Transcription Factor RBPJ as a Molecular Switch in Regulating the Notch Response.
TL;DR: This work focuses on the recent advances concerning RBPJ-corepressor functions, especially in regard to chromatin regulation, and puts this into the context of one of the best-studied model systems for Notch, blood cell development.
Abstract: The Notch signal transduction cascade requires cell-to-cell contact and results in the proteolytic processing of the Notch receptor and subsequent assembly of a transcriptional coactivator complex containing the Notch intracellular domain (NICD) and transcription factor RBPJ. In the absence of a Notch signal, RBPJ remains at Notch target genes and dampens transcriptional output. Like in other signaling pathways, RBPJ is able to switch from activation to repression by associating with corepressor complexes containing several chromatin-modifying enzymes. Here, we focus on the recent advances concerning RBPJ-corepressor functions, especially in regard to chromatin regulation. We put this into the context of one of the best-studied model systems for Notch, blood cell development. Alterations in the RBPJ-corepressor functions can contribute to the development of leukemia, especially in the case of acute myeloid leukemia (AML). The versatile role of transcription factor RBPJ in regulating pivotal target genes like c-MYC and HES1 may contribute to the better understanding of the development of leukemia.
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TL;DR: The 2.85 Å crystal structure of CSL with a target DNA was reported in this article, where the Notch intracellular domain translocates to the nucleus after proteolytic release upon Notch extracellular engagement and there it displaces corepressors from DNA-bound CSL and recruits activators of Notch target genes.
Abstract: Notch signaling is a conserved pathway of communication between neighboring cells that results in cell fate specification, and CSL is the universal transcriptional effector of Notch signaling. The Notch intracellular domain translocates to the nucleus after proteolytic release upon Notch extracellular engagement, and there it displaces corepressors from DNA‐bound CSL and recruits activators of Notch target genes. Here we report the 2.85 Å crystal structure of CSL with a target DNA. CSL comprises three structurally integrated domains: its amino (NTD)‐ and carboxy (CTD)‐terminal domains are strikingly similar to those of Rel transcription factors, but a surprising beta‐trefoil domain (BTD) is inserted between them. CSL‐bound DNA is recognized specifically by conserved residues from NTD and BTD. A hydrophobic pocket on BTD is identified as the likely site of Notch interaction with CSL, which has functional implications for the mechanism of Notch signaling.
18 citations
TL;DR: The results suggest that Panobinostat inhibits the Jak2/Stat3 pathway by inhibiting STAT3 binding to DNA consensus region, rather than modulating nuclear translocation.
9 citations
TL;DR: In this article , the role and underlying mechanisms of Nogo-B in cardiac repair during MI were explored and it was shown that Nogo is a positive regulator of angiogenesis by activating the Notch signaling pathway.
Abstract: Abstract Nogo-B (Reticulon 4B) is reportedly a regulator of angiogenesis during the development and progression of cancer. However, whether Nogo-B regulates angiogenesis and post-myocardial infarction (MI) cardiac repair remains elusive. In the present study, we aimed to explore the role and underlying mechanisms of Nogo-B in cardiac repair during MI. We observed an increased expression level of Nogo-B in the heart of mouse MI models, as well as in isolated cardiac microvascular endothelial cells (CMECs). Moreover, Nogo-B was significantly upregulated in CMECs exposed to oxygen-glucose deprivation (OGD). Nogo-B overexpression in the endothelium via cardiotropic adeno-associated virus serotype 9 (AAV9) with the mouse endothelial-specific promoter Tie2 improved heart function, reduced scar size, and increased angiogenesis. RNA-seq data indicated that Notch signaling is a deregulated pathway in isolated CMECs along the border zone of the infarct with Nogo-B overexpression. Mechanistically, Nogo-B activated Notch1 signaling and upregulated Hes1 in the MI hearts. Inhibition of Notch signaling using a specific siRNA and γ-secretase inhibitor abolished the promotive effects of Nogo-B overexpression on network formation and migration of isolated cardiac microvascular endothelial cells (CMECs). Furthermore, endothelial Notch1 heterozygous deletion inhibited Nogo-B-induced cardioprotection and angiogenesis in the MI model. Collectively, this study demonstrates that Nogo-B is a positive regulator of angiogenesis by activating the Notch signaling pathway, suggesting that Nogo-B is a novel molecular target for ischemic disease.
6 citations
TL;DR: In Hydra, Notch inhibition causes defects in head patterning and prevents differentiation of proliferating nematocyte progenitor cells into mature nematocytes as discussed by the authors, and the Notch pathway regulates these processes.
Abstract: In Hydra, Notch inhibition causes defects in head patterning and prevents differentiation of proliferating nematocyte progenitor cells into mature nematocytes. To understand the molecular mechanisms by which the Notch pathway regulates these processes we performed RNAseq and identified genes that are differentially regulated in response to 48 hours of treating the animals with the Notch-inhibitor DAPT. To identify candidate direct regulators of Notch-signalling, we profiled gene expression changes that occur during subsequent restoration of Notch-activity and performed promoter analyses to identify RBPJ transcription factor binding sites in the regulatory regions of Notch-responsive genes. Interrogating the available single cell sequencing data set revealed gene expression patterns of Notch-regulated Hydra genes. By these analyses a comprehensive picture of the molecular pathways regulated by Notch signalling in head patterning and in interstitial cell differentiation in Hydra emerged. As prime candidates for direct Notch-target genes, in addition to HyHes, we suggest Sp5 and HyAlx. They rapidly recovered their expression levels after DAPT removal and possess Notch-responsive RBPJ transcription factor binding sites in their regulatory regions.
5 citations
TL;DR: In this paper, the authors reviewed the recent advances in understanding the molecular mechanisms of how heterochromatin formation is established and put this into the context of carcinogenesis and disease.
Abstract: Enzymes, such as histone methyltransferases and demethylases, histone acetyltransferases and deacetylases, and DNA methyltransferases are known as epigenetic modifiers that are often implicated in tumorigenesis and disease. One of the best-studied chromatin-based mechanism is X chromosome inactivation (XCI), a process that establishes facultative heterochromatin on only one X chromosome in females and establishes the right dosage of gene expression. The specificity factor for this process is the long non-coding RNA Xinactivespecifictranscript (Xist), which is upregulated from one X chromosome in female cells. Subsequently, Xist is bound by the corepressor SHARP/SPEN, recruiting and/or activating histone deacetylases (HDACs), leading to the loss of active chromatin marks such as H3K27ac. In addition, polycomb complexes PRC1 and PRC2 establish wide-spread accumulation of H3K27me3 and H2AK119ub1 chromatin marks. The lack of active marks and establishment of repressive marks set the stage for DNA methyltransferases (DNMTs) to stably silence the X chromosome. Here, we will review the recent advances in understanding the molecular mechanisms of how heterochromatin formation is established and put this into the context of carcinogenesis and disease.
4 citations
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TL;DR: These findings greatly expand the role of activated NOTCH1 in the molecular pathogenesis of human T-ALL and provide a strong rationale for targeted therapies that interfere with NOTCH signaling.
Abstract: Very rare cases of human T cell acute lymphoblastic leukemia (T-ALL) harbor chromosomal translocations that involve NOTCH1, a gene encoding a transmembrane receptor that regulates normal T cell development. Here, we report that more than 50% of human T-ALLs, including tumors from all major molecular oncogenic subtypes, have activating mutations that involve the extracellular heterodimerization domain and/or the C-terminal PEST domain of NOTCH1. These findings greatly expand the role of activated NOTCH1 in the molecular pathogenesis of human T-ALL and provide a strong rationale for targeted therapies that interfere with NOTCH signaling.
2,700 citations
TL;DR: Although the intracellular transduction of the Notch signal is remarkably simple, with no secondary messengers, this pathway functions in an enormous diversity of developmental processes and its dysfunction is implicated in many cancers.
Abstract: A small number of signalling pathways are used iteratively to regulate cell fates, cell proliferation and cell death in development. Notch is the receptor in one such pathway, and is unusual in that most of its ligands are also transmembrane proteins; therefore signalling is restricted to neighbouring cells. Although the intracellular transduction of the Notch signal is remarkably simple, with no secondary messengers, this pathway functions in an enormous diversity of developmental processes and its dysfunction is implicated in many cancers.
2,450 citations
TL;DR: The results suggest that AML1-regulated target genes are essential for definitive hematopoiesis of all lineages, and that this defect was intrinsic to the stem cells in that AMl1-/-ES cells failed to contribute to hematocerosis in chimeric animals.
1,922 citations
TL;DR: It is shown that the locus on chromosome 9 contains a gene highly homologous to the Drosophila gene Notch, which may be important for normal lymphocyte function and that alteration of TAN-1 may play a role in the pathogenesis of some T cell neoplasms.
1,781 citations
TL;DR: It is suggested that Notch1 plays an obligatory and selective role in T cell lineage induction in mice with a neonatally induced loss of Notch 1 function.
1,442 citations