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Tyler Jacks - One of the best experts on this subject based on the ideXlab platform.
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multiple Response Elements and differential p53 binding control perp expression during apoptosis
Molecular Cancer Research, 2003Co-Authors: Elizabeth E Reczek, Laura D Attardi, Elsa R Flores, Alice S Tsay, Tyler JacksAbstract:The p53 tumor suppressor gene responds to cellular stress by activating either cell cycle arrest or apoptosis. A growing number of target genes involved in each of these pathways have been identified. However, the mechanism by which the apoptosis versus arrest decision is made remains to be elucidated. Perp is a proapoptotic target gene of p53 expressed to high levels in apoptotic cells compared with those undergoing cell cycle arrest. This pattern of expression is unusual among p53 target genes, many of which are induced to similar levels during arrest and apoptosis. Here, we describe the regulation of the Perp gene by p53 through at least three Response Elements in the Perp promoter and first intron. These sites are occupied in vivo in E1A-expressing mouse embryo fibroblasts undergoing apoptosis but not cell cycle arrest, in contrast to the p21 5′ Response element, which is occupied during both. The apoptosis-deficient p53 point mutant, p53V143A, displays a selective deficit in binding to the Perp Elements, demonstrating that p53 can distinguish between Perp and p21 at the level of DNA binding. These results provide mechanistic insight into the selective expression of Perp during apoptosis and may provide a useful model for studying the p53-dependent cell cycle arrest versus apoptosis decision.
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multiple Response Elements and differential p53 binding control perp expression during apoptosis
Molecular Cancer Research, 2003Co-Authors: Elizabeth E Reczek, Laura D Attardi, Elsa R Flores, Alice S Tsay, Tyler JacksAbstract:The p53 tumor suppressor gene responds to cellular stress by activating either cell cycle arrest or apoptosis. A growing number of target genes involved in each of these pathways have been identified. However, the mechanism by which the apoptosis versus arrest decision is made remains to be elucidated. Perp is a proapoptotic target gene of p53 expressed to high levels in apoptotic cells compared with those undergoing cell cycle arrest. This pattern of expression is unusual among p53 target genes, many of which are induced to similar levels during arrest and apoptosis. Here, we describe the regulation of the Perp gene by p53 through at least three Response Elements in the Perp promoter and first intron. These sites are occupied in vivo in E1A-expressing mouse embryo fibroblasts undergoing apoptosis but not cell cycle arrest, in contrast to the p21 5′ Response element, which is occupied during both. The apoptosis-deficient p53 point mutant, p53V143A, displays a selective deficit in binding to the Perp Elements, demonstrating that p53 can distinguish between Perp and p21 at the level of DNA binding. These results provide mechanistic insight into the selective expression of Perp during apoptosis and may provide a useful model for studying the p53-dependent cell cycle arrest versus apoptosis decision.
Judith A Kassis - One of the best experts on this subject based on the ideXlab platform.
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Formation of a Polycomb-Domain in the Absence of Strong Polycomb Response Elements.
Public Library of Science (PLoS), 2016Co-Authors: Apratim Mitra, Yuzhong Cheng, Karl Pfeifer, Judith A KassisAbstract:Polycomb group Response Elements (PREs) in Drosophila are DNA-Elements that recruit Polycomb proteins (PcG) to chromatin and regulate gene expression. PREs are easily recognizable in the Drosophila genome as strong peaks of PcG-protein binding over discrete DNA fragments; many small but statistically significant PcG peaks are also observed in PcG domains. Surprisingly, in vivo deletion of the four characterized strong PREs from the PcG regulated invected-engrailed (inv-en) gene complex did not disrupt the formation of the H3K27me3 domain and did not affect inv-en expression in embryos or larvae suggesting the presence of redundant PcG recruitment mechanism. Further, the 3D-structure of the inv-en domain was only minimally altered by the deletion of the strong PREs. A reporter construct containing a 7.5kb en fragment that contains three weak peaks but no large PcG peaks forms an H3K27me3 domain and is PcG-regulated. Our data suggests a model for the recruitment of PcG-complexes to Drosophila genes via interactions with multiple, weak PREs spread throughout an H3K27me3 domain
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polycomb group Response Elements in drosophila and vertebrates
Advances in Genetics, 2013Co-Authors: Judith A Kassis, Lesley J BrownAbstract:Polycomb group genes (PcG) encode a group of about 16 proteins that were first identified in Drosophila as repressors of homeotic genes. PcG proteins are present in all metazoans and are best characterized as transcriptional repressors. In Drosophila, these proteins are known as epigenetic regulators because they remember, but do not establish, the patterned expression state of homeotic genes throughout development. PcG proteins, in general, are not DNA binding proteins, but act in protein complexes to repress transcription at specific target genes. How are PcG proteins recruited to the DNA? In Drosophila, there are specific regulatory DNA Elements called Polycomb group Response Elements (PREs) that bring PcG protein complexes to the DNA. Drosophila PREs are made up of binding sites for a complex array of DNA binding proteins. Functional PRE assays in transgenes have shown that PREs act in the context of other regulatory DNA and PRE activity is highly dependent on genomic context. Drosophila PREs tend to regulate genes with a complex array of regulatory DNA in a cell or tissue-specific fashion and it is the interplay between regulatory DNA that dictates PRE function. In mammals, PcG proteins are more diverse and there are multiple ways to recruit PcG complexes, including RNA-mediated recruitment. In this review, we discuss evidence for PREs in vertebrates and explore similarities and differences between Drosophila and vertebrate PREs.
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polycomb Response Elements and targeting of polycomb group proteins in drosophila
Current Opinion in Genetics & Development, 2006Co-Authors: Jurg Muller, Judith A KassisAbstract:Polycomb group (PcG) proteins are conserved regulatory proteins that repress transcription of particular target genes in animals and plants. Studies over the past decade have established that most PcG proteins are not classic DNA binding factors but that they exist in multisubunit protein complexes that bind to and modify chromatin. Nevertheless, PcG repression of target genes in Drosophila requires specific cis-regulatory sequences, called Polycomb Response Elements (PREs), and chromatin immunoprecipitation studies have shown that, in vivo, most PcG proteins are specifically bound at the PREs of target genes. However, the mechanisms by which these PcG protein complexes are recruited to PREs and how they repress transcription are still poorly understood. Recent studies challenge earlier models that invoke covalent histone modifications and chromatin binding as the key steps in the recruitment of PcG proteins to PREs. The available evidence suggests that PREs are largely devoid of nucleosomes and that PRE DNA serves as an assembly platform for many different PcG protein complexes through DNA-protein and protein-protein interactions. The emerging picture suggests that the binding and modification of chromatin by PcG proteins is needed for interaction of PRE-tethered PcG protein complexes with nucleosomes in the flanking chromatin in order to maintain a Polycomb-repressed chromatin state at promoters and coding regions of target genes.
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pairing sensitive silencing polycomb group Response Elements and transposon homing in drosophila
Advances in Genetics, 2002Co-Authors: Judith A KassisAbstract:Abstract Regulatory DNA from a diverse group of Drosophila genes causes silencing of the linked reporter gene mini- white in the P-element vector CaSpeR. This silencing can occur in flies heterozygous for the P-element construct but is often enhanced in flies homozygous for the construct. In Drosophila, somatic chromosomes are paired and this pairing is important for the enhancement of silencing in most cases. Thus, this type of silencing has been called pairing-sensitive silencing. Many of the DNA fragments that cause pairing-sensitive silencing are regulatory Elements required for the activity of the Polycomb group of transcriptional repressors (Polycomb group Response Elements, PREs). However, some PREs do not appear to cause pairing-sensitive silencing, and some fragments of DNA that cause pairing-sensitive silencing do not appear to act as PREs. I suggest that many PREs are composite Elements of sites important for silencing and sites important for “pairing” or bringing together distant DNA Elements. Both activities may be required for PRE function. In a related phenomenon, fragments of DNA included within P-element vectors can cause those transposons to insert in the genome near the parent gene of the included DNA (transposon homing). I suggest that DNA fragments that cause transposon homing or pairing-sensitive silencing are bound by protein complexes that can interact to bring together distant DNA fragments.
Elizabeth E Reczek - One of the best experts on this subject based on the ideXlab platform.
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multiple Response Elements and differential p53 binding control perp expression during apoptosis
Molecular Cancer Research, 2003Co-Authors: Elizabeth E Reczek, Laura D Attardi, Elsa R Flores, Alice S Tsay, Tyler JacksAbstract:The p53 tumor suppressor gene responds to cellular stress by activating either cell cycle arrest or apoptosis. A growing number of target genes involved in each of these pathways have been identified. However, the mechanism by which the apoptosis versus arrest decision is made remains to be elucidated. Perp is a proapoptotic target gene of p53 expressed to high levels in apoptotic cells compared with those undergoing cell cycle arrest. This pattern of expression is unusual among p53 target genes, many of which are induced to similar levels during arrest and apoptosis. Here, we describe the regulation of the Perp gene by p53 through at least three Response Elements in the Perp promoter and first intron. These sites are occupied in vivo in E1A-expressing mouse embryo fibroblasts undergoing apoptosis but not cell cycle arrest, in contrast to the p21 5′ Response element, which is occupied during both. The apoptosis-deficient p53 point mutant, p53V143A, displays a selective deficit in binding to the Perp Elements, demonstrating that p53 can distinguish between Perp and p21 at the level of DNA binding. These results provide mechanistic insight into the selective expression of Perp during apoptosis and may provide a useful model for studying the p53-dependent cell cycle arrest versus apoptosis decision.
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multiple Response Elements and differential p53 binding control perp expression during apoptosis
Molecular Cancer Research, 2003Co-Authors: Elizabeth E Reczek, Laura D Attardi, Elsa R Flores, Alice S Tsay, Tyler JacksAbstract:The p53 tumor suppressor gene responds to cellular stress by activating either cell cycle arrest or apoptosis. A growing number of target genes involved in each of these pathways have been identified. However, the mechanism by which the apoptosis versus arrest decision is made remains to be elucidated. Perp is a proapoptotic target gene of p53 expressed to high levels in apoptotic cells compared with those undergoing cell cycle arrest. This pattern of expression is unusual among p53 target genes, many of which are induced to similar levels during arrest and apoptosis. Here, we describe the regulation of the Perp gene by p53 through at least three Response Elements in the Perp promoter and first intron. These sites are occupied in vivo in E1A-expressing mouse embryo fibroblasts undergoing apoptosis but not cell cycle arrest, in contrast to the p21 5′ Response element, which is occupied during both. The apoptosis-deficient p53 point mutant, p53V143A, displays a selective deficit in binding to the Perp Elements, demonstrating that p53 can distinguish between Perp and p21 at the level of DNA binding. These results provide mechanistic insight into the selective expression of Perp during apoptosis and may provide a useful model for studying the p53-dependent cell cycle arrest versus apoptosis decision.
Frank Claessens - One of the best experts on this subject based on the ideXlab platform.
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identification of androgen selective androgen Response Elements in the human aquaporin 5 and rad9 genes
Biochemical Journal, 2008Co-Authors: Udo Moehren, Sarah Denayer, Michael Podvinec, Guy Verrijdt, Frank ClaessensAbstract:The AR (androgen receptor) is known to influence the expression of its target genes by binding to different sets of AREs (androgen-Response Elements) in the DNA. One set consists of the classical steroid-Response Elements which are partial palindromic repeats of the 5'-TGTTCT-3' steroid-receptor monomer-binding element. The second set contains motifs that are AR-specific and that are proposed to be partial direct repeats of the same motif. On the basis of this assumption, we used an in silico approach to identify new androgen-selective AREs in the regulatory regions of known androgen-responsive genes. We have used an extension of the NUBIScan algorithm to screen a collection of 85 known human androgen-responsive genes compiled from literature and database searches. We report the evaluation of the most promising hits resulting from this computational search by in vitro DNA-binding assays using full-size ARs and GRs (glucocorticoid receptors) as well as their isolated DBDs (DNA-binding domains). We also describe the ability of some of these motifs to confer androgen-, but not glucocorticoid-, responsiveness to reporter-gene expression. The Elements found in the aquaporin-5 and the Rad9 (radiation-sensitive 9) genes showed selective AR versus GR binding in band-shift assays and a strong activity and selectivity in functional assays, both as isolated Elements and in their original contexts. Our data indicate the validity of the hypothesis that selective AREs are recognizable as direct 5'-TGTTCT-3' repeats, and extend the list of currently known selective Elements.
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structural basis of androgen receptor binding to selective androgen Response Elements
Proceedings of the National Academy of Sciences of the United States of America, 2004Co-Authors: Paul L Shaffer, Arif Jivan, Eric D Dollins, Frank Claessens, Daniel T GewirthAbstract:Steroid receptors bind as dimers to a degenerate set of Response Elements containing inverted repeats of a hexameric half-site separated by 3 bp of spacer (IR3). Naturally occurring selective androgen Response Elements have recently been identified that resemble direct repeats of the hexameric half-site (ADR3). The 3D crystal structure of the androgen receptor (AR) DNA-binding domain bound to a selective ADR3 reveals an unexpected head-to-head arrangement of the two protomers rather than the expected head-to-tail arrangement seen in nuclear receptors bound to Response Elements of similar geometry. Compared with the glucocorticoid receptor, the DNA-binding domain dimer interface of the AR has additional interactions that stabilize the AR dimer and increase the affinity for nonconsensus Response Elements. This increased interfacial stability compared with the other steroid receptors may account for the selective binding of AR to ADR3 Response Elements.
Renato Paro - One of the best experts on this subject based on the ideXlab platform.
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polycomb trithorax Response Elements and epigenetic memory of cell identity
Development, 2007Co-Authors: Leonie Ringrose, Renato ParoAbstract:Polycomb/Trithorax group Response Elements (PRE/TREs) are fascinating chromosomal pieces. Just a few hundred base pairs long, these Elements can remember and maintain the active or silent transcriptional state of their associated genes for many cell generations, long after the initial determining activators and repressors have disappeared. Recently, substantial progress has been made towards understanding the nuts and bolts of PRE/TRE function at the molecular level and in experimentally mapping PRE/TRE sites across whole genomes. Here we examine the insights, controversies and new questions that have been generated by this recent flood of data.
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genome wide prediction of polycomb trithorax Response Elements in drosophila melanogaster
Developmental Cell, 2003Co-Authors: Leonie Ringrose, Marc Rehmsmeier, Jeanmaurice Dura, Renato ParoAbstract:Polycomb/Trithorax Response Elements (PRE/TREs) maintain transcriptional decisions to ensure correct cell identity during development and differentiation. There are thought to be over 100 PRE/TREs in the Drosophila genome, but only very few have been identified due to the lack of a defining consensus sequence. Here we report the definition of sequence criteria that distinguish PRE/TREs from non-PRE/TREs. Using this approach for genome-wide PRE/TRE prediction, we identify 167 candidate PRE/TREs, which map to genes involved in development and cell proliferation. We show that candidate PRE/TREs are bound and regulated by Polycomb proteins in vivo, thus demonstrating the validity of PRE/TRE prediction. Using the larger data set thus generated, we identify three sequence motifs that are conserved in PRE/TRE sequences.
