 11: 915-926Abstract Full Text Full Text PDF PubMed Scopus (416) Google Scholar). In both of these cases, similar to Shn-mediated repression in Drosophila, Smad proteins associate with cofactors to bring about repression. A somewhat different mechanism for signal-induced transcriptional repression has also been uncovered in mammalian cells. The inhibition of osteoblast differentiation by TGFβ is mediated, in part, by the interaction of Smad3 with Runx2, leading to the repression of the transcriptional activity of Runx2 and, therefore, to a repression of the Runx2 target gene osteocalcin (Alliston et al., 2001Alliston T. Choy L. Ducy P. Karsenty G. Derynck R. TGF-β-induced repression of CBFA1 by Smad3 decreases cbfa1 and osteocalcin expression and inhibits osteoblast differentiation.EMBO J. 2001; 20: 2254-2272Crossref PubMed Scopus (423) Google Scholar, Kang et al., 2005Kang J.S. Alliston T. Delston R. Derynck R. Repression of Runx2 function by TGF-β through recruitment of class II histone deacetylases by Smad3.EMBO J. 2005; 24: 2543-2555Crossref PubMed Scopus (253) Google Scholar). In this particular case, the Smad3-mediated repression neither requires the binding of Smad3 to the promoter nor results from decreased binding of Runx2 to its binding site in osteocalcin. The repression of Runx2 by Smad3 is mediated by the direct recruitment of class IIa HDACs, specifically HDAC4 and HDAC5, by TGFβ-activated Smad3 to the Runx2 binding sequence in the osteocalcin promoter. Similarly, Bmp signaling results in the formation of a complex of Nkx3.2, HDAC1, and Smad1, leading to inh" @default.
• W2028274324 created "2016-06-24" @default.
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• W2028274324 date "2008-07-01" @default.
• W2028274324 modified "2023-10-18" @default.
• W2028274324 title "Signal-Induced Repression: The Exception or the Rule in Developmental Signaling?" @default.
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• W2028274324 doi "https://doi.org/10.1016/j.devcel.2008.06.006" @default.
• W2028274324 hasPubMedId "https://pubmed.ncbi.nlm.nih.gov/18606137" @default.
• W2028274324 hasPublicationYear "2008" @default.
• W2028274324 type Work @default.
• W2028274324 sameAs 2028274324 @default.

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