scholarly journals Notch Signaling Regulation in HCC: From Hepatitis Virus to Non-Coding RNAs

Cells ◽  
2021 ◽  
Vol 10 (3) ◽  
pp. 521
Author(s):  
Catia Giovannini ◽  
Francesca Fornari ◽  
Fabio Piscaglia ◽  
Laura Gramantieri
Keyword(s):  
Notch Signaling ◽  
Cell Fate ◽  
Hepatitis Virus ◽  
Notch Pathway ◽  
Notch Receptor ◽  
Gamma Secretase ◽  
Stem Cell Maintenance ◽  
Pathway Activation ◽  
Promising Therapeutic Approach ◽  
Conserved Genes

The Notch family includes evolutionary conserved genes that encode for single-pass transmembrane receptors involved in stem cell maintenance, development and cell fate determination of many cell lineages. Upon activation by different ligands, and depending on the cell type, Notch signaling plays pleomorphic roles in hepatocellular carcinoma (HCC) affecting neoplastic growth, invasion capability and stem like properties. A specific knowledge of the deregulated expression of each Notch receptor and ligand, coupled with resultant phenotypic changes, is still lacking in HCC. Therefore, while interfering with Notch signaling might represent a promising therapeutic approach, the complexity of Notch/ligands interactions and the variable consequences of their modulations raises concerns when performed in undefined molecular background. The gamma-secretase inhibitors (GSIs), representing the most utilized approach for Notch inhibition in clinical trials, are characterized by important adverse effects due to the non-specific nature of GSIs themselves and to the lack of molecular criteria guiding patient selection. In this review, we briefly summarize the mechanisms involved in Notch pathway activation in HCC supporting the development of alternatives to the γ-secretase pan-inhibitor for HCC therapy.

scholarly journals Rme-8 depletion perturbs Notch recycling and predisposes to pathogenic signaling

2015 ◽  
Vol 210 (2) ◽  
pp. 303-318 ◽  
Author(s):  
Maria J. Gomez-Lamarca ◽  
Laura A. Snowdon ◽  
Ekatarina Seib ◽  
Thomas Klein ◽  
Sarah J. Bray
Keyword(s):  
Notch Signaling ◽  
Cell Fate ◽  
Critical Role ◽  
Notch Pathway ◽  
Notch Receptor ◽  
Dnaj Protein ◽  
Pathway Activation ◽  
Proliferation And Differentiation ◽  
Signal Activation

Notch signaling is a major regulator of cell fate, proliferation, and differentiation. Like other signaling pathways, its activity is strongly influenced by intracellular trafficking. Besides contributing to signal activation and down-regulation, differential fluxes between trafficking routes can cause aberrant Notch pathway activation. Investigating the function of the retromer-associated DNAJ protein Rme-8 in vivo, we demonstrate a critical role in regulating Notch receptor recycling. In the absence of Rme-8, Notch accumulated in enlarged tubulated Rab4-positive endosomes, and as a consequence, signaling was compromised. Strikingly, when the retromer component Vps26 was depleted at the same time, Notch no longer accumulated and instead was ectopically activated. Likewise, depletion of ESCRT-0 components Hrs or Stam in combination with Rme-8 also led to high levels of ectopic Notch activity. Together, these results highlight the importance of Rme-8 in coordinating normal endocytic recycling route and reveal that its absence predisposes toward conditions in which pathological Notch signaling can occur.

Association of Notch signaling pathway expression in liposarcomas with outcome, and targeting with gamma-secretase inhibitors

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. 10526-10526
Author(s):  
R. D. Meng ◽  
L. Qin ◽  
C. C. Shelton ◽  
Y. Li ◽  
R. G. Maki ◽  
...  
Keyword(s):  
Notch Signaling ◽  
Empirical Bayes ◽  
Cox Regression ◽  
Notch Pathway ◽  
Notch Receptor ◽  
Gamma Secretase ◽  
Fat Tissue ◽  
Fat Cell ◽  
Dapi Staining ◽  
Notch 3

10526 Background: The Notch pathway directs normal fat cell development, but its aberrant activation may promote the development of sarcomas. The expression of the Notch pathway in liposarcoma (LPS), however, is unknown. We examined Notch signaling components in LPS's and suppressed Notch activation with drug targeting in LPS cell lines. Methods: RNA was isolated from 18 normal fat and 140 LPS tissue samples from five LPS subtypes: well-differentiated (33%), de-differentiated DD (25%), myxoid (12%), round cell (6%), and pleomorphic (13%), and were hybridized to Affymetrix U133A arrays. Microarray data were normalized with the RMA method. Correlation analysis identified genes expressed between sample classes, using Empirical Bayes t-test, and genes associated with survival, using Cox regression. The Notch pathway in two LPS lines, DDLS and LS141, was suppressed with a novel gamma-secretase inhibitor (GSI) or with siRNA to Notch receptors. Viability was assessed by colony formation, apoptosis by DAPI staining, and Notch expression by immunoblotting. Results: Expression of Notch-3 and its targets, Hes-1, Hey-1, and survivin, was increased in LPS subtypes, compared to fat tissue (p<0.001). Inhibition of Notch signaling with GSI's or siRNA to Notch-1 suppressed the viability of both DD LPS lines (p<0.05), inducing a G1/S arrest followed by apoptosis. Transfection of siRNA to each Notch receptor, especially Notch-3, also suppressed the viability of DD LPS's (p<0.05). Expression of Notch-3 (p=0.027, HR=2.64), Notch-4 (p=0.026, HR=2.70), the ligand JAG-2 (p=0.049, HR=2.32), and Hey-1 (p=0.001, HR=4.25) was associated with reduced distant recurrence free survival in patients with DD LPS's. Expression of the negative Notch regulator Fbxw7 was associated with improved overall survival in patients with LPS (p=0.008, HR=-1.42). Conclusions: Elements of the Notch pathway (receptors, ligands, targets, and modifiers) are overexpressed in LPS's compared to normal fat tissue and associate with outcome. Suppression of Notch signaling decreased DD LPS cell line viability and induced apoptosis. Notch inhibition may represent a new therapeutic strategy for patients with LPS's and deserves further validation in a clinical trial. No significant financial relationships to disclose.

scholarly journals Notch pathway activation targets AML-initiating cell homeostasis and differentiation

2013 ◽  
Vol 210 (2) ◽  
pp. 301-319 ◽  
Author(s):  
Camille Lobry ◽  
Panagiotis Ntziachristos ◽  
Delphine Ndiaye-Lobry ◽  
Philmo Oh ◽  
Luisa Cimmino ◽  
...  
Keyword(s):  
Tumor Suppressor ◽  
Notch Signaling ◽  
Myeloproliferative Neoplasms ◽  
Notch Pathway ◽  
Notch Signaling Pathway ◽  
Notch Receptor ◽  
Pathway Activation ◽  
Function Models

Notch signaling pathway activation is known to contribute to the pathogenesis of a spectrum of human malignancies, including T cell leukemia. However, recent studies have implicated the Notch pathway as a tumor suppressor in myeloproliferative neoplasms and several solid tumors. Here we report a novel tumor suppressor role for Notch signaling in acute myeloid leukemia (AML) and demonstrate that Notch pathway activation could represent a therapeutic strategy in this disease. We show that Notch signaling is silenced in human AML samples, as well as in AML-initiating cells in an animal model of the disease. In vivo activation of Notch signaling using genetic Notch gain of function models or in vitro using synthetic Notch ligand induces rapid cell cycle arrest, differentiation, and apoptosis of AML-initiating cells. Moreover, we demonstrate that Notch inactivation cooperates in vivo with loss of the myeloid tumor suppressor Tet2 to induce AML-like disease. These data demonstrate a novel tumor suppressor role for Notch signaling in AML and elucidate the potential therapeutic use of Notch receptor agonists in the treatment of this devastating leukemia.

Notch Signaling Is Necessary and Sufficient for Runx1-Dependent Stem Cell Induction in the Embryonic Aorta-Gonad-Mesonephros (AGM) Region.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 4161-4161
Author(s):  
Caroline Erter Burns ◽  
Leonard I. Zon
Keyword(s):  
Stem Cell ◽  
Notch Signaling ◽  
Cell Fate ◽  
Notch Pathway ◽  
Notch Receptor ◽  
Dorsal Aorta ◽  
Loss Of Function ◽  
Cardinal Vein ◽  
Hematopoietic Stem

Abstract Vertebrate hematopoiesis can be divided into two embryonic phases: a short primitive wave predominantly generating erythrocytes and a definitive (fetal/adult) wave producing long-term hematopoietic stem cells (HSCs). The definitive wave occurs in the embryonic aorta-gonad-mesonephros (AGM) region through the asymmetric induction of HSCs from the ventral, but not dorsal, aortic endothelial wall. Since Notch signaling is critical for orchestrating a variety of developmental cell fate choices from invertebrates to humans and has been implicated in affecting the differentiation of some hematopoietic lineages, we analyzed whether the Notch pathway regulates definitive HSC induction in vivo. The zebrafish mutant mindbomb harbors a mutation in an essential E3 ligase that ubiquitylates Delta, which in turn allows the Notch intercellular domain to be released and activate downstream target gene transcription. Thus, in the absence of Mindbomb function Notch signaling does not occur. We found that although mindbomb mutants show normal primitive hematopoiesis, definitive c-myb and runx1 HSC expression is lacking. Since embryos injected with synthetic morpholinos designed to inhibit proper splicing of runx1 RNA ( runx morphants) show the same hematopoietic phenotype as mindbomb mutants, we next addressed the epistatic relationship between notch and runx1 using classic gain-of-function and loss-of-function analyses. In runx1 morphants expression of a notch receptor, notch3, and a delta ligand, deltaC, in the developing dorsal aorta was normal. Moreover, injection of runx1 RNA rescued HSCs in the AGM of mindbomb mutants. Together, these results suggest that Runx1 functions downstream of Notch in promoting HSC fate. We next analyzed whether a constitutively activated form of Notch (NICD) is sufficient for HSC specification in the AGM using an inducible binary transgenic system. Zebrafish carrying the heat-shock promoter driving the activator gal4 were mated to animals carrying 6 gal4 -responsive tandem upstream activating sequences (UAS) driving NICD. At the 10 somite-stage the embryos were heat-shocked at 37°C for 1 hour to activate NICD throughout the double transgenic animals. Surprisingly, expression of both HSC markers, c-myb and runx1, were expanded from their normal restricted domain in the ventral endothelium to the entire circumference of the dorsal aorta. Most interestingly, the presence of ectopic c-myb and runx1 transcripts were observed in the developing post-cardinal vein, a vessel that normally does not produce HSCs. These data imply that activation of the Notch pathway generates increased numbers of HSCs in vivo. When runx1 RNA is injected into wild-type embryos a similar expansion of c-myb transcripts is seen throughout the entire dorsal aorta and post-cardinal vein, further indicating that Runx1 functions downstream of Notch in HSC induction. In summary, discovery of the molecular programs essential and sufficient for fetal/adult hematopoietic ontogeny will lead to a further understanding of the physiologic and pathologic processes regulating stem cell homeostasis and translate into more effective therapies for blood disorders.

scholarly journals The Drosophila melanogaster Suppressor of deltex Gene, a Regulator of the Notch Receptor Signaling Pathway, Is an E3 Class Ubiquitin Ligase

Genetics ◽  
1999 ◽  
Vol 152 (2) ◽  
pp. 567-576 ◽  
Author(s):  
M Cornell ◽  
D A P Evans ◽  
R Mann ◽  
M Fostier ◽  
M Flasza ◽  
...  
Keyword(s):  
Notch Signaling ◽  
Signaling Pathway ◽  
Cell Fate ◽  
Ubiquitin Ligase ◽  
Notch Pathway ◽  
Notch Receptor ◽  
Negative Regulator ◽  
Loss Of Function ◽  
Wing Vein ◽  
Cell Fate Decisions

Abstract During development, the Notch receptor regulates many cell fate decisions by a signaling pathway that has been conserved during evolution. One positive regulator of Notch is Deltex, a cytoplasmic, zinc finger domain protein, which binds to the intracellular domain of Notch. Phenotypes resulting from mutations in deltex resemble loss-of-function Notch phenotypes and are suppressed by the mutation Suppressor of deltex [Su(dx)]. Homozygous Su(dx) mutations result in wing-vein phenotypes and interact genetically with Notch pathway genes. We have previously defined Su(dx) genetically as a negative regulator of Notch signaling. Here we present the molecular identification of the Su(dx) gene product. Su(dx) belongs to a family of E3 ubiquitin ligase proteins containing membrane-targeting C2 domains and WW domains that mediate protein-protein interactions through recognition of proline-rich peptide sequences. We have identified a seven-codon deletion in a Su(dx) mutant allele and we show that expression of Su(dx) cDNA rescues Su(dx) mutant phenotypes. Overexpression of Su(dx) also results in ectopic vein differentiation, wing margin loss, and wing growth phenotypes and enhances the phenotypes of loss-of-function mutations in Notch, evidence that supports the conclusion that Su(dx) has a role in the downregulation of Notch signaling.

scholarly journals Notch Signaling during Oogenesis in Drosophila melanogaster

2012 ◽  
Vol 2012 ◽  
pp. 1-10 ◽  
Author(s):  
Jingxia Xu ◽  
Thomas Gridley
Keyword(s):  
Drosophila Melanogaster ◽  
Notch Signaling ◽  
Cell Fate ◽  
Notch Pathway ◽  
Notch Signaling Pathway ◽  
Intercellular Signaling ◽  
Signaling Mechanism ◽  
Stem Cell Maintenance ◽  
Evolutionarily Conserved ◽  
Biochemical Mechanisms

The Notch signaling pathway is an evolutionarily conserved intercellular signaling mechanism that is required for embryonic development, cell fate specification, and stem cell maintenance. Discovered and studied initially in Drosophila melanogaster, the Notch pathway is conserved and functionally active throughout the animal kingdom. In this paper, we summarize the biochemical mechanisms of Notch signaling and describe its role in regulating one particular developmental pathway, oogenesis in Drosophila.

Expression of Hes-1 (Notch-1 Effector) during “In Vitro” Normal Erythroid Differentiation.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 4287-4287
Author(s):  
Maria D. Cappellini ◽  
Ilaria V. Libani ◽  
Elisabetta Calzavara ◽  
Luisa Ronzoni ◽  
Raffaella Chiaramonte ◽  
...  
Keyword(s):  
Stem Cells ◽  
Notch Signaling ◽  
Cell Fate ◽  
Notch Pathway ◽  
Erythroid Differentiation ◽  
Notch Receptor ◽  
Erythroid Progenitors ◽  
Notch 1 ◽  
Multipotent Stem Cells

Abstract Hematopoiesis involves highly regulated proliferation and differentiation during which a small number of multipotent stem cells give rise to differentiated progenies. In several developmental systems stem cells fate is influenced by soluble molecules acting via cell-cell interaction, including those mediate by the Notch receptor family. Members of Notch family transmembrane receptors are found on primitive hematopoietic precursors, suggesting a role for Notch signaling in mammalian blood cells development. Notch signaling regulates cell fate controlling asymmetric cell division during stem/progenitor cell differentiation. A previous study on K562 cell line showed that Notch signaling inhibits erythroid/megakaryocytic development by suppressing GATA-1 activity. Furthermore there are evidences that Notch is expressed in early murine erythroid precursors. Probably Notch signaling in these uncommittted precursors may lead to enhanced survival, preserving multilineage potential. The role of Notch pathway during human adult erytropiesis has not been described. The aim of this study is to investigate the modulation of Notch activity during “in vitro” human erythropiesis. Human CD34+ from perpheral blood of normal adult subjects were differentiate “in vitro” for two weeks by the addiction of IL-3, SCF and Epo. This method of colture reproduces all stages of adult erythropoiesis. We analized the modulation of the expression of Notch-1, of its effector Hes-1 and of several erythoid specific genes, at different stages of differentiation using real time PCR. Our analysis shows that Hes-1 expression, which indicates the activation of Notch-1 pathway, is very high in the early steps of differentiation (BFU-E, CFU-E) while in the late stages rapidly decreases to undetectable levels. The Notch-1 gene expression doesn’t seem to be modulated way, but we didn’t invstigate the protein levels yet. These data suggest that Notch pathway is involved in the early stages of erythroid differentiation where it may enhance erythroid progenitors survival up to CFU-E, as hypothisized in mouse model, preventing them from apoptotic stimuli and promoting their proliferation. Involvement of Notch-1 signaling in preventing erythroid progenitors from apoptosis during erythroid differentiation could be important in some erythropoietic disorders such as b-Thalassemia syndromes or diserythropoietic anemias.

Antagonism of notch signaling activity by members of a novel protein family encoded by the bearded and enhancer of split gene complexes

Development ◽  
2000 ◽  
Vol 127 (2) ◽  
pp. 291-306 ◽  
Author(s):  
E.C. Lai ◽  
R. Bodner ◽  
J. Kavaler ◽  
G. Freschi ◽  
J.W. Posakony
Keyword(s):  
Notch Signaling ◽  
Cell Fate ◽  
Notch Pathway ◽  
Notch Receptor ◽  
Principal Mechanism ◽  
Cell Fate Decisions ◽  
Amino Terminal ◽  
Small Proteins ◽  
High Affinity Binding Site ◽  
Enhancer Of Split

Cell-cell signaling through the Notch receptor is a principal mechanism underlying cell fate specification in a variety of developmental processes in metazoans, such as neurogenesis. In this report we describe our investigation of seven members of a novel gene family in Drosophila with important connections to Notch signaling. These genes all encode small proteins containing predicted basic amphipathic (α)-helical domains in their amino-terminal regions, as described originally for Bearded; accordingly, we refer to them as Bearded family genes. Five members of the Bearded family are located in a newly discovered gene complex, the Bearded Complex; two others reside in the previously identified Enhancer of split Complex. All members of this family contain, in their proximal upstream regions, at least one high-affinity binding site for the Notch-activated transcription factor Suppressor of Hairless, suggesting that all are directly regulated by the Notch pathway. Consistent with this, we show that Bearded family genes are expressed in a variety of territories in imaginal tissue that correspond to sites of active Notch signaling. We demonstrate that overexpression of any family member antagonizes the activity of the Notch pathway in multiple cell fate decisions during adult sensory organ development. These results suggest that Bearded family genes encode a novel class of effectors or modulators of Notch signaling.

Barbu: an E(spl) m4/m(alpha)-related gene that antagonizes Notch signaling and is required for the establishment of ommatidial polarity

Development ◽  
2000 ◽  
Vol 127 (5) ◽  
pp. 1115-1130 ◽  
Author(s):  
S. Zaffran ◽  
M. Frasch
Keyword(s):  
Notch Signaling ◽  
Cell Fate ◽  
Sequence Similarity ◽  
Ectopic Expression ◽  
Notch Pathway ◽  
Imaginal Discs ◽  
Notch Receptor ◽  
Cell Type ◽  
Cell Fate Decisions ◽  
Signaling Activity

The Notch signaling pathway is required, in concert with cell-type-specific transcriptional regulators and other signaling processes, for multiple cell fate decisions during mesodermal and ectodermal tissue development. In many instances, Notch signaling occurs initially in a bidirectional manner and then becomes unidirectional upon amplification of small inherent differences in signaling activity between neighboring cells. In addition to ligands and extracellular modulators of the Notch receptor, several intracellular proteins have been identified that can positively or negatively influence the activity of the Notch pathway during these dynamic processes. Here, we describe a new gene, Barbu, whose product can antagonize Notch signaling activity during Drosophila development. Barbu encodes a small and largely cytoplasmic protein with sequence similarity to the proteins encoded by the transcription units m4 and m(alpha) of the E(spl) complex. Ectopic expression studies with Barbu provide evidence that Barbu can antagonize Notch during lateral inhibition processes in the embryonic mesoderm, sensory organ specification in imaginal discs and cell type specification in developing ommatidia. Barbu loss-of-function mutations cause lethality and disrupt the establishment of planar polarity and photoreceptor specification in eye imaginal discs, which may also be a consequence of altered Notch signaling activities. Furthermore, in the embryonic neuroectoderm, Barbu expression is inducible by activated Notch. Taken together, we propose that Barbu functions in a negative feed-back loop, which may be important for the accurate adjustment of Notch signaling activity and the extinction of Notch activity between successive rounds of signaling events.

Suppressor of Hairless-independent events in Notch signaling imply novel pathway elements

Development ◽  
1997 ◽  
Vol 124 (21) ◽  
pp. 4265-4273 ◽  
Author(s):  
K. Matsuno ◽  
M.J. Go ◽  
X. Sun ◽  
D.S. Eastman ◽  
S. Artavanis-Tsakonas
Keyword(s):  
Notch Signaling ◽  
Cell Fate ◽  
Notch Pathway ◽  
Notch Receptor ◽  
Signaling Mechanism ◽  
Independent Events ◽  
Suppressor Of Hairless ◽  
Local Cell ◽  
Mutant Phenotypes

The Notch (N) pathway defines an evolutionarily conserved cell signaling mechanism that governs cell fate choices through local cell interactions. The ankyrin repeat region of the Notch receptor is essential for signaling and has been implicated in the interactions between Notch and two intracellular elements of the pathway: Deltex (Dx) and Suppressor of Hairless (Su(H)). Here we examine directly the function of the Notch cdc10/ankyrin repeats (ANK repeats) by transgenic and biochemical analysis. We present evidence implicating the ANK repeats in the regulation of Notch signaling through homotypic interactions. In vivo expression of the Notch ANK repeats reveals a cell non-autonomous effect and elicits mutant phenotypes that indicate the existence of novel downstream events in Notch signaling. These signaling activities are independent of the known effector Su(H) and suggest the existence of yet unidentified Notch pathway components.

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