AES/GRG5: More than just a dominant‐negative TLE/GRG family member

Beagle, Brandon; Johnson, Gail V.W.

doi:10.1002/dvdy.22439

Cited by 34 publications

(33 citation statements)

References 69 publications

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“…As has been discussed previously [8], [28], [29], this study also provides further evidence that AES is not a general dominant-inhibitor of TLE, highlighting the need for caution when interpreting the results of studies based on the use of AES overexpression strategies.…”

Section: Discussionsupporting

confidence: 70%

Establishment of Motor Neuron-V3 Interneuron Progenitor Domain Boundary in Ventral Spinal Cord Requires Groucho-Mediated Transcriptional Corepression

et al. 2012

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BackgroundDorsoventral patterning of the developing spinal cord is important for the correct generation of spinal neuronal types. This process relies in part on cross-repressive interactions between specific transcription factors whose expression is regulated by Sonic hedgehog. Groucho/transducin-like Enhancer of split (TLE) proteins are transcriptional corepressors suggested to be recruited by at least certain Sonic hedgehog-controlled transcription factors to mediate the formation of spatially distinct progenitor domains within the ventral spinal cord. The aim of this study was to characterize the involvement of TLE in mechanisms regulating the establishment of the boundary between the most ventral spinal cord progenitor domains, termed pMN and p3. Because the pMN domain gives rise to somatic motor neurons while the p3 domain generates V3 interneurons, we also examined the involvement of TLE in the acquisition of these neuronal fates.Methodology and Principal FindingsA combination of in vivo loss- and gain-of-function studies in the developing chick spinal cord was performed to characterize the role of TLE in ventral progenitor domain formation. It is shown here that TLE overexpression causes increased numbers of p3 progenitors and promotes the V3 interneuron fate while suppressing the motor neuron fate. Conversely, dominant-inhibition of TLE increases the numbers of pMN progenitors and postmitotic motor neurons.ConclusionBased on these results, we propose that TLE is important to promote the formation of the p3 domain and subsequent generation of V3 interneurons.

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Section: Discussionsupporting

confidence: 70%

Establishment of Motor Neuron-V3 Interneuron Progenitor Domain Boundary in Ventral Spinal Cord Requires Groucho-Mediated Transcriptional Corepression

et al. 2012

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“…To determine whether Grg4 represses Nodal pathway activity in the ectoderm and prevents inappropriate activation of mesodermal genes, Groucho-related gene 5 (Grg5) was used to antagonize Grg4 function (Beagle and Johnson, 2010; Brantjes et al, 2001). Grg5 lacks the canonical HDAC-recruitment “WD” domain of Grg4, and thus, relieves Grg4-dependent repression, resulting in upregulation of Grg4 target genes (Brantjes et al, 2001).…”

Section: Resultsmentioning

confidence: 99%

FoxH1 mediates a Grg4 and Smad2 dependent transcriptional switch in Nodal signaling during Xenopus mesoderm development

Reid

Steiner

Yaklichkin

et al. 2016

Developmental Biology

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In the vertebrate blastula and gastrula the Nodal pathway is essential for formation of the primary germ layers and the organizer. Nodal autoregulatory feedback potentiates signaling activity, but mechanisms limiting embryonic Nodal ligand transcription are poorly understood. Here we describe a transcriptional switch mechanism mediated by FoxH1, the principle effector of Nodal autoregulation. FoxH1 contains a conserved engrailed homology (EH1) motif that mediates direct binding of groucho-related gene 4 (Grg4), a Groucho family corepressor. Nodal-dependent gene expression is suppressed by FoxH1, but enhanced by a FoxH1 EH1 mutant, indicating that the EH1 motif is necessary for repression. Grg4 blocks Nodal-induced mesodermal gene expression and Nodal autoregulation, suggesting that Grg4 limits Nodal pathway activity. Conversely, blocking Grg4 function in the ectoderm results in ectopic expression of Nodal target genes. FoxH1 and Grg4 occupy the Xnr1 enhancer, and Grg4 occupancy is dependent on the FoxH1 EH1 motif. Grg4 occupancy at the Xnr1 enhancer significantly decreases with Nodal activation or Smad2 overexpression, while FoxH1 occupancy is unaffected. These results suggest that Nodal-activated Smad2 physically displaces Grg4 from FoxH1, an essential feature of the transcriptional switch mechanism. In support of this model, when FoxH1 is unable to bind Smad2, Grg4 occupancy is maintained at the Xnr1 enhancer, even in the presence of Nodal signaling. Our findings reveal that FoxH1 mediates both activation and repression of Nodal gene expression. We propose that this transcriptional switch is essential to delimit Nodal pathway activity in vertebrate germ layer formation.

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“…40,41 Upon nuclear translocation, TLE1 heterooligomerizes with the amino-terminal enhancer of Split (AES), another member of the Groucho/TLE/Grg family. 42 In cancer cells losing the integrin-ECM interaction, the AES/TLE1 heterooligomers are translocated from the nucleus to the cytoplasm following translocation of Bit1 into the cytoplasm. 43 The subsequent downregulation of nuclear TLE1 expression activates the death signaling pathway (Fig.…”

Section: Signaling Death To “Homeless” Cellsmentioning

confidence: 99%

Anoikis and EMT: Lethal "Liaisons" during Cancer Progression

2016

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Anoikis is a unique mode of apoptotic cell death that occurs consequentially to insufficient cell–matrix interactions. Resistance to anoikis is a critical contributor to tumor invasion and metastasis. The phenomenon is regulated by integrins, which upon engagement with components of the extracellular matrix (ECM) form adhesion complexes and the actin cytoskeleton drives the formation of cell protrusions used to adhere to ECM, directing cell migration. The epithelial-mesenchymal transition (EMT) confers stem cell properties and leads to acquisition of a migratory and invasive phenotype by causing adherens junction breakdown and circumventing anoikis in the tumor microenvironment. The investigation of drug discovery platforms for apoptosis-driven therapeutics identified several novel agents with antitumor action via reversing resistance to anoikis, inhibiting survival pathways and impacting the EMT landscape in human cancer. In this review, we discuss current evidence on the contribution of the anoikis phenomenon functionally linked to EMT to cancer metastasis and the therapeutic value of antitumor drugs that selectively reverse anoikis resistance and/or EMT to impair tumor progression toward the development/optimization of apoptosis-driven therapeutic targeting of metastatic disease.

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AES/GRG5: More than just a dominant‐negative TLE/GRG family member

Cited by 34 publications

References 69 publications

Establishment of Motor Neuron-V3 Interneuron Progenitor Domain Boundary in Ventral Spinal Cord Requires Groucho-Mediated Transcriptional Corepression

Establishment of Motor Neuron-V3 Interneuron Progenitor Domain Boundary in Ventral Spinal Cord Requires Groucho-Mediated Transcriptional Corepression

FoxH1 mediates a Grg4 and Smad2 dependent transcriptional switch in Nodal signaling during Xenopus mesoderm development

Anoikis and EMT: Lethal "Liaisons" during Cancer Progression

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