Search PubMed⌕ Search

SEARCH · Search PubMed

Results for “Receptor, Notch1”

Search indexed PubMed citations on genomics, clinical trials, systematic reviews and public health. Explore titles, authors and supplied subject terms, then open the PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 307 records · Page 17Linked to original sources
PubMed2001

NFkappaB2 (p52) promoter activation via Notch signaling pathway in rheumatoid synoviocytes.

Rheumatoid synoviocytes produce inflammatory cytokines and exhibit strong proliferation activity, which cause severe cartilage destruction in the joints. Previously, we reported that NFkappaB, a transcriptional factor that activated by mitogenic signals, was activated in rheumatoid synoviocytes. In addition, we revealed that Notch-1, the transcriptional factor that is involved in the developmental stages, was abnormally activated in rheumatoid synoviocytes. In this study, as one of the roles of Notch-1 for the chronic inflammation in RA, we examined its implication to NFkappaB2 activation in rheumatoid synoviocytes. Western blotting analysis showed that NFkappaB2 expression was elevated in rheumatoid synoviocytes compared with patients with osteoarthritis studied as control. We then analyzed NFkappaB2 binding activity to the promoter and revealed that kappaB binding complexes to the NFkappaB2 promoter was elevated in rheumatoid synoviocytes. We analyzed implication of Notch-1 signaling pathway on NFkappaB2 activation, and found that Notch-1 made a complex with recombination binding protein Jkappa (RBPJkappa), a repressor for NFkappaB2 promoter, and blocked binding of RBPJkappa to the promoter. These results indicated that as one of the mechanisms for nuclear translocated Notch-1, complex formation with RBPJkappa induces blocking of the NFkappaB2 promoter suppression, which might cause NFkappaB2 promoter activation.

Arthritis, Rheumatoid↗
PubMed1999

Notch-1 expression levels in 3T3-L1 cells influence ras signaling and transformation by oncogenic ras.

Notch proteins participate in interactions between several cell types involved on the specification of numerous cell fates during development. We previously showed that enforced downregulation of Notch-1 expression prevented adipogenesis of 3T3-L1 cells. Since adipogenesis of 3T3-L1 cells can be induced by oncogenic ras, we studied whether this was also the case in 3T3-L1 cells with decreased levels of Notch-1 expression. We found that oncogenic ras induces transformation and not differentiation of 3T3-L1 cells with diminished levels of Notch-1. This result suggests that Notch-1 is implicated in the interpretation of signals leading to activation of p21 Ras.

3T3 Cells↗
PubMed2000

Imbalanced expression of TAN-1 and human Notch4 in endometrial cancers.

The development of cancer is a cellular process that reflects and is partly driven by alterations in cell determination. Mutations in various genes responsible for cell determination have been identified as being oncogenic; however, little is known about the involvement of normal cell fate-determining mechanisms in the oncogenic process. The Notch pathway is an evolutionarily conserved, general cell-interaction mechanism that controls fundamental aspects of cell determination during the development of vertebrates and invertebrates. We have explored the roles of the recently cloned human Notch4 gene, which is a homologue of Drosophila Notch, in endometrial tissue, a cellular environment where cell fate changes take place and neoplastic conditions have been characterized. Northern blot analysis, dot blot analysis, and in situ hybridization were performed on samples of normal endometria at different phases of the menstrual cycle and endometrial cancers. Our results showed that: a) Both human Notch4 and translocation-associated Notch homologue-1 (TAN-1), another human homologue of Drosophila Notch, are expressed in the normal endometrium, mainly in the endometrial glandular cells. b) The level of expression of human Notch4, but not TAN-1, changes during the normal menstrual cycle; i.e., the level of Notch4 expression was significantly lower during the secretory phase than during the proliferative phase. c) Endometrial cancers express a significantly lower level of human Notch4 and a significantly higher level of TAN-1 than normal endometria. These results suggest that human Notch4 and/or TAN-1 are involved in the changes of the endometrium during the menstrual cycle, and also in the development of endometrial cancer.

Adenocarcinoma↗
PubMed2000

Cutting edge: an essential role for Notch-1 in the development of both thymus-independent and -dependent T cells in the gut.

Whereas most T cells arise in the thymus, a distinct lineage of extrathymically derived T cells is present in the gut mucosa. The developmental origin of extrathymic T cells is poorly understood. We show here that Notch-1, a transmembrane receptor involved in T cell fate specification of bipotential T/B precursors in the thymus, is absolutely required for the development of extrathymic (as well as thymus-derived) mature T cells in the intestinal epithelium. In the absence of Notch-1, CD117(+) T cell precursors are relatively more abundant in the gut than the thymus, whereas immature B cells accumulate in the thymus but not the gut. Collectively, these data demonstrate that Notch-1 is essential for both thymic and extrathymic T cell fate specification and further suggest that bipotential T/B precursors that do not receive a Notch-1 signal adopt a B cell fate in the thymus but become developmentally arrested in the gut.

Animals↗
PubMed2001

Human Notch-1 inhibits NF-kappa B activity in the nucleus through a direct interaction involving a novel domain.

Notch participates in diverse cell fate decisions throughout embryonic development and postnatal life. Members of the NF-kappaB/Rel family of transcription factors are involved in the regulation of a variety of genes important for immune function. The biological activity of the NF-kappaB transcription factors is controlled by IkappaB proteins. Our previous work demonstrated that an intracellular, constitutively active form of human Notch-1/translocation-associated Notch homologue-1 (Notch(IC)) functions as an IkappaB molecule with specificity for the NF-kappaB p50 subunit and physically interacts with NF-kappaB in T cells. In the current study, we investigated the roles of different domains of Notch(IC) in the regulation of NF-kappaB-directed gene expression and NF-kappaB DNA binding activity. We found that Notch(IC) localizes to the nucleus and that a region in the N-terminal portion of Notch(IC), not the six ankyrin repeats, is responsible for the inhibitory effects of Notch on NF-kappaB-directed gene expression and NF-kappaB DNA binding activity. The N-terminal portion of Notch(IC) inhibited p50 DNA binding and interacted specifically with p50 subunit, not p65 of NF-kappaB. The interaction between Notch and NF-kappaB indicates that in addition to its role in the development of the immune system, Notch-1 may also have critical functions in the immune response, inflammation, viral infection, and apoptosis through control of NF-kappaB-mediated gene expression.

Amino Acid Sequence↗
PubMed2001

Notch-1 regulates NF-kappaB activity in hemopoietic progenitor cells.

We investigated the interaction between two elements critical for differentiation of hemopoietic cells, the Notch-1 receptor and the transcription factor NF-kappaB. These factors were studied in hemopoietic progenitor cells (HPC) using Notch-1 antisense transgenic (Notch-AS-Tg) mice. DNA binding of NF-kappaB as well as its ability to activate transcription was strongly decreased in HPC from Notch-AS-Tg mice. NF-kappaB-driven transcriptional activity was completely restored after transduction of the cells with retroviral constructs containing activated Notch-1 gene. HPC from Notch-AS-Tg mice have decreased levels of several members of the NF-kappaB family, p65, p50, RelB, and c-Rel and this is due to down-regulation of the gene expression. To investigate functional consequences of decreased NF-kappaB activity in transgenic mice, we studied LPS-induced proliferation of B cells and GM-CSF-dependent differentiation of dendritic cells from HPC. These two processes are known to be closely dependent on NF-kappaB. B cells from Notch-AS-Tg mice had almost 3-fold lower response to LPS than B cells isolated from control mice. Differentiation of dendritic cells was significantly affected in Notch-AS-Tg mice. However, it was restored by transduction of activated Notch-1 into HPC. Taken together, these data indicate that in HPC NF-kappaB activity is regulated by Notch-1 via transcriptional control of NF-kappaB.

Animals↗
PubMed2002

The Notch ligand Jagged-1 is able to induce maturation of monocyte-derived human dendritic cells.

Notch receptors play a key role in several cellular processes including differentiation, proliferation, and apoptosis. This study investigated whether the activation of Notch signaling would affect the maturation of dendritic cells (DCs). Direct stimulation of Notch signaling in DCs with a peptide ligand induced DC maturation, similar to LPS: DCs up-regulated maturation markers, produced IL-12, lost endocytosis capacity, and became able to activate allogeneic T cells. Furthermore, coculture of DCs with cells expressing Notch ligand Jagged-1 induced up-regulation of maturation markers, IL-12 production, T cell proliferative responses, and IFN-gamma production. Our data suggest that activation of Notch by Jagged-1 plays an important role in maturation of human DCs. Additionally, they reveal a novel role for Notch signaling in cell maturation events distal to the cell fate decision fork. These data may have important medical implications, since they provide new reagents to induce DC activity, which may be beneficial as adjuvants in situations where an immune response needs to be elicited, such as tumor immunotherapy.

Amino Acid Sequence↗
PubMed2004

Attenuation of experimental autoimmune encephalomyelitis and nonimmune demyelination by IFN-beta plus vitamin B12: treatment to modify notch-1/sonic hedgehog balance.

Interferon-beta is a mainstay therapy of demyelinating diseases, but its effects are incomplete in human multiple sclerosis and several of its animal models. In this study, we demonstrate dramatic improvements of clinical, histological, and laboratory parameters in in vivo mouse models of demyelinating disease through combination therapy with IFN-beta plus vitamin B(12) cyanocobalamin (B(12)CN) in nonautoimmune primary demyelinating ND4 (DM20) transgenics, and in acute and chronic experimental autoimmune encephalomyelitis in SJL mice. Clinical improvement (p values <0.0001) was paralleled by near normal motor function, reduced astrocytosis, and reduced demyelination. IFN-beta plus B(12)CN enhanced in vivo and in vitro oligodendrocyte maturation. In vivo and in vitro altered expression patterns of reduced Notch-1 and enhanced expression of sonic hedgehog and its receptor were consistent with oligodendrocyte maturation and remyelination. IFN-beta-B(12)CN combination therapy may be promising for the treatment of multiple sclerosis.

Acute Disease↗
PubMed2004

A general survey of thymocyte differentiation by transcriptional analysis of knockout mouse models.

The thymus is the primary site of T cell lymphopoiesis. To undergo proper differentiation, developing T cells follow a well-ordered genetic program that strictly depends on the heterogeneous and highly specialized thymic microenvironment. In this study, we used microarray technology to extensively describe transcriptional events regulating alphabeta T cell fate. To get an integrated view of these processes, both whole thymi from genetically engineered mice together with purified thymocytes were analyzed. Using mice exhibiting various transcriptional perturbations and developmental blockades, we performed a transcriptional microdissection of the organ. Multiple signatures covering both cortical and medullary stroma as well as various thymocyte maturation intermediates were clearly defined. Beyond the definition of histological and functional signatures (proliferation, rearrangement), we provide the first evidence that such an approach may also highlight the complex cross-talk events that occur between maturing T cells and stroma. Our data constitute a useful integrated resource describing the main gene networks set up during thymocyte development and a first step toward a more systematic transcriptional analysis of genetically modified mice.

Animals↗
PubMed2005

Impairment of thymocyte development by dominant-negative Kuzbanian (ADAM-10) is rescued by the Notch ligand, delta-1.

Although Notch plays a crucial role in T cell development, regulation of Notch signaling in the thymus is not well understood. Kuzbanian, an ADAM protease, has been implicated in the cleavage of both Notch receptors and the Notch ligand, Delta. In this study we show that the expression of a dominant-negative form of Kuzbanian (dnKuz) leads to reduced TCRbeta expression in double-negative thymocytes and to a partial block between the double-negative to double-positive stages of development. These defects were rescued by overexpression of Delta-1 on thymocytes. Mixed chimeras showed a cell-autonomous block by dnKuz, but non-cell-autonomous rescue by Delta-1. This suggests that dnKuz impairs Notch signaling in receiving cells, and increasing Delta-1 on sending cells overcomes this defect. Interestingly, the expression of an activated form of Notch-1 rescued some, but not all, the defects in dnKuz Tg mice. Our data suggest that multiple Notch-dependent steps in early thymocyte development require Kuzbanian, but differ in the involvement of other Notch signaling components.

ADAM Proteins↗
PubMed2005

The Notch regulator Numb links the Notch and TCR signaling pathways.

Both the Notch and TCR signaling pathways play an important role in T cell development, but the links between these signaling pathways are largely unexplored. The adapter protein Numb is a well-characterized inhibitor of Notch and also contains a phosphotyrosine binding domain, suggesting that Numb could provide a link between these pathways. We explored this possibility by investigating the physical interactions among Notch, Numb, and the TCR signaling apparatus and by examining the consequences of a Numb mutation on T cell development. We found that Notch and Numb cocluster with the TCR at the APC contact during Ag-driven T cell-APC interactions in both immature and mature T cells. Furthermore, Numb coimmunoprecipitates with components of the TCR signaling apparatus. Despite this association, T cell development and T cell activation occur normally in the absence of Numb, perhaps due to the expression of the related protein, Numblike. Together our data suggest that Notch and TCR signals may be integrated at the cell membrane, and that Numb may be an important adapter in this process.

Animals↗
PubMed2000

Dll4, a novel Notch ligand expressed in arterial endothelium.

We report the cloning and characterization of a new member of the Delta family of Notch ligands, which we have named Dll4. Like other Delta genes, Dll4 is predicted to encode a membrane-bound ligand, characterized by an extracellular region containing several EGF-like domains and a DSL domain required for receptor binding. In situ analysis reveals a highly selective expression pattern of Dll4 within the vascular endothelium. The activity and expression of Dll4 and the known actions of other members of this family suggest a role for Dll4 in the control of endothelial cell biology.

Adaptor Proteins, Signal Transducing↗
PubMed2001

[Possible pathogenesis of rheumatoid arthritis].

Rheumatoid fibroblast-like synoviocytes characteristically proliferate in an anchorage-independent manner, and are deeply implicated in cartilage destruction. Our previous results showed that rheumatoid synoviocytes expressed Fas ligand and were induced apoptosis by anti-Fas antibody treatment. In addition, several transcriptional factors, such as NF kappa B and AP-1 significantly activated in rheumatoid synoviocytes. We are now clarifying the pathogenesis of RA with the method, yeast two-hybrid system as 'post genome' strategy. We recently found that several factors that related with cell differentiation highly expressed in rheumatoid synoviocytes. In this report we discuss possible pathogenesis of RA based on our recent data and application to the therapy tool against RA.

Apoptosis↗
PubMed2000

Notch signaling as a target in multimodality cancer therapy.

Notch signaling is an extremely conserved and widely used mechanism controlling cell fate determination. Recent evidence shows that Notch receptors regulate cell differentiation, proliferation and apoptosis in many cells, including neoplastic cells. In the context of cancer experimental immunotherapy and multimodality therapy, the Notch signaling network is acquiring increasing importance for its possible roles in both neoplastic cells and the immune system. In this review, we discuss: (i) the roles of Notch signaling in cancer cells and the immune system; and (ii) strategies through which Notch-targeting biologicals may be used to increase the effectiveness of multimodality cancer treatment, including cancer vaccines.

Animals↗
PubMed2001

Asymmetric segregation of Numb in retinal development and the influence of the pigmented epithelium.

Asymmetric segregation of cell-fate determinants during cytokinesis plays an important part in controlling cell-fate choice in invertebrates. During Drosophila neurogenesis, for example, asymmetric segregation of the Numb protein, which inhibits Notch signaling, is necessary for the two daughter cells of a division to have different fates. In vertebrates, the role of asymmetric segregation of cell-fate determinants is uncertain, and the way the process might be regulated is unknown. We have studied the orientation of cell divisions and the distribution of Numb in the developing rat retina. We show that, whereas most retinal neuroepithelial cells divide with their mitotic spindles oriented parallel to the plane of the neuroepithelium, a substantial minority divides with their spindles oriented perpendicularly. The proportion of these vertically dividing cells changes during development, peaking around the day of birth. Numb appears to be inherited only by the apical daughter cell when a neuroepithelial cell divides vertically. Similarly, in dissociated cell cultures, some retinal neuroepithelial cells divide asymmetrically and distribute Numb to only one of the two daughter cells, suggesting that the dissociated cells can retain their polarity in vitro. Using retinal explant cultures, we find that the retinal pigment epithelium apparently promotes vertical divisions in the neural retina. To our knowledge, this is the first evidence that asymmetric segregation of cell-fate determinants may contribute to cell diversification in the mammalian retina and that an epithelium controls this process by influencing the plane of division in the adjacent neural retina.

Animals↗
PubMed2002

Defining the cell lineages of the islets of Langerhans using transgenic mice.

In this Special Issue of the Int. J. Dev. Biol., we summarize our own studies on the development of the mouse endocrine pancreas, with special emphasis on the cell lineage relationships between the four islet cell types. Considerable knowledge concerning the ontogeny of the endocrine pancreas has been gained in recent years, mainly through the use of two complementary genetic approaches in mice: gene inactivation and genetic labelling of precursor cells. However, neither gene inactivation in KO mice nor co-localisation of hormones in single cells during development can be taken as evidence for cell lineage relationships among different cell types. The beta-cell lineage analysis was started by selectively ablating specific islet cell types in transgenic mice. We used the diphtheria toxin A subunit coding region under the control of insulin, glucagon or pancreatic polypeptide (PP) promoters, in order to eliminate insulin-, glucagon- or PP-expressing cells, respectively. Contrary to the common view, we demonstrated that glucagon cells are not precursors of insulin-producing cells. These results were in addition the first evidence of a close ontogenetic relationship between insulin and somatostatin cells. We pursued these analyses using a novel, more subtle approach: progenitor cell labelling through the expression of Cre recombinase in doubly transgenic mice. We were able to unequivocally establish that 1) adult glucagon- and insulin-producing cells derive from precursors which have never transcribed insulin or glucagon, respectively; 2) insulin cell progenitors, but not glucagon cell progenitors transcribe the PP gene and 3) adult glucagon cells derive from progenitors which do express pdx1.

Animals↗
PubMedDate not supplied

Notch signal transduction is not regulated by SEL1L in leukaemia and lymphoma cells in culture.

The transduction of Notch signal plays an intricate role in cell differentiation and pathogenesis of haematological malignancies as well as in certain congenital conditions. The functionality of Notch signalling was tested using HES1 gene activation. SEL1 gene product has been postulated to be a negative regulator of Notch signalling. We investigated the relationship between Notch signalling and the expression of SEL1L gene in a number of leukaemia and lymphoma cells in culture. The cell lines could be separated into two groups. Group 1 contained lymphoma cell lines in which Notch signalling was intact; of these 4 cell lines were SEL1L+/HES1- and 3 SEL1L-/HES1-. Notch signalling was not subverted by EBNA2 expression in these lymphoma cells. In Group 2 cell lines Notch signalling was constitutively active but 6 out of 7 cell lines expressed SEL1L at high levels. In summary, a majority of cell lines of both groups express SEL1L and no inverse relationship is evident between SEL1L expression and the status of Notch signalling. The present investigation therefore suggests that SEL1L may not exert a negative regulatory influence on Notch signalling. No genomic alterations affecting SEL1L were detected either in the lymphoma or T-ALL cell lines tested. Taken together the present findings do not support the postulated negative regulatory role for SEL1L in Notch signalling.

Basic Helix-Loop-Helix Proteins↗
PubMed2003

Beta-amyloid secretases and beta-amloid degrading enzyme expression in lens.

PURPOSE: Beta- and gamma-secretases are proteases involved in the processing of the Alzheimer precursor protein (AbetaPP) that releases the transmembrane beta-amyloid fragment (Abeta), associated with age-dependent disease in lens and brain. Gamma-secretase is a protein complex containing Presenilin and Nicastrin proteins, which also processes Notch and other receptors involved in the eye and lens development. Neprilysin (NEP), a major protease involved in degrading Abeta, acts with beta- and gamma-secretases to regulate steady-state levels of Abeta. Previously, we demonstrated AbetaPP and Presenilin expression and processing in the lens and demonstrated cell degeneration in classic Alzheimer disease (AD) transgenic and systemic oxidative stress animal models, suggesting that additional AbetaPP processing proteins are also present in the lens. Here we investigate lens expression of beta-secretases, nicastrin and NEP proteins, and compare their protein distribution to Notch and Presenilin in lens. METHODS: RT-PCR was used to analyze mRNA transcripts. Immunoblots and immunohistochemistry were used to examine the protein expression and distribution of secretase and Abeta degrading proteins, as well as Presenilin and Notch proteins in mouse lenses. RESULTS: Beta-acting cleaving enzymes, BACE (BACE1) and BACE2, Nicastrin, Presenilins, Notch and NEP are expressed in the lens. In situ examination of protein distribution in lens indicates expression of each of these proteins is upregulated in peripheral elongating fiber cells at the lens equatorial margin and overlaps with Notch and Presenilin proteins, and also with the distribution of AbetaPP and Abeta proteins demonstrated in a previous study. Neprilysin exon 1-4 splicing, previously described as diagnostic for neuronal expression, also occurs in lens. CONCLUSIONS: BACE, BACE2, Nicastrin and NEP are expressed primarily in elongating peripheral fiber cells, overlapping with Notch, Presenilin, and AbetaPP protein distribution in lens, consistent with their role in regulating Notch and AbetaPP ectodomain shedding in lens. Lens expression of beta- and gamma-secretases together with NEP suggests these proteins may also regulate Abeta turnover in the lens. The presence of Abeta processing and degrading proteases in lens provides further evidence that Alzheimer-related cell biology is fundamentally involved in lens development, and provides additional evidence that mechanisms of Alzheimer pathophysiology can contribute to lens degeneration, suggesting further that therapeutics targeting Abeta proteases may be applicable to lens degenerative disease.

Amyloid Precursor Protein Secretases↗