The Experts below are selected from a list of 144 Experts worldwide ranked by ideXlab platform
Hans Clevers - One of the best experts on this subject based on the ideXlab platform.
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The Yin-Yang of TCF/beta-catenin signaling.
Advances in Cancer Research, 2008Co-Authors: Nick Barker, Patrice J Morin, Hans CleversAbstract:Publisher Summary Wingless/Wnt signaling directs cell-fate choices during embryonic development. Upon Wingless/Wnt signaling, a cascade is initiated that results in the accumulation of cytoplasmic β-catenin. In the absence of Wingless/Wnt signals, a key negative regulator of the pathway, GSK3β, is activated that mediates the downregulation of cytoplasmic β-catenin/Armadillo via the ubiquitin-proteasome pathway. In the absence of nuclear β-catenin, the Tcfs recruit the Corepressor Protein Groucho to the target gene enhancers and actively repress their transcription. An additional Corepressor Protein, CREB-binding Protein (CBP), is also involved in repression of Tcf target gene activity. In APC-deficient colon carcinoma cell lines, β-catenin accumulates and is complexed with nuclear Tcf-4. A proportion of APC wild-type colon carcinomas and melanomas also contains constitutive nuclear Tcf-4/β-catenin complexes as a result of dominant mutations in the N terminus of β-catenin that render it insensitive to downregulation by APC, GSK3β, and Axin/Conductin. This results in the unregulated expression of Tcf-4 target genes such as c-myc . Based on the established role for Tcf-4 in maintaining intestinal stem cells it is likely that deregulation of c-myc expression because of constitutive Tcf-4/ β-catenin activity promotes uncontrolled intestinal cell proliferation.
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the yin yang of tcf beta catenin signaling
Advances in Cancer Research, 2000Co-Authors: Nick Barker, Patrice J Morin, Hans CleversAbstract:Publisher Summary Wingless/Wnt signaling directs cell-fate choices during embryonic development. Upon Wingless/Wnt signaling, a cascade is initiated that results in the accumulation of cytoplasmic β-catenin. In the absence of Wingless/Wnt signals, a key negative regulator of the pathway, GSK3β, is activated that mediates the downregulation of cytoplasmic β-catenin/Armadillo via the ubiquitin-proteasome pathway. In the absence of nuclear β-catenin, the Tcfs recruit the Corepressor Protein Groucho to the target gene enhancers and actively repress their transcription. An additional Corepressor Protein, CREB-binding Protein (CBP), is also involved in repression of Tcf target gene activity. In APC-deficient colon carcinoma cell lines, β-catenin accumulates and is complexed with nuclear Tcf-4. A proportion of APC wild-type colon carcinomas and melanomas also contains constitutive nuclear Tcf-4/β-catenin complexes as a result of dominant mutations in the N terminus of β-catenin that render it insensitive to downregulation by APC, GSK3β, and Axin/Conductin. This results in the unregulated expression of Tcf-4 target genes such as c-myc . Based on the established role for Tcf-4 in maintaining intestinal stem cells it is likely that deregulation of c-myc expression because of constitutive Tcf-4/ β-catenin activity promotes uncontrolled intestinal cell proliferation.
David C Schultz - One of the best experts on this subject based on the ideXlab platform.
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the kap1 Corepressor functions to coordinate the assembly of de novo hp1 demarcated microenvironments of heterochromatin required for krab zinc finger Protein mediated transcriptional repression
Molecular and Cellular Biology, 2006Co-Authors: Smitha P Sripathy, Jessica Stevens, David C SchultzAbstract:KAP1/TIF1β is proposed to be a universal Corepressor Protein for the KRAB zinc finger Protein (KRAB-zfp) superfamily of transcriptional repressors. To characterize the role of KAP1 and KAP1-interacting Proteins in transcriptional repression, we investigated the regulation of stably integrated reporter transgenes by hormone-responsive KRAB and KAP1 repressor Proteins. Here, we demonstrate that depletion of endogenous KAP1 levels by small interfering RNA (siRNA) significantly inhibited KRAB-mediated transcriptional repression of a chromatin template. Similarly, reduction in cellular levels of HP1α/β/γ and SETDB1 by siRNA attenuated KRAB-KAP1 repression. We also found that direct tethering of KAP1 to DNA was sufficient to repress transcription of an integrated transgene. This activity is absolutely dependent upon the interaction of KAP1 with HP1 and on an intact PHD finger and bromodomain of KAP1, suggesting that these domains function cooperatively in transcriptional corepression. The achievement of the repressed state by wild-type KAP1 involves decreased recruitment of RNA polymerase II, reduced levels of histone H3 K9 acetylation and H3K4 methylation, an increase in histone occupancy, enrichment of trimethyl histone H3K9, H3K36, and histone H4K20, and HP1 deposition at proximal regulatory sequences of the transgene. A KAP1 Protein containing a mutation of the HP1 binding domain failed to induce any change in the histone modifications associated with DNA sequences of the transgene, implying that HP1-directed nuclear compartmentalization is required for transcriptional repression by the KRAB/KAP1 repression complex. The combination of these data suggests that KAP1 functions to coordinate activities that dynamically regulate changes in histone modifications and deposition of HP1 to establish a de novo microenvironment of heterochromatin, which is required for repression of gene transcription by KRAB-zfps.
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kap 1 Corepressor Protein interacts and colocalizes with heterochromatic and euchromatic hp1 Proteins a potential role for kruppel associated box zinc finger Proteins in heterochromatin mediated gene silencing
Molecular and Cellular Biology, 1999Co-Authors: Robert Ryan, David C Schultz, Kasirajan Ayyanathan, Prim B Singh, Josh R Friedman, William J Fredericks, Frank J RauscherAbstract:Kruppel-associated box (KRAB) domains are present in approximately one-third of all human zinc finger Proteins (ZFPs) and are potent transcriptional repression modules. We have previously cloned a Corepressor for the KRAB domain, KAP-1, which is required for KRAB-mediated repression in vivo. To characterize the repression mechanism utilized by KAP-1, we have analyzed the ability of KAP-1 to interact with murine (M31 and M32) and human (HP1α and HP1γ) homologues of the HP1 Protein family, a class of nonhistone heterochromatin-associated Proteins with a well-established epigenetic gene silencing function in Drosophila. In vitro studies confirmed that KAP-1 is capable of directly interacting with M31 and hHP1α, which are normally found in centromeric heterochromatin, as well as M32 and hHP1γ, both of which are found in euchromatin. Mapping of the region in KAP-1 required for HP1 interaction showed that amino acid substitutions which abolish HP1 binding in vitro reduce KAP-1 mediated repression in vivo. We observed colocalization of KAP-1 with M31 and M32 in interphase nuclei, lending support to the biochemical evidence that M31 and M32 directly interact with KAP-1. The colocalization of KAP-1 with M31 is sometimes found in subnuclear territories of potential pericentromeric heterochromatin, whereas colocalization of KAP-1 and M32 occurs in punctate euchromatic domains throughout the nucleus. This work suggests a mechanism for the recruitment of HP1-like gene products by the KRAB-ZFP–KAP-1 complex to specific loci within the genome through formation of heterochromatin-like complexes that silence gene activity. We speculate that gene-specific repression may be a consequence of the formation of such complexes, ultimately leading to silenced genes in newly formed heterochromatic chromosomal environments.
Nick Barker - One of the best experts on this subject based on the ideXlab platform.
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The Yin-Yang of TCF/beta-catenin signaling.
Advances in Cancer Research, 2008Co-Authors: Nick Barker, Patrice J Morin, Hans CleversAbstract:Publisher Summary Wingless/Wnt signaling directs cell-fate choices during embryonic development. Upon Wingless/Wnt signaling, a cascade is initiated that results in the accumulation of cytoplasmic β-catenin. In the absence of Wingless/Wnt signals, a key negative regulator of the pathway, GSK3β, is activated that mediates the downregulation of cytoplasmic β-catenin/Armadillo via the ubiquitin-proteasome pathway. In the absence of nuclear β-catenin, the Tcfs recruit the Corepressor Protein Groucho to the target gene enhancers and actively repress their transcription. An additional Corepressor Protein, CREB-binding Protein (CBP), is also involved in repression of Tcf target gene activity. In APC-deficient colon carcinoma cell lines, β-catenin accumulates and is complexed with nuclear Tcf-4. A proportion of APC wild-type colon carcinomas and melanomas also contains constitutive nuclear Tcf-4/β-catenin complexes as a result of dominant mutations in the N terminus of β-catenin that render it insensitive to downregulation by APC, GSK3β, and Axin/Conductin. This results in the unregulated expression of Tcf-4 target genes such as c-myc . Based on the established role for Tcf-4 in maintaining intestinal stem cells it is likely that deregulation of c-myc expression because of constitutive Tcf-4/ β-catenin activity promotes uncontrolled intestinal cell proliferation.
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the yin yang of tcf beta catenin signaling
Advances in Cancer Research, 2000Co-Authors: Nick Barker, Patrice J Morin, Hans CleversAbstract:Publisher Summary Wingless/Wnt signaling directs cell-fate choices during embryonic development. Upon Wingless/Wnt signaling, a cascade is initiated that results in the accumulation of cytoplasmic β-catenin. In the absence of Wingless/Wnt signals, a key negative regulator of the pathway, GSK3β, is activated that mediates the downregulation of cytoplasmic β-catenin/Armadillo via the ubiquitin-proteasome pathway. In the absence of nuclear β-catenin, the Tcfs recruit the Corepressor Protein Groucho to the target gene enhancers and actively repress their transcription. An additional Corepressor Protein, CREB-binding Protein (CBP), is also involved in repression of Tcf target gene activity. In APC-deficient colon carcinoma cell lines, β-catenin accumulates and is complexed with nuclear Tcf-4. A proportion of APC wild-type colon carcinomas and melanomas also contains constitutive nuclear Tcf-4/β-catenin complexes as a result of dominant mutations in the N terminus of β-catenin that render it insensitive to downregulation by APC, GSK3β, and Axin/Conductin. This results in the unregulated expression of Tcf-4 target genes such as c-myc . Based on the established role for Tcf-4 in maintaining intestinal stem cells it is likely that deregulation of c-myc expression because of constitutive Tcf-4/ β-catenin activity promotes uncontrolled intestinal cell proliferation.
Riccardo Baron - One of the best experts on this subject based on the ideXlab platform.
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a complete configurational ensemble approach to expand lsd1 corest druggability
Biophysical Journal, 2014Co-Authors: James C Robertson, Nathan C Hurley, Julie M Kneller, Nadeem A. Vellore, Andrea Mattevi, Riccardo BaronAbstract:Lysine specific demethylase-1 (LSD1/KDM1A) in complex with the Corepressor Protein CoREST is a promising target for epigenetic drugs yet no therapeutics targeting LSD1/CoREST are currently available. Extended molecular dynamics (MD) simulations have indicated that LSD1/CoREST nanoscale clamp dynamics are regulated by substrate binding and highlighted key hinge points of this large-scale motion as well as the relevance of local residue dynamics. Prompted by the urgent need for new molecular probes and inhibitors to understand LSD1/CoREST interactions with small-molecules, peptides, Protein partners, and chromatin, we undertake here a complete configurational ensemble approach to expand LSD1/CoREST druggability. The independent algorithms FTMap and SiteMap and a newly developed Druggable Site Visualizer (DSV) software tool were used to predict and inspect favorable binding sites on an ensemble of structures generated by MD simulation. We found that three hinge points revealed by MD simulations are new potential targets for the discovery of molecular probes to block association of LSD1/CoREST with chromatin or Protein partners. A fourth region was also predicted from simulated configurational ensembles and was experimentally validated to have strong binding propensity for a small peptide. This prediction would be prevented when using only the X-ray structures available (including the X-ray structure bound to the same peptide), which underscores the relevance of Protein conformational dynamics in Protein interactions. A fifth region was also highlighted corresponding to a small pocket on the AOD domain. This study sets the basis for future virtual screening campaigns targeting the five novel regions reported herein and for the design of LSD1/CoREST mutants to probe LSD1/CoREST binding with chromatin and various Protein partners. The newly developed computational methods are being further validated on various Protein receptors and have shown promising preliminary results.
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LSD1/CoREST reversible opening-closing dynamics: discovery of a nanoscale clamp for chromatin and Protein binding.
Biochemistry, 2012Co-Authors: Riccardo Baron, Nadeem A. VelloreAbstract:: LSD1 associated with its Corepressor Protein CoREST is an exceptionally relevant target for epigenetic drugs. Hypotheses for the role of LSD1/CoREST as a multidocking site for chromatin and Protein binding would require significant molecular flexibility, and LSD1/CoREST large-amplitude conformational dynamics is currently unknown. Here, molecular dynamics simulation reveals that the LSD1/CoREST complex in solution functions as a reversible nanoscale binding clamp. We show that the H3 histone tail binding pocket is a potential allosteric site for regulation of the rotation of SWIRM/SANT2 domains around the Tower domain. Thus, targeting this site and including receptor flexibility are crucial strategies for future drug discovery.
Patrice J Morin - One of the best experts on this subject based on the ideXlab platform.
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The Yin-Yang of TCF/beta-catenin signaling.
Advances in Cancer Research, 2008Co-Authors: Nick Barker, Patrice J Morin, Hans CleversAbstract:Publisher Summary Wingless/Wnt signaling directs cell-fate choices during embryonic development. Upon Wingless/Wnt signaling, a cascade is initiated that results in the accumulation of cytoplasmic β-catenin. In the absence of Wingless/Wnt signals, a key negative regulator of the pathway, GSK3β, is activated that mediates the downregulation of cytoplasmic β-catenin/Armadillo via the ubiquitin-proteasome pathway. In the absence of nuclear β-catenin, the Tcfs recruit the Corepressor Protein Groucho to the target gene enhancers and actively repress their transcription. An additional Corepressor Protein, CREB-binding Protein (CBP), is also involved in repression of Tcf target gene activity. In APC-deficient colon carcinoma cell lines, β-catenin accumulates and is complexed with nuclear Tcf-4. A proportion of APC wild-type colon carcinomas and melanomas also contains constitutive nuclear Tcf-4/β-catenin complexes as a result of dominant mutations in the N terminus of β-catenin that render it insensitive to downregulation by APC, GSK3β, and Axin/Conductin. This results in the unregulated expression of Tcf-4 target genes such as c-myc . Based on the established role for Tcf-4 in maintaining intestinal stem cells it is likely that deregulation of c-myc expression because of constitutive Tcf-4/ β-catenin activity promotes uncontrolled intestinal cell proliferation.
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the yin yang of tcf beta catenin signaling
Advances in Cancer Research, 2000Co-Authors: Nick Barker, Patrice J Morin, Hans CleversAbstract:Publisher Summary Wingless/Wnt signaling directs cell-fate choices during embryonic development. Upon Wingless/Wnt signaling, a cascade is initiated that results in the accumulation of cytoplasmic β-catenin. In the absence of Wingless/Wnt signals, a key negative regulator of the pathway, GSK3β, is activated that mediates the downregulation of cytoplasmic β-catenin/Armadillo via the ubiquitin-proteasome pathway. In the absence of nuclear β-catenin, the Tcfs recruit the Corepressor Protein Groucho to the target gene enhancers and actively repress their transcription. An additional Corepressor Protein, CREB-binding Protein (CBP), is also involved in repression of Tcf target gene activity. In APC-deficient colon carcinoma cell lines, β-catenin accumulates and is complexed with nuclear Tcf-4. A proportion of APC wild-type colon carcinomas and melanomas also contains constitutive nuclear Tcf-4/β-catenin complexes as a result of dominant mutations in the N terminus of β-catenin that render it insensitive to downregulation by APC, GSK3β, and Axin/Conductin. This results in the unregulated expression of Tcf-4 target genes such as c-myc . Based on the established role for Tcf-4 in maintaining intestinal stem cells it is likely that deregulation of c-myc expression because of constitutive Tcf-4/ β-catenin activity promotes uncontrolled intestinal cell proliferation.