Identification of Notch target genes in uncommitted T-cell progenitors: no direct induction of a T-cell specific gene program

Weerkamp, Floor; Luís, Tiago C.; Naber, Brigitta A.E.; Koster, E.; Jeannotte, Lucie; Dongen, Jacques J. M. van; Staal, Frank J. T.

doi:10.1038/sj.leu.2404396

Cited by 54 publications

(48 citation statements)

References 61 publications

(90 reference statements)

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“…34 To determine Notchdependent expression in ␤-catenin-induced lymphomas, we interrogated the microarray analyses for significant expression changes (P Ͻ .05) in members of the Notch family as well as target genes. [50][51][52] These analyses indicated that the expression of Notch1 and Notch3, as well as the targets Deltex-1, Hes-1, and the positive regulator Lunatic-Fringe, was reduced in CD4Cre-Ctnnb ⌬ex3 pretransformed thymocytes as well as lymphomas when compared to LckCre controls ( Figure 6A). This information was confirmed by semiquantitative RT-PCR analyses using RNA extracted from sorted control and CD4Cre-Ctnnb ⌬ex3 DP thymocytes as well as 3 independent CD4Cre-Ctnnb ⌬ex3 lymphomas ( Figure 6B).…”

Section: ␤-Catenin-dependent Lymphomagenesis Does Not Require Notch Amentioning

confidence: 96%

β-Catenin stabilization stalls the transition from double-positive to single-positive stage and predisposes thymocytes to malignant transformation

Guo

Dose

Kovalovsky

et al. 2007

Blood

117

123

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Activation of ␤-catenin has been causatively linked to the etiology of colon cancer. Conditional stabilization of this molecule in pro-T cells promotes thymocyte development without the requirement for pre-TCR signaling. We show here that activated ␤-catenin stalls the developmental transition from the double-positive (DP) to the single-positive (SP) thymocyte stage and predisposes DP thymocytes to transformation. ␤-Catenin-induced thymic lymphomas have a leukemic arrest at the early DP stage. Lymphomagenesis requires Rag activity, which peaks at this developmental stage, as well as additional secondary genetic events. A consistent secondary event is the transcriptional up-regulation of c-Myc, whose activity is required for transformation because its conditional ablation abrogates lymphomagenesis. In contrast, the expression of Notch receptors as well as targets is reduced in DP thymocytes with stabilized ␤-catenin and remains low in the lymphomas, indicating that Notch activation is not required or selected for in ␤-catenininduced lymphomas. Thus, ␤-catenin activation may provide a mechanism for the induction of T-cell-acute lymphoblastic leukemia ( IntroductionThe canonical ␤-catenin/TCF-LEF signaling is stimulated by wnts, a family of secreted cysteine-rich glycoproteins that bind to cell surface Frizzled receptors. In unstimulated cells, newly synthesized ␤-catenin is captured by a large cytoplasmic complex consisting of the tumor suppressor adenomatous polyposis coli (APC), the constitutively active kinase glycogen synthase kinase 3␤ (GSK-3␤), and Axin. In this complex, ␤-catenin is phosphorylated by GSK-3␤ at 4 N-terminal serine and threonine residues and targeted for degradation. [1][2][3][4] Activation of the Wnt/␤-catenin cascade results in inhibition of the constitutive activity of GSK-3␤ 5 by the cytoplasmic protein Dishevelled (Dvl). [6][7][8][9] Consequently, ␤-catenin is no longer phosphorylated and can accumulate in the cytoplasm and nucleus. Once in the nucleus, ␤-catenin binds to members of the TCF/LEF family of transcription factors, the most downstream components of the Wnt-signaling pathway. For reviews, see van de Wetering 10 and Staal and Clevers. 11 The Wnt/␤-catenin signaling cascade has been implicated in multiple stages of hematopoietic development. It was proposed that Wnt signaling controls the self-renewal of hematopoietic stem cells (HSCs). 12 More recently it was shown that deregulated activation of this pathway enforced cell cycle entry in HSCs leading to the exhaustion of the long-term stem cell pool and a multilineage developmental block. 13,14 In the thymus, loss-and gain-of-function studies have indicated that at least 2 stages of thymopoiesis require Wnt/␤-catenin signaling. Thymocytes express the TCF-1 and LEF-1 effectors of the canonical Wnt/␤-catenin signaling pathway. Ablation of TCF-1 activity affects all proliferating stages of thymocyte development including the CD44 ϩ CD25 ϩ DN2 and the pre-TCR-dependent CD44 Ϫ CD25 Ϫ DN4 and CD8 ϩ TCR␤ Ϫ immature single-positive (IS...

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Section: ␤-Catenin-dependent Lymphomagenesis Does Not Require Notch Amentioning

confidence: 96%

β-Catenin stabilization stalls the transition from double-positive to single-positive stage and predisposes thymocytes to malignant transformation

Guo

Dose

Kovalovsky

et al. 2007

Blood

117

123

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“…Other Notch target genes are NFkB2 [29], Ifi-202, Ifi-204, Ifi-D3, and ADAM19 [19]. A number of other genes have been reported including Notch1 itself and Notch3 [16], bcl-2 [30] and E2A [31] and HoxA5, 9 and 10 [32].…”

Section: Notch Target Genesmentioning

confidence: 99%

The Notch signaling pathway: Transcriptional regulation at Notch target genes

Borggrefe

Oswald

2009

Cell. Mol. Life Sci.

574

499

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. The Notch gene encodes a transmembrane receptor that gave the name to the evolutionary highly conserved Notch signaling cascade. It plays a pivotal role in the regulation of many fundamental cellular processes such as proliferation, stem cell maintenance and differentiation during embryonic and adult development. After specific ligand binding, the intracellular part of the Notch receptor is cleaved off and translocates to the nucleus, where it binds to the transcription factor RBP-J. In the absence of activated Notch, RBP-J represses Notch target genes by recruiting a corepressor complex. Here, we review Notch signaling with a focus on gene regulatory events at Notch target genes. This is of utmost importance to understand Notch signaling since certain RBP-J associated cofactors and particular epigenetic marks determine the specificity of Notch target gene expression in different cell types. We subsequently summarize the current knowledge about Notch target genes and the physiological significance of Notch signaling in development and cancer.

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“…Genome-wide transcriptome studies in healthy or mutated T-cells (Chadwick et al, 2009;Dohda et al, 2007;Palomero et al, 2006;Weerkamp et al, 2006), mouse embryonic stem (ES) cells (Main et al, 2010;Meier-Stiegen et al, 2010), alveolar epithelial cells (Aoyagi-Ikeda et al, 2011), endometrial stromal cells (Mikhailik et al, 2009), C2C12 mouse myoblast cells (Buas et al, 2009) and Drosophila myogenic cells (Krejci et al, 2009) have unraveled distinct sets of Notch target genes with rather limited overlap of the transcriptomes. This is the case even when comparing transcriptome studies that were carried out with relatively similar modes and durations of Notch induction (summarized in Fig.…”

Section: Reviewmentioning

confidence: 99%

Notch signaling: simplicity in design, versatility in function

2011

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Notch signaling is evolutionarily conserved and operates in many cell types and at various stages during development. Notch signaling must therefore be able to generate appropriate signaling outputs in a variety of cellular contexts. This need for versatility in Notch signaling is in apparent contrast to the simple molecular design of the core pathway. Here, we review recent studies in nematodes, Drosophila and vertebrate systems that begin to shed light on how versatility in Notch signaling output is generated, how signal strength is modulated, and how cross-talk between the Notch pathway and other intracellular signaling systems, such as the Wnt, hypoxia and BMP pathways, contributes to signaling diversity.Key words: Cis-inhibition, Delta-like, Signaling diversity, Jagged, Notch, Notch intracellular domain Introduction Cells need to sense cues from their extracellular environment and integrate this information into appropriate developmental or physiological responses. Although there are a number of mechanisms that relay information from the exterior of the cell to the interior, a relatively small set of highly evolutionarily conserved signaling pathways stand out as playing particularly crucial roles in this transmission of information. In this roster of 'elite' intracellular signaling mechanisms are the Wnt pathway, the sonic hedgehog (Shh) pathway, the bone morphogenetic protein/transforming growth factor  (BMP/TGF) pathway, phosphatidylinositol 3-kinase/thymoma viral proto-oncogene (PI3K/AKT) and Janus kinase/signal transducer and activator of transcription (JAK/STAT) signaling, and, the subject of this review, the Notch signaling pathway. Each of these pathways converts information about the concentration of extracellular ligands into specific transcriptional responses in the nucleus. In most cases, the signaling mechanism consists of the 'core' signaling pathway, i.e. the minimal set of protein components required for transducing the signal, and a more elaborate set of 'auxiliary' proteins, which, in various ways, impinge upon the core pathway and modify the signal but are not intrinsically necessary for relaying the signal.Among these highly conserved pathways (Gazave et al., 2009;Richards and Degnan, 2009), the Notch signaling pathway scores highly with regard to simplicity in molecular design, as it contains only a small number of core signaling components (Fig. 1). Despite this, Notch signaling affects cell differentiation decisions not only across a wide spectrum of metazoan species, but also across a broad range of cell types in a single organism and at different steps during cell lineage progression. The pleiotropic actions of Notch in different cell types and organs have recently been reviewed and are summarized in Table 1. In keeping with its important role in many cell types, the mutation of Notch genes leads to diseases in various organs and tissues (Table 2). These studies highlight the fact that the Notch pathway must be able to elicit appropriate responses in many spatially and temporally...

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Identification of Notch target genes in uncommitted T-cell progenitors: no direct induction of a T-cell specific gene program

Cited by 54 publications

References 61 publications

β-Catenin stabilization stalls the transition from double-positive to single-positive stage and predisposes thymocytes to malignant transformation

β-Catenin stabilization stalls the transition from double-positive to single-positive stage and predisposes thymocytes to malignant transformation

The Notch signaling pathway: Transcriptional regulation at Notch target genes

Notch signaling: simplicity in design, versatility in function

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