Hairless-Mediated Repression of Notch Target Genes Requires the Combined Activity of Groucho and CtBP Corepressors

Nagel, Anja C.; Krejčı́, Alena; Tenin, Gennadiy; Bravo-Patiño, Alejandro; Bray, Sarah; Maier, Dieter; Preiss, Anette

doi:10.1128/mcb.25.23.10433-10441.2005

Cited by 125 publications

(221 citation statements)

References 48 publications

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“…For example, both Hairless and HDAC4 are important in Notch signaling because downstream genes in the Notch pathway are activated through binding of the NICD to the DNA-binding complex CSL (22). NICD competes for CSL binding with a corepressor complex, which consists of Hairless, CtBP, and Groucho, and additionally recruits histone deacetylases (HDAC) (23). Such enrichment of polymorphic differences in Notch pathway-related genes and the evidence of Notch activation revealed by expression profiling suggested a potentially important role of Notch in hypoxia tolerance.…”

Section: Spatial-temporal Activation Of Notch and Its Downstream Genementioning

confidence: 99%

Experimental selection of hypoxia-tolerant Drosophila melanogaster

Zhou

Udpa

Gersten

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

107

156

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Through long-term laboratory selection (over 200 generations), we have generated Drosophila melanogaster populations that tolerate severe, normally lethal, levels of hypoxia. Because of initial experiments suspecting genetic mechanisms underlying this adaptation, we compared the genomes of the hypoxia-selected flies with those of controls using deep resequencing. By applying unique computing and analytical methods we identified a number of DNA regions under selection, mostly on the X chromosome. Several of the hypoxia-selected regions contained genes encoding or regulating the Notch pathway. In addition, previous expression profiling revealed an activation of the Notch pathway in the hypoxia-selected flies. We confirmed the contribution of Notch activation to hypoxia tolerance using a specific γ-secretase inhibitor, N-[N-(3,5-Difluorophenacetyl)-L-alanyl]-S-phenylglycine t-butyl ester (DAPT), which significantly reduced adult survival and life span in the hypoxiaselected flies. We also demonstrated that flies with loss-of-function Notch mutations or RNAi-mediated Notch knockdown had a significant reduction in hypoxia tolerance, but those with a gain-of-function had a dramatic opposite effect. Using the UAS-Gal4 system, we also showed that specific overexpression of the Notch intracellular domain in glial cells was critical for conferring hypoxia tolerance. Unique analytical tools and genetic and bioinformatic strategies allowed us to discover that Notch activation plays a major role in this hypoxia tolerance in Drosophila melanogaster.evolution | next-generation sequencing O xygen homoeostasis is essential for development, growth, and integrity of cells, tissues, and organisms. Limited oxygen supply to cells and tissues (hypoxia) has a wide range of physiologic and potentially pathologic consequences, ranging from ischemic/hypoxic heart disease, stroke, and pulmonary hypertension to a number of obstetrical/perinatal complications, to high-altitude illnesses, to organ transplantation, and finally to intratumor hypoxia and cancer progression. Despite the clinical importance and societal disease impact of such a wide range of disorders, the molecular underpinnings of susceptibility or tolerance of cells or tissues to lack of O 2 are not well understood. Many studies have investigated the mechanisms that lead to injury when cells are deprived of O 2 , but to potentially treat or prevent the consequences of hypoxia necessitates also the understanding of the inherent tissue mechanisms that are critical for tolerance and survival. To do so, we use a long-term laboratory selection strategy that unmasks mechanisms that play an important role in hypoxia tolerance in a genetic model, Drosophila melanogaster (1, 2). In this attempt, starting with 27 isofemale D. melanogaster strains, and applying decreasing levels of O 2 over >200 generations, we generated Drosophila populations that tolerate severe levels of hypoxia, which are lethal to the original parental lines. These hypoxia-adapted flies (AF) pass the tolerance trait ...

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Section: Spatial-temporal Activation Of Notch and Its Downstream Genementioning

confidence: 99%

Experimental selection of hypoxia-tolerant Drosophila melanogaster

Zhou

Udpa

Gersten

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

107

156

View full text Add to dashboard Cite

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“…CSL recruits NCoR/SMRT (26), SHARP/MINT/ SPEN (41), CIR (21), SKIP (54), HAIRLESS, CtBP, and Groucho/TLE (8,38,39) to repress transcription of canonical Notch target genes. Activation of Notch signaling stimulates the release of N-ICD, which enters the nucleus to bind CSL and trigger its conversion to an activator of Notch target genes.…”

Section: Notch Target Gene Expression Is Altered In Lsk Hematopoieticmentioning

confidence: 99%

“…In the absence of N-ICD, CSL is a constitutive repressor of Notch target genes, reflecting its direct and indirect interactions with components of the transcriptional repression machinery (7). Corepressors that interact directly with CSL include NCoR/SMRT (26), SHARP/MINT/SPEN (41), CIR (21), SKIP (54), HAIRLESS, CtBP, and Groucho/TLE (8,38,39). While the conversion of CSL from constitutive repressor to activator of Notch targets is triggered by N-ICD, the underlying mechanism is poorly understood.…”

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confidence: 99%

Myeloid Translocation Gene 16 (MTG16) Interacts with Notch Transcription Complex Components To Integrate Notch Signaling in Hematopoietic Cell Fate Specification

Engel

Nguyen²,

Mariotti³

et al. 2010

Molecular and Cellular Biology

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The Notch signaling pathway regulates gene expression programs to influence the specification of cell fate in diverse tissues. In response to ligand binding, the intracellular domain of the Notch receptor is cleaved by the ␥-secretase complex and then translocates to the nucleus. There, it binds the transcriptional repressor CSL, triggering its conversion to an activator of Notch target gene expression. The events that control this conversion are poorly understood. We show that the transcriptional corepressor, MTG16, interacts with both CSL and the intracellular domains of Notch receptors, suggesting a pivotal role in regulation of the Notch transcription complex. The Notch1 intracellular domain disrupts the MTG16-CSL interaction. Ex vivo fate specification in response to Notch signal activation is impaired in Mtg16 ؊/؊ hematopoietic progenitors, and restored by MTG16 expression. An MTG16 derivative lacking the binding site for the intracellular domain of Notch1 fails to restore Notch-dependent cell fate. These data suggest that MTG16 interfaces with critical components of the Notch transcription complex to affect Notch-dependent lineage allocation in hematopoiesis.

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“…The outcome of these events is the release of the intracellular domain of Notch (known variously as Nact, ICN, or NICD), which acts as a transcriptional activator (Struhl and Adachi 1998) and activates gene expression in combination with Su(H). In the absence of the Notch intracellular domain, Su(H) interacts with corepressors such as Hairless, dCtBP, Groucho, and SMRTR, to inhibit transcription (Morel et al 2001;Barolo et al 2002;Tsuda et al 2002;Nagel et al 2005). When Notch is activated, it binds to Su(H) and transforms it from a negative regulator to a positive regulator (Furriols and Bray 2001;Morel et al 2001).…”

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confidence: 99%

Phylogenetic Footprinting Analysis in the Upstream Regulatory Regions of the DrosophilaEnhancer of splitGenes

et al. 2007

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During Drosophila development Suppressor of Hairless ½Su(H)-dependent Notch activation upregulates transcription of the Enhancer of split-Complex ½E(spl)-C genes. Drosophila melanogaster E(spl) genes share common transcription regulators including binding sites for Su(H), proneural, and E(spl) basic-helix-loophelix (bHLH) proteins. However, the expression patterns of E(spl) genes during development suggest that additional factors are involved. To better understand regulators responsible for these expression patterns, recently available sequence and annotation data for multiple Drosophila genomes were used to compare the E(spl) upstream regulatory regions from more than nine Drosophila species. The mg and mb regulatory regions are the most conserved of the bHLH genes. Fine analysis of Su(H) sites showed that high-affinity Su(H) paired sites and the Su(H) paired site plus proneural site (SPS 1 A) architecture are completely conserved in a subset of Drosophila E(spl) genes. The SPS 1 A module is also present in the upstream regulatory regions of the more ancient mosquito and honeybee E(spl) bHLH genes. Additional transcription factor binding sites were identified upstream of the E(spl) genes and compared between species of Drosophila. Conserved sites provide new understandings about E(spl) regulation during development. Conserved novel sequences found upstream of multiple E(spl) genes may play a role in the expression of these genes.

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Hairless-Mediated Repression of Notch Target Genes Requires the Combined Activity of Groucho and CtBP Corepressors

Cited by 125 publications

References 48 publications

Experimental selection of hypoxia-tolerant Drosophila melanogaster

Experimental selection of hypoxia-tolerant Drosophila melanogaster

Myeloid Translocation Gene 16 (MTG16) Interacts with Notch Transcription Complex Components To Integrate Notch Signaling in Hematopoietic Cell Fate Specification

Phylogenetic Footprinting Analysis in the Upstream Regulatory Regions of the DrosophilaEnhancer of splitGenes

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