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Journal articles on the topic 'Groucho/TLE'

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Author: Grafiati
Published: 11 March 2023

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1

Desjobert, Cecile, Peter Noy, Tracey Swingler, Hannah Williams, Kevin Gaston, and Padma-Sheela Jayaraman. "The PRH/Hex repressor protein causes nuclear retention of Groucho/TLE co-repressors." Biochemical Journal 417, no. 1 (December 12, 2008): 121–32. http://dx.doi.org/10.1042/bj20080872.

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The PRH (proline-rich homeodomain) [also known as Hex (haematopoietically expressed homeobox)] protein is a transcription factor that functions as an important regulator of vertebrate development and many other processes in the adult including haematopoiesis. The Groucho/TLE (transducin-like enhancer) family of co-repressor proteins also regulate development and modulate the activity of many DNA-binding transcription factors during a range of diverse cellular processes including haematopoiesis. We have shown previously that PRH is a repressor of transcription in haematopoietic cells and that an Eh-1 (Engrailed homology) motif present within the N-terminal transcription repression domain of PRH mediates binding to Groucho/TLE proteins and enables co-repression. In the present study we demonstrate that PRH regulates the nuclear retention of TLE proteins during cellular fractionation. We show that transcriptional repression and the nuclear retention of TLE proteins requires PRH to bind to both TLE and DNA. In addition, we characterize a trans-dominant-negative PRH protein that inhibits wild-type PRH activity by sequestering TLE proteins to specific subnuclear domains. These results demonstrate that transcriptional repression by PRH is dependent on TLE availability and suggest that subnuclear localization of TLE plays an important role in transcriptional repression by PRH.
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2

Chen, Guoqing, and Albert J. Courey. "Groucho/TLE family proteins and transcriptional repression." Gene 249, no. 1-2 (May 2000): 1–16. http://dx.doi.org/10.1016/s0378-1119(00)00161-x.

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3

HUSAIN, Junaid, Rita LO, Diane GRBAVEC, and Stefano STIFANI. "Affinity for the nuclear compartment and expression during cell differentiation implicate phosphorylated Groucho/TLE1 forms of higher molecular mass in nuclear functions." Biochemical Journal 317, no. 2 (July 15, 1996): 523–31. http://dx.doi.org/10.1042/bj3170523.

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The Drosophila protein Groucho is involved in embryonic segmentation and neural development, and is implicated in the Notch signal transduction pathway. We are investigating the molecular mechanisms underlying the function of Groucho and of its mammalian homologues, the TLE (‘transducin-like Enhancer of split’) proteins. We show that Groucho/TLE1 proteins are phosphorylated. We also show that two populations of phosphorylated Groucho proteins can be identified based on their interaction with the nuclear compartment. More slowly migrating proteins with an apparent molecular mass of roughly 110 kDa interact strongly with the nuclei, while faster migrating proteins displaying molecular masses of roughly 84–85 kDa show lower affinity for the nuclear compartment. Similarly, TLE1 proteins with an apparent molecular mass of roughly 118 kDa exhibit higher affinity for the nuclear compartment than do faster migrating forms with apparent molecular masses of 90–93 kDa. Moreover, we show that the nuclear, more slowly migrating, TLE1 proteins are induced during neural determination of P19 embryonic carcinoma cells. These results implicate phosphorylation in the activity of Groucho/TLE1 proteins and suggest that phosphorylated forms of higher molecular mass are involved in nuclear functions. Finally, we show that different TLE proteins respond in different ways to the neural commitment of P19 cells, suggesting that individual members of this protein family may have non-redundant functions.
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4

Heimbucher, Thomas, Christina Murko, Baubak Bajoghli, Narges Aghaallaei, Anja Huber, Ronald Stebegg, Dirk Eberhard, Maria Fink, Antonio Simeone, and Thomas Czerny. "Gbx2 and Otx2 Interact with the WD40 Domain of Groucho/Tle Corepressors." Molecular and Cellular Biology 27, no. 1 (October 23, 2006): 340–51. http://dx.doi.org/10.1128/mcb.00811-06.

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ABSTRACT One of the earliest organizational decisions in the development of the vertebrate brain is the division of the neural plate into Otx2-positive anterior and Gbx2-positive posterior territories. At the junction of these two expression domains, a local signaling center is formed, known as the midbrain-hindbrain boundary (MHB). This tissue coordinates or “organizes” the development of neighboring brain structures, such as the midbrain and cerebellum. Correct positioning of the MHB is thought to depend on mutual repression involving these two homeobox genes. Using a cell culture colocalization assay and coimmunoprecipitation experiments, we show that engrailed homology region 1 (eh1)-like motifs of both transcription factors physically interact with the WD40 domain of Groucho/Tle corepressor proteins. In addition, heat shock-induced expression of wild-type and mutant Otx2 and Gbx2 in medaka embryos demonstrates that Groucho is required for the repression of Otx2 by Gbx2. On the other hand, the repressive functions of Otx2 on Gbx2 do not appear to be dependent on corepressor interaction. Interestingly, the association of Groucho with Otx2 is also required for the repression of Fgf8 in the MHB. Therefore Groucho/Tle family members appear to regulate key aspects in the MHB development of the vertebrate brain.
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5

GRBAVEC, Diane, Rita LO, Yanling LIU, Andy GREENFIELD, and Stefano STIFANI. "Groucho/transducin-like Enhancer of split (TLE) family members interact with the yeast transcriptional co-repressor SSN6 and mammalian SSN6-related proteins: implications for evolutionary conservation of transcription repression mechanisms." Biochemical Journal 337, no. 1 (December 17, 1998): 13–17. http://dx.doi.org/10.1042/bj3370013.

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The yeast proteins TUP1 and SSN6 form a transcription repressor complex that is recruited to different promoters via pathway-specific DNA-binding proteins and regulates the expression of a variety of genes. TUP1 is functionally related to invertebrate and vertebrate transcriptional repressors of the Groucho/transducin-like Enhancer of split (TLE) family. The aim was to examine whether similar mechanisms underlie the transcription repression functions of TUP1 and Groucho/TLEs by determining whether TLE family members can interact with yeast SSN6 and mammalian SSN6-like proteins. It is shown in the present work that SSN6 binds to TLE1 and mediates transcriptional repression when expressed in mammalian cells. Moreover, TLE1 and TLE2 interact with two mammalian proteins related to SSN6, designated as the products of the ubiquitously transcribed tetratricopeptide-repeat genes on the Y (or X) chromosomes (UTY/X). These findings suggest that mammalian TLE and UTY/X proteins may mediate repression mechanisms similar to those performed by TUP1–SSN6 in yeast.
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6

Hoffman, Brad G., Bogard Zavaglia, Mike Beach, and Cheryl D. Helgason. "Expression of Groucho/TLE proteins during pancreas development." BMC Developmental Biology 8, no. 1 (2008): 81. http://dx.doi.org/10.1186/1471-213x-8-81.

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7

Cinnamon, Einat, and Ze’ev Paroush. "Context-dependent regulation of Groucho/TLE-mediated repression." Current Opinion in Genetics & Development 18, no. 5 (October 2008): 435–40. http://dx.doi.org/10.1016/j.gde.2008.07.010.

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8

Fisher, A. L., S. Ohsako, and M. Caudy. "The WRPW motif of the hairy-related basic helix-loop-helix repressor proteins acts as a 4-amino-acid transcription repression and protein-protein interaction domain." Molecular and Cellular Biology 16, no. 6 (June 1996): 2670–77. http://dx.doi.org/10.1128/mcb.16.6.2670.

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Hairy-related proteins include the Drosophila Hairy and Enhancer of Split proteins and mammalian Hes proteins. These proteins are basic helix-loop-helix (bHLH) transcriptional repressors that control cell fate decisions such as neurogenesis or myogenesis in both Drosophila melanogaster and mammals. Hairy-related proteins are site-specific DNA-binding proteins defined by the presence of both a repressor-specific bHLH DNA binding domain and a carboxyl-terminal WRPW (Trp-Arg-Pro-Trp) motif. These proteins act as repressors by binding to DNA sites in target gene promoters and not by interfering with activator proteins, indicating that these proteins are active repressors which should therefore have specific repression domains. Here we show the WRPW motif to be a functional transcriptional repression domain sufficient to confer active repression to Hairy-related proteins or a heterologous DNA-binding protein, Ga14. This motif was previously shown to be necessary for interactions with Groucho, a genetically defined corepressor for Drosophila Hairy-related proteins. Here we show that the WRPW motif is sufficient to recruit Groucho or the TLE mammalian homologs to target gene promoters. We also show that Groucho and TLE proteins actively repress transcription when directly bound to a target gene promoter and identify a novel, highly conserved transcriptional repression domain in these proteins. These results directly demonstrate that Groucho family proteins are active transcriptional corepressors for Hairy-related proteins and are recruited by the 4-amino acid protein-protein interaction domain, WRPW.
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9

Jennings, Barbara H., and David Ish-Horowicz. "The Groucho/TLE/Grg family of transcriptional co-repressors." Genome Biology 9, no. 1 (2008): 205. http://dx.doi.org/10.1186/gb-2008-9-1-205.

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10

Patel, Sanjeevkumar R., Samina S. Bhumbra, Raghavendra S. Paknikar, and Gregory R. Dressler. "Epigenetic Mechanisms of Groucho/Grg/TLE Mediated Transcriptional Repression." Molecular Cell 45, no. 2 (January 2012): 185–95. http://dx.doi.org/10.1016/j.molcel.2011.11.007.

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11

Hanson, Alison J., Heather A. Wallace, Tanner J. Freeman, R. Daniel Beauchamp, Laura A. Lee, and Ethan Lee. "XIAP Monoubiquitylates Groucho/TLE to Promote Canonical Wnt Signaling." Molecular Cell 45, no. 5 (March 2012): 619–28. http://dx.doi.org/10.1016/j.molcel.2011.12.032.

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12

Aghaallaei, Narges, Baubak Bajoghli, Ingrid Walter, and Thomas Czerny. "Duplicated members of the Groucho/Tle gene family in fish." Developmental Dynamics 234, no. 1 (2005): 143–50. http://dx.doi.org/10.1002/dvdy.20510.

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13

Nuthall, Hugh N., Junaid Husain, Keith W. McLarren, and Stefano Stifani. "Role for Hes1-Induced Phosphorylation in Groucho-Mediated Transcriptional Repression." Molecular and Cellular Biology 22, no. 2 (January 15, 2002): 389–99. http://dx.doi.org/10.1128/mcb.22.2.389-399.2002.

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ABSTRACT Transcriptional corepressors of the Groucho/transducin-like Enhancer of split (Gro/TLE) family regulate a number of developmental pathways in both invertebrates and vertebrates. They form transcription repression complexes with members of several DNA-binding protein families and participate in the regulation of the expression of numerous genes. Despite their pleiotropic roles, little is known about the mechanisms that regulate the functions of Gro/TLE proteins. It is shown here that Gro/TLEs become hyperphosphorylated in response to neural cell differentiation and interaction with the DNA-binding cofactor Hairy/Enhancer of split 1 (Hes1). Hyperphosphorylation of Gro/TLEs is correlated with a tight association with the nuclear compartment through interaction with chromatin, suggesting that hyperphosphorylated Gro/TLEs may mediate transcriptional repression via chromatin remodeling mechanisms. Pharmacological inhibition of protein kinase CK2 reduces the Hes1-induced hyperphosphorylation of Gro/TLEs and causes a decrease in the chromatin association of the latter. Moreover, the transcription repression activity of Gro/TLEs is reduced by protein kinase CK2 inhibition. Consistent with these observations, Gro/TLEs are phosphorylated in vitro by purified protein kinase CK2. Taken together, these results implicate protein kinase CK2 in Gro/TLE functions. They suggest further that this kinase is involved in a hyperphosphorylation mechanism activated by Hes1 that promotes the transcription repression functions of Hes1-Gro/TLE protein complexes.
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14

Martinez, Carlos A., and David N. Arnosti. "Spreading of a Corepressor Linked to Action of Long-Range Repressor Hairy." Molecular and Cellular Biology 28, no. 8 (February 19, 2008): 2792–802. http://dx.doi.org/10.1128/mcb.01203-07.

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ABSTRACT Transcriptional repressor proteins play key roles in the control of gene expression in development. For the Drosophila embryo, the following two functional classes of repressors have been described: short-range repressors such as Knirps that locally inhibit the activity of enhancers and long-range repressors such as Hairy that can dominantly inhibit distal elements. Several long-range repressors interact with Groucho, a conserved corepressor that is homologous to mammalian TLE proteins. Groucho interacts with histone deacetylases and histone proteins, suggesting that it may effect repression by means of chromatin modification; however, it is not known how long-range effects are mediated. Using embryo chromatin immunoprecipitation, we have analyzed a Hairy-repressible gene in the embryo during activation and repression. When inactivated, repressors, activators, and coactivators cooccupy the promoter, suggesting that repression is not accomplished by the displacement of activators or coactivators. Strikingly, the Groucho corepressor is found to be recruited to the transcribed region of the gene, contacting a region of several kilobases, concomitant with a loss of histone H3 and H4 acetylation. Groucho has been shown to form higher-order complexes in vitro; thus, our observations suggest that long-range effects may be mediated by a “spreading” mechanism, modifying chromatin over extensive regions to inhibit transcription.
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15

Kawamura, Akinori, Sumito Koshida, and Shinji Takada. "Activator-to-Repressor Conversion of T-Box Transcription Factors by the Ripply Family of Groucho/TLE-Associated Mediators." Molecular and Cellular Biology 28, no. 10 (March 10, 2008): 3236–44. http://dx.doi.org/10.1128/mcb.01754-07.

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ABSTRACT The T-box family of transcription factors, defined by a conserved DNA binding domain called the T-box, regulate various aspects of embryogenesis by activating and/or repressing downstream genes. In spite of the biological significance of the T-box proteins, how they regulate transcription remains to be elucidated. Here we show that the Groucho/TLE-associated protein Ripply converts T-box proteins from activators to repressors. In cultured cells, zebrafish Ripply1, an essential component in somite segmentation, and its structural relatives, Ripply2 and -3, suppress the transcriptional activation mediated by the T-box protein Tbx24, which is coexpressed with ripply1 during segmentation. Ripply1 associates with Tbx24 and converts it to a repressor. Ripply1 also antagonizes the transcriptional activation of another T-box protein, No tail (Ntl), the zebrafish ortholog of Brachyury. Furthermore, injection of a high dosage of ripply1 mRNA into zebrafish eggs causes defective development of the posterior trunk, similar to the phenotype observed in homozygous mutants of ntl. A mutant form of Ripply1 defective in association with Tbx24 also lacks activity in zebrafish embryos. These results indicate that the intrinsic transcriptional property of T-box proteins is controlled by Ripply family proteins, which act as specific adaptors that recruit the global corepressor Groucho/TLE to T-box proteins.
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16

Sweetser, David, Selvi Ramasamy, Jessica S. Blackburn, and David M. Langenau. "The TLE1 Tumor Suppressor Regulates Myc Induced Leukemogenesis." Blood 118, no. 21 (November 18, 2011): 2473. http://dx.doi.org/10.1182/blood.v118.21.2473.2473.

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Abstract Abstract 2473 The Groucho/TLE family of corepressors has been described as master regulatory genes during development, affecting multiple cell fate decisions. These proteins bind to a variety of transcription factors and recruit inhibitory proteins to repress transcription. We previously identified TLE1 as a novel tumor suppressor gene that is deleted or methylated in subgroups of acute myeloid leukemia (AML) and other hematological malignancies. We find the loss of Tle1 alone is insufficient to induce leukemia in mice and apparently requires cooperation with additional oncogenes. Our studies, and those from other groups, have shown that over-expression of TLE1 in leukemia cells slows cell cycle progression, colony formation and tumor growth in xenografts, while silencing results in increased cell proliferation. The pathways by which TLE1 affects oncogenesis is unclear, but this gene family is capable of interacting with effectors of Myc, Wnt, Notch, TGFB signaling–prominent pathways dysregulated in malignancies. Myc is important for hematopoietic stem cell proliferation, survival and differentiation and is over-expressed in most AML samples. The TLE homologue Groucho binds and represses Drosophila Myc expression of target genes, thus we postulated that TLE1 could be an important regulator of Myc activity in leukemia. Using hematopoietic progenitor cells from Tle1 knockout and wild-type fetal livers we found that the loss of Tle1 dramatically increased proliferation and serial replating efficiency. Expression of N-Myc by itself in wild type fetal liver cells triggered significant cell death and apoptosis. However, when N-Myc expression was combined with the additional loss of Tle1, not only was N-Myc induced apoptosis inhibited, but a dramatic cell proliferation, well in excess of that seen with Tle1 loss by itself, was seen. Furthermore, mice transplanted with N-Myc transduced hematopoietic cells from Tle1 knockout mice fetal liver developed a more aggressive leukemia, compared to N-Myc transfected wild type mice fetal liver hematopoietic cells, with increased proliferation of leukemic cells as demonstrated by in vitro colony assays and higher secondary transplantability. We extended these studies to a zebrafish model of Rag2-Myc mediated T-ALL. Using these zebrafish we demonstrated over-expression of the TLE homologue, Groucho, completely blocked the initiation and progression of Myc induced leukemia development. Expression of a truncated version of Groucho reduced the initiation of T-ALL and prolonged the survival of fish developing leukemia. These studies demonstrate TLE1 can inhibit the oncogenicity of Myc, and suggests modulation of expression of this gene family may be of importance for a variety of malignancies. Disclosures: No relevant conflicts of interest to declare.
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17

Xing, Shaojun, Peng Shao, Fengyin Li, Xudong Zhao, Wooseok Seo, Justin C. Wheat, Selvi Ramasamy, et al. "Tle corepressors are differentially partitioned to instruct CD8+ T cell lineage choice and identity." Journal of Experimental Medicine 215, no. 8 (July 25, 2018): 2211–26. http://dx.doi.org/10.1084/jem.20171514.

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Tle/Groucho proteins are transcriptional corepressors interacting with Tcf/Lef and Runx transcription factors, but their physiological roles in T cell development remain unknown. Conditional targeting of Tle1, Tle3 and Tle4 revealed gene dose–dependent requirements for Tle proteins in CD8+ lineage cells. Upon ablating all three Tle proteins, generation of CD8+ T cells was greatly diminished, largely owing to redirection of MHC-I–selected thymocytes to CD4+ lineage; the remaining CD8-positive T cells showed aberrant up-regulation of CD4+ lineage-associated genes including Cd4, Thpok, St8sia6, and Foxp3. Mechanistically, Tle3 bound to Runx-occupied Thpok silencer, in post-selection double-positive thymocytes to prevent excessive ThPOK induction and in mature CD8+ T cells to silence Thpok expression. Tle3 also bound to Tcf1-occupied sites in a few CD4+ lineage-associated genes, including Cd4 silencer and St8sia6 introns, to repress their expression in mature CD8+ T cells. These findings indicate that Tle corepressors are differentially partitioned to Runx and Tcf/Lef complexes to instruct CD8+ lineage choice and cooperatively establish CD8+ T cell identity, respectively.
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18

Bajoghli, Baubak. "Evolution of the Groucho/Tle gene family: gene organization and duplication events." Development Genes and Evolution 217, no. 8 (July 12, 2007): 613–18. http://dx.doi.org/10.1007/s00427-007-0167-y.

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19

Nuthall, Hugh N., Kerline Joachim, and Stefano Stifani. "Phosphorylation of Serine 239 of Groucho/TLE1 by Protein Kinase CK2 Is Important for Inhibition of Neuronal Differentiation." Molecular and Cellular Biology 24, no. 19 (October 1, 2004): 8395–407. http://dx.doi.org/10.1128/mcb.24.19.8395-8407.2004.

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ABSTRACT Transcriptional corepressors of the Groucho (Gro)/TLE family play important roles during a variety of developmental pathways, including neuronal differentiation. In particular, they act as negative regulators of neurogenesis, together with Hairy/Enhancer of split (Hes) DNA-binding proteins. The interaction with Hes1 leads to Gro/TLE hyperphosphorylation and increased transcription repression activity in mammalian cells, but the underlying molecular mechanisms are poorly characterized. We now show that Gro/TLE1 is phosphorylated in vivo by protein kinase CK2. This phosphorylation occurs at serine 239 within the conserved CcN domain present in all Gro/TLE family members. Mutation of serine 239 into alanine decreases Hes1-induced hyperphosphorylation of Gro/TLE1 and also reduces its nuclear association and transcription repression activity. We demonstrate further that Gro/TLE1 inhibits the transition of cortical neural progenitors into neurons and that its antineurogenic activity is inhibited by a serine-239-alanine mutation but not by a serine-239-glutamate mutation. These results suggest that CK2 phosphorylation of serine 239 of Gro/TLE1 is important for its function during neuronal differentiation.
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20

Bajoghli, Baubak, Narges Aghaallaei, Daniele Soroldoni, and Thomas Czerny. "The roles of Groucho/Tle in left–right asymmetry and Kupffer’s vesicle organogenesis." Developmental Biology 303, no. 1 (March 2007): 347–61. http://dx.doi.org/10.1016/j.ydbio.2006.11.020.

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21

Jan, Yiwen, Michelle Matter, Jih-tung Pai, Yen-Liang Chen, Jan Pilch, Masanobu Komatsu, Edgar Ong, Minoru Fukuda, and Erkki Ruoslahti. "A Mitochondrial Protein, Bit1, Mediates Apoptosis Regulated by Integrins and Groucho/TLE Corepressors." Cell 122, no. 3 (August 2005): 485–86. http://dx.doi.org/10.1016/j.cell.2005.07.022.

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22

Jan, Yiwen, Michelle Matter, Jih-tung Pai, Yen-Liang Chen, Jan Pilch, Masanobu Komatsu, Edgar Ong, Minoru Fukuda, and Erkki Ruoslahti. "A Mitochondrial Protein, Bit1, Mediates Apoptosis Regulated by Integrins and Groucho/TLE Corepressors." Cell 116, no. 5 (March 2004): 751–62. http://dx.doi.org/10.1016/s0092-8674(04)00204-1.

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23

Bachar-Dahan, Liora, Janna Goltzmann, Abraham Yaniv, and Arnona Gazit. "Engrailed-1 Negatively Regulates β-Catenin Transcriptional Activity by Destabilizing β-Catenin via a Glycogen Synthase Kinase-3β–independent Pathway." Molecular Biology of the Cell 17, no. 6 (June 2006): 2572–80. http://dx.doi.org/10.1091/mbc.e06-01-0052.

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The Wnt signaling pathway plays a major role in development, and upon deregulation it is implicated in neoplasia. The hallmark of the canonical Wnt signal is the protection of β-catenin from ubiquitination and proteasomal degradation induced by glycogen synthase kinase (GSK)-3β inhibition. The stabilized β-catenin translocates to the nucleus where it binds to T-cell factor/lymphoid enhancer factor (TCF/LEF) transcription factors, activating the expression of Wnt target genes. In the absence of Wnt signal, TCF/LEF bind to Groucho (Gro)/TLE corepressors and repress Wnt target genes. Gro/TLE bind also to Engrailed (En) transcription factors mediating En-repressive activity on En target genes. Here, we present data suggesting that En-1 serves also as a negative regulator of β-catenin transcriptional activity; however, its repressive effect is independent of Gro/TLE. Our data suggest that En-1 acts by destabilizing β-catenin via a proteasomal degradation pathway that is GSK-3β–independent. Moreover, because En-1-mediated β-catenin degradation is also Siah independent, our data imply that En-1 exerts its repressive effect by a novel mechanism negatively controlling the level of β-catenin.
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24

Yochum, Gregory S., and Donald E. Ayer. "Pf1, a Novel PHD Zinc Finger Protein That Links the TLE Corepressor to the mSin3A-Histone Deacetylase Complex." Molecular and Cellular Biology 21, no. 13 (July 1, 2001): 4110–18. http://dx.doi.org/10.1128/mcb.21.13.4110-4118.2001.

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ABSTRACT The mSin3A-histone deacetylase corepressor is a multiprotein complex that is recruited by DNA binding transcriptional repressors. Sin3 has four paired amphipathic alpha helices (PAH1 to -4) that are protein-protein interaction motifs and is the scaffold upon which the complex assembles. We identified a novel mSin3A-interacting protein that has two plant homeodomain (PHD) zinc fingers we term Pf1, for PHD factor one. Pf1 associates with mSin3A in vivo and recruits the mSin3A complex to repress transcription when fused to the DNA binding domain of Gal4. Pf1 interacts with Sin3 through two independent Sin3 interaction domains (SIDs), Pf1SID1 and Pf1SID2. Pf1SID1 binds PAH2, while Pf1SID2 binds PAH1. Pf1SID1 has sequence and structural similarity to the well-characterized 13-amino-acid SID of the Mad bHLHZip repressor. Pf1SID2 does not have sequence similarity with either Mad SID or Pf1SID1 and therefore represents a novel Sin3 binding domain. Mutations in a minimal fragment of Pf1 that encompasses Pf1SID1 inhibited mSin3A binding yet only slightly impaired repression when targeted to DNA, implying that Pf1 might interact with other corepressors. We show that Pf1 interacts with a mammalian homolog of the Drosophila Groucho corepressor, transducin-like enhancer (TLE). Pf1 binds TLE in an mSin3A-independent manner and recruits functional TLE complexes to repress transcription. These findings suggest that Pf1 may serve to bridge two global transcription networks, mSin3A and TLE.
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25

Wang, Jianfeng, Farshid Dayyani, Christopher Brynczka, and David A. Sweetser. "Groucho/TLE Corepressors Regulate Myeloid Differentiation and Size of the Stem Cell/Progenitor Population." Blood 112, no. 11 (November 16, 2008): 1396. http://dx.doi.org/10.1182/blood.v112.11.1396.1396.

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Abstract The Groucho (Gro)/TLE family of transcriptional co-repressor proteins have been called master regulatory genes based on their interaction with a variety of transcription factors and their critical role in development. The TLEs have also been shown to play major roles in brain and lymphocyte differentiation. We became interested in this gene family after finding two family members, TLE1 and TLE4, localized to the commonly deleted region on chromosome 9q in acute myeloid leukemia (AML). This deletion is tightly associated with t(8;21), and we recently showed loss of TLE1 and TLE4 cooperated with AML1-ETO to affect myeloid cell proliferation and survival, implicating TLE1 and 4 as potential tumor suppressor genes in AML. Based on their known ability to inhibit the function of several signaling pathways and transcription factors including Wnt/b-catenin, NF-kB, AML1, and Pu.1 known to be important in leukemogenesis and hematopoiesis, we undertook a series of experiments to determine whether the TLEs could affect myeloid cell differentiation and proliferation. We showed that expression of either TLE1 or TLE4 was able to induce differentiation in the HL-60 myeloid cell line as demonstrated by morphological changes, increased expression of the myeloid differentiation makers CD11b, CD14 and CD15, downregulated myeloperoxidase activity, as well as increased nitroblue tetrazolium (NBT) staining. Furthermore, when HL-60 cells were induced to differentiate by exposure to all-trans-retinoic acid (ATRA) we observed a 150-fold transient increase in TLE1 message after three days. Knockdown of TLE1 with specific shRNAs partially blocked ATRA-induced differentiation as monitored by CD11b expression, suggesting this burst of TLE1 expression is critical for ATRA induced myeloid cell differentiation. To determine the role of the TLEs in primary human cells, human cord blood cells were sorted, and TLE mRNA levels were determined in progenitor cells (CD34+/CD33−/CD16−/CD15−/CD14−), early myeloid precursors (CD34−/CD33+/CD16−/CD15−CD14−) and mature granulocytes (CD34−/CD33+/CD16+/CD15−CD14−). Lowest levels of TLE1 and TLE4 were found in progenitor cells with a peak of expression in early myeloid precursors. To help determine the significance of these low TLE levels in hematopoietic stem/progenitor cells, we designed shRNAs to simultaneously knockdown both TLE1 and TLE4. Knockdown of TLE1/4 in cord blood cells resulted in a 6.3-fold expansion of CD34+CD38− cells after 4 days’ coculture with M2-10B4 in the presence of hSCF, hFlt3-ligand, and hTPO, as compared with only 2.6-fold expansion of cells transfected with control shRNA. Similarly, using mouse bone marrow cells cultured in vitro in the presence of mIL-3, mIL-6 and mSCF, we found a 2.1-fold increase in mouse bone marrow Lin−/Sca-1+/c-kit+ (LSK) cells transfected with TLE1/4 shRNA as compared to cells transfected with scrambled control shRNA. Our results indicate that modulation of TLE levels is capable of influencing both myeloid differentiation, as well as expansion of the stem cell and/or progenitor population.
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26

Yarmus, M., E. Woolf, Y. Bernstein, O. Fainaru, V. Negreanu, D. Levanon, and Y. Groner. "Groucho/transducin-like Enhancer-of-split (TLE)-dependent and -independent transcriptional regulation by Runx3." Proceedings of the National Academy of Sciences 103, no. 19 (May 1, 2006): 7384–89. http://dx.doi.org/10.1073/pnas.0602470103.

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27

Levanon, D., R. E. Goldstein, Y. Bernstein, H. Tang, D. Goldenberg, S. Stifani, Z. Paroush, and Y. Groner. "Transcriptional repression by AML1 and LEF-1 is mediated by the TLE/Groucho corepressors." Proceedings of the National Academy of Sciences 95, no. 20 (September 29, 1998): 11590–95. http://dx.doi.org/10.1073/pnas.95.20.11590.

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28

Gratton, Michel-Olivier, Elena Torban, Stephanie Belanger Jasmin, Francesca M. Theriault, Michael S. German, and Stefano Stifani. "Hes6 Promotes Cortical Neurogenesis and Inhibits Hes1 Transcription Repression Activity by Multiple Mechanisms." Molecular and Cellular Biology 23, no. 19 (October 1, 2003): 6922–35. http://dx.doi.org/10.1128/mcb.23.19.6922-6935.2003.

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ABSTRACT Hes1 is a mammalian basic helix-loop-helix transcriptional repressor that inhibits neuronal differentiation together with corepressors of the Groucho (Gro)/Transducin-like Enhancer of split (TLE) family. The interaction of Hes1 with Gro/TLE is mediated by a WRPW tetrapeptide present in all Hairy/Enhancer of split (Hes) family members. In contrast to Hes1, the related protein Hes6 promotes neuronal differentiation. Little is known about the molecular mechanisms that underlie the neurogenic activity of Hes6. It is shown here that Hes6 antagonizes Hes1 function by two mechanisms. Hes6 inhibits the interaction of Hes1 with its transcriptional corepressor Gro/TLE. Moreover, it promotes proteolytic degradation of Hes1. This effect is maximal when both Hes1 and Hes6 contain the WRPW motif and is reduced when Hes6 is mutated to eliminate a conserved site (Ser183) that can be phosphorylated by protein kinase CK2. Consistent with these findings, Hes6 inhibits Hes1-mediated transcriptional repression in cortical neural progenitor cells and promotes the differentiation of cortical neurons, a process that is normally inhibited by Hes1. Mutation of Ser183 impairs the neurogenic ability of Hes6. Taken together, these findings clarify the molecular events underlying the neurogenic function of Hes6 and suggest that this factor can antagonize Hes1 activity by multiple mechanisms.
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29

Javed, A., B. Guo, S. Hiebert, J. Y. Choi, J. Green, S. C. Zhao, M. A. Osborne, et al. "Groucho/TLE/R-esp proteins associate with the nuclear matrix and repress RUNX (CBF(alpha)/AML/PEBP2(alpha)) dependent activation of tissue-specific gene transcription." Journal of Cell Science 113, no. 12 (June 15, 2000): 2221–31. http://dx.doi.org/10.1242/jcs.113.12.2221.

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The Runt related transcription factors RUNX (AML/CBF(alpha)/PEBP2(alpha)) are key regulators of hematopoiesis and osteogenesis. Using co-transfection experiments with four natural promoters, including those of the osteocalcin (OC), multi drug resistance (MDR), Rous Sarcoma Virus long terminal repeat (LTR), and bone sialoprotein (BSP) genes, we show that each of these promoters responds differently to the forced expression of RUNX proteins. However, the three RUNX subtypes (i.e. AML1, AML2, and AML3) regulate each promoter in a similar manner. Although the OC promoter is activated in a C terminus dependent manner, the MDR, LTR and BSP promoters are repressed by three distinct mechanisms, either independent of or involving the AML C terminus, or requiring only the conserved C-terminal pentapeptide VWRPY. Using yeast two hybrid assays we find that the C terminus of AML1 interacts with a Groucho/TLE/R-esp repressor protein. Co-expression assays reveal that TLE proteins repress AML dependent activation of OC gene transcription. Western and northern blot analyses suggest that TLE expression is regulated reciprocally with the levels of OC gene expression during osteoblast differentiation. Digital immunofluorescence microscopy results show that TLE1 and TLE2 are both associated with the nuclear matrix, and that a significant subset of each colocalizes with AML transcription factors. This co-localization of TLE and AML proteins is lost upon removing the C terminus of AML family members. Our findings indicate that suppression of AML-dependent gene activation by TLE proteins involves functional interactions with the C terminus of AML at the nuclear matrix in situ. Our data are consistent with the concept that the C termini of AML proteins support activation or repression of cell-type specific genes depending on the regulatory organization of the target promoter and subnuclear localization.
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30

Yu, Xin, Peng Li, Robert G. Roeder, and Zhengxin Wang. "Inhibition of Androgen Receptor-Mediated Transcription by Amino-Terminal Enhancer of split." Molecular and Cellular Biology 21, no. 14 (July 15, 2001): 4614–25. http://dx.doi.org/10.1128/mcb.21.14.4614-4625.2001.

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ABSTRACT A yeast two-hybrid assay has identified an androgen-dependent interaction of androgen receptor (AR) with amino-terminal enhancer of split (AES), a member of the highly conserved Groucho/TLE family of corepressors. Full-length AR, as well as the N-terminal fragment of AR, showed direct interactions with AES in in vitro protein-protein interaction assays. AES specifically inhibited AR-mediated transcription in a well-defined cell-free transcription system and interacted specifically with the basal transcription factor (TFIIE) in HeLa nuclear extract. These observations implicate AES as a selective repressor of ligand-dependent AR-mediated transcription that acts by directly interacting with AR and by targeting the basal transcription machinery.
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31

Daniels, Danette L., and William I. Weis. "β-catenin directly displaces Groucho/TLE repressors from Tcf/Lef in Wnt-mediated transcription activation." Nature Structural & Molecular Biology 12, no. 4 (March 13, 2005): 364–71. http://dx.doi.org/10.1038/nsmb912.

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32

Jennings, Barbara H., Laura M. Pickles, S. Mark Wainwright, S. Mark Roe, Laurence H. Pearl, and David Ish-Horowicz. "Molecular Recognition of Transcriptional Repressor Motifs by the WD Domain of the Groucho/TLE Corepressor." Molecular Cell 22, no. 5 (June 2006): 645–55. http://dx.doi.org/10.1016/j.molcel.2006.04.024.

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33

Malin, S. "DNA-dependent conversion of Oct-1 and Oct-2 into transcriptional repressors by Groucho/TLE." Nucleic Acids Research 33, no. 14 (August 2, 2005): 4618–25. http://dx.doi.org/10.1093/nar/gki744.

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34

Marçal, Nathalie, Harshila Patel, Zhifeng Dong, Stephanie Belanger-Jasmin, Brad Hoffman, Cheryl D. Helgason, Jinjun Dang, and Stefano Stifani. "Antagonistic Effects of Grg6 and Groucho/TLE on the Transcription Repression Activity of Brain Factor 1/FoxG1 and Cortical Neuron Differentiation." Molecular and Cellular Biology 25, no. 24 (December 15, 2005): 10916–29. http://dx.doi.org/10.1128/mcb.25.24.10916-10929.2005.

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ABSTRACT Groucho (Gro)/TLE transcriptional corepressors are involved in a variety of developmental mechanisms, including neuronal differentiation. They contain a conserved C-terminal WD40 repeat domain that mediates interactions with several DNA-binding proteins. In particular, Gro/TLE1 interacts with forkhead transcription factor brain factor 1 (BF-1; also termed FoxG1). BF-1 is an essential regulator of neuronal differentiation during cerebral cortex development and represses transcription together with Gro/TLE1. Gro/TLE-related gene product 6 (Grg6) shares with Gro/TLEs a conserved WD40 repeat domain but is more distantly related at its N-terminal half. We demonstrate that Grg6 is expressed in cortical neural progenitor cells and interacts with BF-1. In contrast to Gro/TLE1, however, Grg6 does not promote, but rather suppresses, BF-1-mediated transcriptional repression. Consistent with these observations, Grg6 interferes with the binding of Gro/TLE1 to BF-1 and does not repress transcription when targeted to DNA. Moreover, coexpression of Grg6 and BF-1 in cortical progenitor cells leads to a decrease in the number of proliferating cells and increased neuronal differentiation. Conversely, Grg6 knockdown by RNA interference causes decreased neurogenesis. These results identify a new role for Grg6 in cortical neuron development and establish a functional link between Grg6 and BF-1.
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35

Sweetser, David A., Farshid Dayyani, Jianfeng Wang, Yuntian Zhang, and Tanweer Zaidi. "The Groucho Corepressors, TLE1 and TLE4, Are Candidate Del(9q) AML Tumor Suppressor Genes That Can Complement AML1-ETO." Blood 108, no. 11 (November 16, 2006): 1406. http://dx.doi.org/10.1182/blood.v108.11.1406.1406.

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Abstract Deletion of the long arm of chromosome 9, del(9q), is one of the most common cytogenetic abnormalities seen with t(8;21) AML. This close association suggests that that the loss of a critical gene(s) on chr9q cooperates with the AML1-ETO (RUNX1-MTG8) fusion gene produced by t(8;21) in leukemogenesis. We recently mapped the commonly deleted region of del(9q) AML to less than 2.4 Mb and identified all the genes mapping to this region. Extensive sequence analysis of these genes failed to reveal obvious mutations in del(9q) AML samples although the expression of a number of these genes appeared low specifically in del(9q) samples (Genes Chr and Ca 44, 279–291). To help determine the critical affected genes in the del(9q) CDR we used an siRNA expression library directed against all del(9q) CDR gene transcripts in an in vitro complementation assay with AML1-ETO. Inducible expression of AML1-ETO in U937 cells (U937T-A/E, Mol Cell Biol 21, 5577–5590) leads to cell cycle arrest and apoptosis. We introduced the del(9q) CDR siRNA library into U937T-A/E cells with the goal of finding siRNAs that rescued these cells after induction of AML1-ETO expression. The most commonly recovered siRNA using flanking PCR primers was directed against TLE1. Transducin-like enhancer of split (TLE) 1 and TLE4, are two members of the Groucho family of co-repressors that map adjacent to the del(9q) CDR. We subsequently demonstrated that knockdown of either TLE1 or TLE4 with specific siRNAs were able to overcome the induced cell cycle arrest in U937T-A/E cells. We further demonstrate that knockdown of either TLE in the AML1-ETO+ Kasumi-1 cell line increased cell division, increased expression of cyclin D1 and Ki67 and reduced the G0/G1 fraction, while expression of TLE1 or TLE4 in Kasumi-1 cells induced cell cycle arrest and apoptosis. Understanding how various mutations work cooperatively to produce a malignant phenotype is one of the great challenges in oncology. The TLEs are known to inhibit NFKB as well as Wnt signaling, two pathways implicated leukemic stem cell expansion. TLE inhibition may represent an important cooperating mutation with AML11-ETO in AML that links Wnt signaling and core binding protein transcription factors. Studies are currently underway to demonstrate this cooperativity and more directly evaluate the role of TLE inhibition in leukemogenesis.
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36

Flack, Joshua E., Juliusz Mieszczanek, Nikola Novcic, and Mariann Bienz. "Wnt-Dependent Inactivation of the Groucho/TLE Co-repressor by the HECT E3 Ubiquitin Ligase Hyd/UBR5." Molecular Cell 67, no. 2 (July 2017): 181–93. http://dx.doi.org/10.1016/j.molcel.2017.06.009.

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37

Mahadeveraju, Sharvani, Young-Ho Jung, and James W. Erickson. "Evidence That Runt Acts as a Counter-Repressor of Groucho During Drosophila melanogaster Primary Sex Determination." G3: Genes|Genomes|Genetics 10, no. 7 (May 26, 2020): 2487–96. http://dx.doi.org/10.1534/g3.120.401384.

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Runx proteins are bifunctional transcription factors that both repress and activate transcription in animal cells. Typically, Runx proteins work in concert with other transcriptional regulators, including co-activators and co-repressors to mediate their biological effects. In Drosophila melanogaster the archetypal Runx protein, Runt, functions in numerous processes including segmentation, neurogenesis and sex determination. During primary sex determination Runt acts as one of four X-linked signal element (XSE) proteins that direct female-specific activation of the establishment promoter (Pe) of the master regulatory gene Sex-lethal (Sxl). Successful activation of SxlPe requires that the XSE proteins overcome the repressive effects of maternally deposited Groucho (Gro), a potent co-repressor of the Gro/TLE family. Runx proteins, including Runt, contain a C-terminal peptide, VWRPY, known to bind to Gro/TLE proteins to mediate transcriptional repression. We show that Runt’s VWRPY co-repressor-interaction domain is needed for Runt to activate SxlPe. Deletion of the Gro-interaction domain eliminates Runt-ability to activate SxlPe, whereas replacement with a higher affinity, VWRPW, sequence promotes Runt-mediated transcription. This suggests that Runt may activate SxlPe by antagonizing Gro function, a conclusion consistent with earlier findings that Runt is needed for Sxl expression only in embryonic regions with high Gro activity. Surprisingly we found that Runt is not required for the initial activation of SxlPe. Instead, Runt is needed to keep SxlPe active during the subsequent period of high-level Sxl transcription suggesting that Runt helps amplify the difference between female and male XSE signals by counter-repressing Gro in female, but not in male, embryos.
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38

Hasson, P., and Z. Paroush. "Crosstalk between the EGFR and other signalling pathways at the level of the global transcriptional corepressor Groucho/TLE." British Journal of Cancer 94, no. 6 (February 28, 2006): 771–75. http://dx.doi.org/10.1038/sj.bjc.6603019.

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39

Imai, Yoichi, Mineo Kurokawa, Kozo Tanaka, Alan D. Friedman, Seishi Ogawa, Kinuko Mitani, Yoshio Yazaki, and Hisamaru Hirai. "TLE, the Human Homolog of Groucho, Interacts with AML1 and Acts as a Repressor of AML1-Induced Transactivation." Biochemical and Biophysical Research Communications 252, no. 3 (November 1998): 582–89. http://dx.doi.org/10.1006/bbrc.1998.9705.

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40

Kumar, Amit, Ravindra B. Chalamalasetty, Mark W. Kennedy, Sara Thomas, Shreya N. Inala, Robert J. Garriock, and Terry P. Yamaguchi. "Zfp703 Is a Wnt/β-Catenin Feedback Suppressor Targeting the β-Catenin/Tcf1 Complex." Molecular and Cellular Biology 36, no. 12 (April 18, 2016): 1793–802. http://dx.doi.org/10.1128/mcb.01010-15.

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The Wnt/β-catenin signaling pathway controls embryonic development and adult stem cell maintenance through the regulation of transcription. Failure to downregulate Wnt signaling can result in embryonic malformations and cancer, highlighting the important role of negative regulators of the pathway. The Wnt pathway activates several negative feedback targets, including axin2 and Dkk1, that function at different levels of the signaling cascade; however, none have been identified that directly target active β-catenin/Tcf1 transcriptional complexes. We show thatZfp703is a Wnt target gene that inhibits Wnt/β-catenin activity in Wnt reporter assays and in Wnt-dependent mesoderm differentiation in embryonic stem cells. Zfp703 binds directly to Tcf1 to inhibit β-catenin/Tcf1 complex formation and does so independently of the Groucho/Tle transcriptional corepressor. We propose that Zfp703 is a novel feedback suppressor of Wnt/β-catenin signaling that functions by inhibiting the association of β-catenin with Tcf1 on Wnt response elements in target gene enhancers.
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41

Bullinger, Lars, Konstanze Dohner, Raphael Kranz, Frank G. Rucker, Stefan Frohling, Richard F. Schlenk, Jonathan R. Pollack, and Hartmut Dohner. "Characterization of NPM1-Mutated/FLT3 ITD-Negative Acute Myeloid Leukemia with Normal Karyotype by Gene Expression Profiling." Blood 108, no. 11 (November 16, 2006): 155. http://dx.doi.org/10.1182/blood.v108.11.155.155.

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Abstract Acute myeloid leukemia (AML) with normal karyotype comprises a large number of molecularly distinct variants. For example the presence of internal tandem duplications (ITDs) of the FLT3 (fms-related tyrosine kinase 3) gene is associated with poor outcome, whereas mutations of the NPM1 (nucleophosmin) gene are prognostically favorable. However, this effect is mainly attributed to the NPM1-mutated/FLT3 ITD-negative AML cases. While NPM1-mutated cases are characterized by a distinct gene expression pattern, it remains unclear whether NPM1-mutated/FLT3 ITD-negative cases also display a characteristic signature, which might provide additional insights into the molecular basis for the good clinical outcome. Thus, we sought to identify a molecular profile for AML cases with NPM1-mutated/FLT3 ITD-negative normal karyotype disease. Towards this goal, we profiled gene expression of 138 samples of adult AML patients with normal karyotype using DNA microarray technology. All samples analyzed were derived from AML patients entered within the randomized multicenter treatment trial HD-98A of the German-Austrian AML Study Group (AMLSG). Based on supervised data analyses we were able to identify a 116-genes comprising expression pattern correlated with NPM1-mutated and FLT3 ITD-negative AML cases. In accordance with previous findings in NPM1-mutated cases (Alcalay et al. 2005, Verhaak et al. 2005), the NPM1-mutated/FLT3 ITD-negative pattern was also in part characterized by a prominent HOX gene cluster, which clearly separated the NPM1-wildtype from the NPM1-mutated cases. Similarly, the expression levels of BAALC and MN1 were correlated with the NPM1 mutational status, with NPM1-unmutated cases displaying higher BAALC and MN1 expression in our data set. However, as expected the newly defined signature also defined a NPM1-mutated group that did not contain many FLT3 ITD-positive samples. This group was characterized by several interesting genes including for example TLE1, which encodes a Groucho/TLE family protein. Groucho/TLE family proteins are transcriptional co-repressors, which mediate repression essential in embryonic development and are involved in regulation of Wnt signaling in adult tissue. Moreover, we identified several other genes of potential pathogenic relevance which also have been previously shown to be predictive in normal karyotype AML. Our findings support a distinct molecular mechanism associated with the favorable outcome of NPM1-mutated/FLT3 ITD-negative AML cases. Furthermore, the reported signature might contribute to improved risk stratification and clinical management of AML patients with normal karyotype disease.
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42

Li, Fengyin, Xin Zhao, Yali Zhang, Peng Shao, Xiaoke Ma, William J. Paradee, Chengyu Liu, Jianmin Wang, and Hai-Hui Xue. "TFH cells depend on Tcf1-intrinsic HDAC activity to suppress CTLA4 and guard B-cell help function." Proceedings of the National Academy of Sciences 118, no. 2 (December 28, 2020): e2014562118. http://dx.doi.org/10.1073/pnas.2014562118.

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Precise regulation of coinhibitory receptors is essential for maintaining immune tolerance without interfering with protective immunity, yet the mechanism underlying such a balanced act remains poorly understood. In response to protein immunization, T follicular helper (TFH) cells lacking Tcf1 and Lef1 transcription factors were phenotypically normal but failed to promote germinal center formation and antibody production. Transcriptomic profiling revealed that Tcf1/Lef1-deficient TFH cells aberrantly up-regulated CTLA4 and LAG3 expression, and treatment with anti-CTLA4 alone or combined with anti-LAG3 substantially rectified B-cell help defects by Tcf1/Lef1-deficient TFH cells. Mechanistically, Tcf1 and Lef1 restrain chromatin accessibility at the Ctla4 and Lag3 loci. Groucho/Tle corepressors, which are known to cooperate with Tcf/Lef factors, were essential for TFH cell expansion but dispensable for repressing coinhibitory receptors. In contrast, mutating key amino acids in histone deacetylase (HDAC) domain in Tcf1 resulted in CTLA4 derepression in TFH cells. These findings demonstrate that Tcf1-instrinsic HDAC activity is necessary for preventing excessive CTLA4 induction in protein immunization–elicited TFH cells and hence guarding their B-cell help function.
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Sekiya, Takashi, and Kenneth S. Zaret. "Repression by Groucho/TLE/Grg Proteins: Genomic Site Recruitment Generates Compacted Chromatin In Vitro and Impairs Activator Binding In Vivo." Molecular Cell 28, no. 2 (October 2007): 291–303. http://dx.doi.org/10.1016/j.molcel.2007.10.002.

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44

Song, Shilin, Diana Andrejeva, Flávia C. P. Freitas, Stephen M. Cohen, and Héctor Herranz. "dTcf/Pangolinsuppresses growth and tumor formation inDrosophila." Proceedings of the National Academy of Sciences 116, no. 28 (June 24, 2019): 14055–64. http://dx.doi.org/10.1073/pnas.1816981116.

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Wnt/Wingless (Wg) signaling controls many aspects of animal development and is deregulated in different human cancers. The transcription factor dTcf/Pangolin (Pan) is the final effector of the Wg pathway inDrosophilaand has a dual role in regulating the expression of Wg target genes. In the presence of Wg, dTcf/Pan interacts with β-catenin/Armadillo (Arm) and induces the transcription of Wg targets. In absence of Wg, dTcf/Pan partners with the transcriptional corepressor TLE/Groucho (Gro) and inhibits gene expression. Here, we use the wing imaginal disk ofDrosophilaas a model to examine the functions that dTcf/Pan plays in a proliferating epithelium. We report a function of dTcf/Pan in growth control and tumorigenesis. Our results show that dTcf/Pan can limit tissue growth in normal development and suppresses tumorigenesis in the context of oncogene up-regulation. We identify the conserved transcription factorsSox box protein 15(Sox15) andFtz transcription factor 1(Ftz-f1) as genes controlled by dTcf/Pan involved in tumor development. In conclusion, this study reports a role for dTcf/Pan as a repressor of normal and oncogenic growth and identifies the genes inducing tumorigenesis downstream of dTcf/Pan.
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45

Yao, Jing, Yanling Liu, Junaid Husain, Rita Lo, Anuradha Palaparti, Janet Henderson, and Stefano Stifani. "Combinatorial expression patterns of individual TLE proteins during cell determination and differentiation suggest non-redundant functions for mammalian homologs of Drosophila Groucho." Development, Growth and Differentiation 40, no. 2 (April 1998): 133–46. http://dx.doi.org/10.1046/j.1440-169x.1998.00003.x.

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46

Walrad, Pegine B., Saiyu Hang, Genevieve S. Joseph, Julia Salas, and J. Peter Gergen. "Distinct Contributions of Conserved Modules to Runt Transcription Factor Activity." Molecular Biology of the Cell 21, no. 13 (July 2010): 2315–26. http://dx.doi.org/10.1091/mbc.e09-11-0953.

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Runx proteins play vital roles in regulating transcription in numerous developmental pathways throughout the animal kingdom. Two Runx protein hallmarks are the DNA-binding Runt domain and a C-terminal VWRPY motif that mediates interaction with TLE/Gro corepressor proteins. A phylogenetic analysis of Runt, the founding Runx family member, identifies four distinct regions C-terminal to the Runt domain that are conserved in Drosophila and other insects. We used a series of previously described ectopic expression assays to investigate the functions of these different conserved regions in regulating gene expression during embryogenesis and in controlling axonal projections in the developing eye. The results indicate each conserved region is required for a different subset of activities and identify distinct regions that participate in the transcriptional activation and repression of the segmentation gene sloppy-paired-1 (slp1). Interestingly, the C-terminal VWRPY-containing region is not required for repression but instead plays a role in slp1 activation. Genetic experiments indicating that Groucho (Gro) does not participate in slp1 regulation further suggest that Runt's conserved C-terminus interacts with other factors to promote transcriptional activation. These results provide a foundation for further studies on the molecular interactions that contribute to the context-dependent properties of Runx proteins as developmental regulators.
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47

Shooshtarizadeh, Peiman, Ryan Chen, and Tarik Moroy. "The Zinc Finger Transcription Factor Growth Factor Independence 1b (Gfi1b) Regulates The Wnt/Beta-Catenin Signaling Pathway In Hematopoietic Stem Cells Through Interaction With Inhibitory Proteins." Blood 122, no. 21 (November 15, 2013): 2417. http://dx.doi.org/10.1182/blood.v122.21.2417.2417.

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Abstract Hematopoietic stem cells (HSCs) reside in the bone marrow in specific niches at the border between bone cells and the bone marrow (endosteal niche) or around blood vessels (perivascular niche). In the endosteal niche, HSCs are maintained at low oxygen levels in a quiescent (dormant) state by adhesion to niche cells. We have previously shown that Gfi1b restricts the expansion and proliferation of HSCs as well as their mobilization or re-localization into peripheral blood. We have proposed that Gfi1b exerts this function by regulating the expression of surface molecules such as integrins on HSCs that are required to maintain them in their bone marrow niche at a quiescent state. The objective of this study was to gain more insight into the precise molecular mechanisms by which Gfi1b regulates HSCs dormancy and mobilization and to obtain insights that may be exploited in the future to improve stem cell therapies or the expansion of human hematopoietic stem cells for clinical use. Immune precipitation and mass spectrometry identified a series of Gfi1b interacting proteins, most notably a group of regulators of the canonical Wnt/beta-catenin pathway. Independent protein IP validation of these findings suggested that Gfi1b can interact with several inhibitors of the canonical Wnt/beta catenin pathway namely with APC (Adenomatous polyposis coli) a tumor suppressor protein and important factor in the beta-catenin destruction complex, with the DNA helicase and chromatin remodeling factor CHD8, which silences beta catenin mediated transcription, with CtBP which antagonizes beta-catenin activity and is part of the LSD1/CoRest histone demethylase complex and with the direct beta-catenin inhibitors TLE1 and TLE3 (also called Groucho). Of particular interest was that the interactions between the Groucho proteins and Gfi1b were dependent on a previously unidentified Groucho binding domain (GBD) in Gfi1b. This is a well-conserved six-amino acid stretch that is found in the middle part of the Gfi1b protein. In addition, the binding of CtBP was dependent on the presence of the 20 amino acid N-terminal SNAG domain in Gfi1b that also mediates LSD1 binding. Using luciferase reporter gene assays (TOP/FOP reporter assay), we found that Gfi1b was able to significantly up-regulates TCF/beta-catenin-dependent transcription upon activation by LiCl or Wnt3A in HEK293 cells. This activity of Gfi1b was dependent on both the presence of the SNAG domain and the newly identified Groucho binding domain. Also, Gfi1b was able to reverse partially the inhibitory effect of CtBP and TLE3 on beta-catenin activity in the TOP/FOP reporter assays. To obtain further evidence that Gfi1b is indeed implicated in regulating the Wnt/beta catenin signaling pathway in hematopoietic stem cells, we FACS sorted Lin-Kit1+Sca+ hematopoietic progenitors (LSK cells) from wt and Gfi1b deficient mice and tested them for expression of Wnt effector genes using a Wnt signaling specific PCR array. We observed that the majority of Wnt target genes were significantly down regulated in Gfi1 deficient LSKs compared to wt LSKs. Among the genes affected the most were typical Wnt targets such as Axin2, Frz7, Tcf4, Klf5, Vegfa and Ccnd1. To show that Gfi1b is able to regulate Wnt pathway effectors in vivo in HSCs, we crossed Gfi1b flox/flox, Mx-Cre mice with animals that carry a NLS-lacZ reporter gene under the control of the endogenous Axin2 promoter/enhancer region. Treatment with pIpC, which deletes Gfi1b correlated with a significant decrease of Axin2 expression in HSCs and MPP1, which are high Gfi1b expressing cells. The Axin2 reporter was not affected by Gfi1b deletion in MPP2 or GMPs, which express low levels or no Gfi1b. The canonical Wnt/b-catenin signaling pathway is recognized as one of the elements that are critically important in the regulation of HSC function. Here we have identified Gfi1b as a potential new player in the Wnt-beta catenin signaling pathway. Our data suggest that Gfi1b acts on at least two inhibitory complexes of this pathway, on the TLE family of Groucho proteins and the CtBP/LSD1 complex and regulates effectors of the Wnt/beta-catenin signaling cascade. We propose therefore that Gfi1b may titer the level of activation of the Wnt/beta-catenin signaling pathway in HSCs, which offers an explanation of the hematopoietic stem cell phenotype seen in mice lacking Gfi1b. Disclosures: No relevant conflicts of interest to declare.
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Iso, Tatsuya, Vittorio Sartorelli, Coralie Poizat, Simona Iezzi, Hung-Yi Wu, Gene Chung, Larry Kedes, and Yasuo Hamamori. "HERP, a Novel Heterodimer Partner of HES/E(spl) in Notch Signaling." Molecular and Cellular Biology 21, no. 17 (September 1, 2001): 6080–89. http://dx.doi.org/10.1128/mcb.21.17.6080-6089.2001.

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ABSTRACT HERP1 and -2 are members of a new basic helix-loop-helix (bHLH) protein family closely related to HES/E(spl), the only previously known Notch effector. Like that of HES, HERP mRNA expression is directly up-regulated by Notch ligand binding without de novo protein synthesis. HES and HERP are individually expressed in certain cells, but they are also coexpressed within single cells after Notch stimulation. Here, we show that HERP has intrinsic transcriptional repression activity. Transcriptional repression by HES/E(spl) entails the recruitment of the corepressor TLE/Groucho via a conserved WRPW motif, whereas unexpectedly the corresponding—but modified—tetrapeptide motif in HERP confers marginal repression. Rather, HERP uses its bHLH domain to recruit the mSin3 complex containing histone deacetylase HDAC1 and an additional corepressor, N-CoR, to mediate repression. HES and HERP homodimers bind similar DNA sequences, but with distinct sequence preferences, and they repress transcription from specific DNA binding sites. Importantly, HES and HERP associate with each other in solution and form a stable HES-HERP heterodimer upon DNA binding. HES-HERP heterodimers have both a greater DNA binding activity and a stronger repression activity than do the respective homodimers. Thus, Notch signaling relies on cooperation between HES and HERP, two transcriptional repressors with distinctive repression mechanisms which, either as homo- or as heterodimers, regulate target gene expression.
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49

Westendorf, Jennifer J., S. Kaleem Zaidi, Jonathan E. Cascino, Rachel Kahler, André J. van Wijnen, Jane B. Lian, Minoru Yoshida, Gary S. Stein, and Xiaodong Li. "Runx2 (Cbfa1, AML-3) Interacts with Histone Deacetylase 6 and Represses the p21CIP1/WAF1 Promoter." Molecular and Cellular Biology 22, no. 22 (November 15, 2002): 7982–92. http://dx.doi.org/10.1128/mcb.22.22.7982-7992.2002.

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ABSTRACT Runx2 (Cbfa1, AML-3) is multifunctional transcription factor that is essential for osteoblast development. Runx2 binds specific DNA sequences and interacts with transcriptional coactivators and corepressors to either activate or repress transcription of tissue-specific genes. In this study, the p21 CIP/WAF1 promoter was identified as a repressible target of Runx2. A carboxy-terminal repression domain distinct from the well-characterized TLE/Groucho-binding domain contributed to Runx2-mediated p21 repression. This carboxy-terminal domain was sufficient to repress a heterologous GAL reporter. The repressive activity of this domain was sensitive to the histone deacetylase inhibitor trichostatin A but not to trapoxin B. HDAC6, which is insensitive to trapoxin B, specifically interacted with the carboxy terminus of Runx2. The HDAC6 interaction domain of Runx2 was mapped to a region overlapping the nuclear matrix-targeting signal. The Runx2 carboxy terminus was necessary for recruitment of HDAC6 from the cytoplasm to chromatin. HDAC6 also colocalized and coimmunoprecipitated with the nuclear matrix-associated protein Runx2 in osteoblasts. Finally, we show that HDAC6 is expressed in differentiating osteoblasts and that the Runx2 carboxy terminus is necessary for maximal repression of the p21 promoter in preosteoblasts. These data identify Runx2 as the first transcription factor to interact with HDAC6 and suggest that HDAC6 may bind to Runx2 in differentiating osteoblasts to regulate tissue-specific gene expression.
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50

BESS, Kirstin L., Tracey E. SWINGLER, A. Jennifer RIVETT, Kevin GASTON, and Padma-Sheela JAYARAMAN. "The transcriptional repressor protein PRH interacts with the proteasome." Biochemical Journal 374, no. 3 (September 15, 2003): 667–75. http://dx.doi.org/10.1042/bj20030769.

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PRH (proline-rich homeodomain protein)/Hex is important in the control of cell proliferation and differentiation. We have shown previously that PRH contains two domains that can bring about transcriptional repression independently; the PRH homeodomain represses transcription by binding to TATA box sequences, whereas the proline-rich N-terminal domain can repress transcription by interacting with members of the Groucho/TLE (transducin-like enhancer of split) family of co-repressor proteins. The proteasome is a multi-subunit protein complex involved in the processing and degradation of proteins. Some proteasome subunits have been suggested to play a role in the regulation of transcription. In the present study, we show that PRH interacts with the HC8 subunit of the proteasome in the context of both 20 and 26 S proteasomes. Moreover, we show that PRH is associated with the proteasome in haematopoietic cells and that the proline-rich PRH N-terminal domain is responsible for this interaction. Whereas PRH can be cleaved by the proteasome, it does not appear to be degraded rapidly in vitro or in vivo, and the proteolytic activity of the proteasome is not required for transcriptional repression by PRH. However, proteasomal digestion of PRH can liberate truncated PRH proteins that retain the ability to bind to DNA. We discuss these findings in terms of the biological role of PRH in gene regulation and the control of cell proliferation.
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