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PubMed2004

Notch and epithelial-mesenchyme transition in development and tumor progression: another turn of the screw.

Notch is an ancient cell signaling system that regulates cell fate specification, stem cell maintenance and initiation of differentiation in embryonic and postnatal tissues.(1) Alteration of these functions in the adult have been associated to various types of cancer in which Notch may act as an oncogene or as a tumor suppressor. As occurs during development, Notch cooperates with other signaling pathways in the transformation process. Notch has recently been shown to promote epithelial-to-mesenchymal transition (EMT) during cardiac valve formation, via snail induction and subsequent cadherin downregulation. One implication of this work is that Notch acting through a similar mechanism, may also be involved in the EMT process that occurs during tumor progression and converts polarized epithelial cells into motile, invasive cells.

Animals↗
PubMed2005

[Notch signaling in the regulation of hematopoiesis].

Notch signaling defines an evolutionarily ancient cell interaction mechanism. The signals transmitted through the Notch receptor, in combination with other cellular factors influence differentiation, proliferation and apoptotic events at all stages of development. Recent advances have elucidated both the biochemical mechanism regulating receptor activation and the molecular participants forming the intracellular signaling cascade. Authors present description of the main signaling components involved in the Notch pathway and how it can affect the growth and function of lymphocytes. Notch signaling is critical during lymphocyte development, and dysregulation of the pathway can give rise to leukemia. It is conceivable that appropriate manipulation of Notch signaling may become a useful tool in addressing a variety of human dysplastic condition and tissue regeneration.

Animals↗
PubMed1996

[Role of the Notch receptors in intercellular communication].

The Notch gene was discovered in Drosophila at the beginning of the century and is currently the subject of intensive investigation, not only in invertebrates but also in vertebrates where remarkably well conserved homologues have been recently found. Notch encodes a new kind of cellular receptor whose functioning is still unclear and plays a role in a large number of cell interactions throughout development and in tissue renewal in the adult. Detailed study in invertebrates of some of these interactions has led to the identification of other genes required for transduction of the signal initiated by the receptor. Notch is always involved in processes where cells have the potential to choose between several different programmes of differentiation. Cells adopt a specific developmental pathway as a result of the inhibition of some programmes through Notch signalling. In this review we discuss the contribution of different experimental models to an understanding of the role of Notch in intercellular signalling.

Animals↗
PubMed1997

Developmental restriction of Mash-2 expression in trophoblast correlates with potential activation of the notch-2 pathway.

Mash-2 expression begins during preimplantation development, but is restricted to trophoblasts after the blastocyst stage. Within the trophoblast lineage, Mash-2 transcripts are first expressed in the ectoplacental cone and chorion, but not in terminally differentiated trophoblast giant cells. After day 8.5 of gestation, Mash-2 expression becomes further restricted to focal sites within the spongiotrophoblast and labyrinth. Downregulation is probably important for normal development since overexpression of Mash-2 reduces giant cell formation. We have investigated the role that the Notch signaling pathway may play in trophoblast development. Mash-2 is a homologue of Drosophila achaete/scute complex genes. In Drosophila, activation of the Notch receptor induces transcriptional repressors encoded by the hairy/Enhancer of split (HES) genes, which interact with the Groucho protein to shut off achaete-scute transcription. In the developing mouse placenta, we found that all elements of the Notch pathway were expressed. In particular, the Notch-2, HES-2, and HES-3 genes were coexpressed in trophoblast giant cells and in foci within the spongiotrophoblast at day 10.5 when Mash-2 transcription becomes restricted. Two members of the mammalian Groucho family were expressed in trophoblasts; TLE3 was expressed broadly in the giant cell, spongiotrophoblast, and labyrinthine regions, whereas TLE2 was limited to giant cells and focal regions of the spongiotrophoblast. These data suggest that Notch signaling through activation of HES transcriptional repressors may play a role in murine placental development.

Animals↗
PubMed2006

Inhibition of nuclear factor kappab activity by genistein is mediated via Notch-1 signaling pathway in pancreatic cancer cells.

Pancreatic cancer remains the fourth most common cause of cancer related death in the United States. Therefore, novel strategies for the prevention and treatment are urgently needed. Genistein is a prominent isoflavonoid found in soy products and has been proposed to be responsible for lowering the rate of pancreatic cancer in Asians. However, the molecular mechanism(s) by which genistein elicits its effects on pancreatic cancer cells has not been fully elucidated. We have previously shown that genistein induces apoptosis and inhibits the activation of nuclear factor kappaB (NF-kappaB) pathway. Moreover, Notch signaling is known to play a critical role in maintaining the balance between cell proliferation, differentiation and apoptosis, and thereby may contribute to the development of pancreatic cancer. Hence, in our study, we investigated whether there is any cross talk between Notch and NF-kappaB during genistein-induced apoptosis in BxPC-3 pancreatic cancer cells. We used multiple cellular and molecular approaches such as MTT assay, apoptosis assay, gene transfection, Western blotting and EMSA for measuring DNA binding activity of NF-kappaB. We found that genistein inhibits cell growth and induces apoptotic processes in BxPC-3 pancreatic cancer cells. This was partly due to inhibition of Notch-1 activity. BxPC-3 cells transfected with Notch-1 cDNA showed induction of NF-kappaB activity, and this was inhibited by genistein treatment. From these results, we conclude that the inhibition of Notch-1 and NF-kappaB activity and their cross talk provides a novel mechanism by which genistein inhibits cell growth and induces apoptotic processes in pancreatic cancer cells.

Antineoplastic Agents↗
PubMed1991

Developmental analysis of the facets, a group of intronic mutations at the Notch locus of Drosophila melanogaster that affect postembryonic development.

The activity of the Notch locus of Drosophila melanogaster during embryogenesis is necessary for the correct segregation of neural from epidermal lineages. The action of Notch is not confined to embryogenesis but is also essential for normal development during the postembryonic stages. Its action is pleiotropic, as revealed by the existence of several classes of mutations which affect various imaginal structures. Here, we examine a group of six recessive mutations, the facets (fa, fa3, fag, fag-2, fafx and fasw), which affect eye and optic lobe morphology and have been previously shown to be associated with the insertion of transposable elements into an intronic region of Notch. Using both somatic recombination and gynandromorph analysis, we find that their behavior in a mosaic analysis is not identical. While in the majority of alleles abnormal Notch function in the retina is sufficient to induce optic lobe abnormalities, in the case of fag-2, a considerable number of individuals having mosaic retinas exhibit normal optic lobe structure. All the facet alleles appear to behave in a cell-autonomous manner. A developmental analysis of the eye and optic lobe defects associated with the facet mutations support the contention that Notch may be involved not only in the formation of certain structures but also in their maintenance.

Alleles↗
PubMed2002

Enlarged spinoglenoid notch veins causing suprascapular nerve compression.

OBJECTIVE: To report the magnetic resonance (MR) imaging findings of enlarged veins in the spinoglenoid notch as a cause of suprascapular nerve compression. DESIGN AND PATIENTS: Six patients presented to MR imaging for evaluation of chronic shoulder pain. Clinical information and MR imaging studies were reviewed. The spinoglenoid notch vascular structures were compared with measurements made in 10 age-matched controls. RESULTS: Spinoglenoid notch vascular structures measured in 10 asymptomatic age-matched control patients ranged from 1 to 4 mm in diameter with an average of 2.2 mm. The six study patients had vascular structures that ranged from 6 to 10 mm in diameter with an average of 8.4 mm. Atrophy and fatty infiltration of the infraspinatus muscle was noted as an associated finding at MR imaging in all six patients. Surgery was performed in three of the six patients, at which time a venous varix was identified in the spinoglenoid notch in all three patients. CONCLUSION: We describe distended veins in the spinoglenoid notch. These may be readily apparent at MR imaging and should be distinguished from paralabral ganglion cysts compressing the suprascapular nerve in the absence of labral tears, especially if percutaneous aspiration of a ganglion cyst is entertained.

Adult↗
PubMed1986

Local function of the Notch gene for embryonic ectodermal pathway choice in Drosophila.

Mutations at the Notch locus affect the fate of cells in the neurogenic region of the Drosophila embryo so that epidermal precursors become neuroblasts. We have analyzed the cellular requirements for wild-type Notch gene function by means of genetic mosaics, using a cuticle marker to distinguish hypodermal cell genotype. Cells that were genotypically Notch never gave rise to hypoderm within the neurogenic region of mosaic embryos. Mosaic dividing lines within the neurogenic region juxtapose N+ hypoderm with regions of neural hypertrophy. This autonomous action of Notch in hypodermal cells is consistent with a local function of the protein during neurogenesis. Comparison of clone distribution in Notch mosaics and controls suggests that islands of wild-type hypodermal cells fail to differentiate cuticle.

Animals↗
PubMed1987

Mutations altering the structure of epidermal growth factor-like coding sequences at the Drosophila Notch locus.

The Drosophila neurogenic protein Notch is largely composed of tandemly repeated copies of an epidermal growth factor-like sequence. Notch protein contains 36 EGF-like elements, but no two are identical. In the present study, eight mutations are correlated with single amino acid substitutions in EGF-homologous elements of this protein. Genetic analyses of the mutations and comparisons of DNA from mutant and wild-type flies indicate that differentiation of function exists among the tandemly repeated EGF-like sequences and that the total number of repeats and minor variations from the consensus repeat sequence are important for wild-type Notch protein function. One group of EGF-like repeats may be involved in the formation of functional Notch dimers or multimeric proteins. EGF-like elements in a second region of the Notch protein appear to govern its interaction with the product of Enhancer of split, another neurogenic locus of D. melanogaster.

Alleles↗
PubMed1988

Real time microprocessor-based 50 Hz notch filter for ECG.

High performance analogue notch filters are difficult to realize in practice. Their real time digital counterparts, when implemented on an inexpensive microprocessor with no additional hardware, also have limitations of their own. To overcome these limitations, we have developed a new type of 50 Hz notch filter with its poles close to the zero of the transfer function 1 + Z-N. This new type of digital notch filter can be used for suppression of 50 Hz noise in the ECG. The filter is simple to design and easy to implement on most 8-bit microprocessors. It has a high execution speed, low analogue to digital noise, low recursive noise and good frequency response with no overshoot or ringing. It is capable of suppressing 50 Hz noise by at least 40 db. Its finite bandwidth of 4 Hz causes about 2% attenuation on the QRS peak, which is acceptable for almost all practical applications. One possible drawback is that multiple notches occur at higher frequencies. However, this has hardly any effect on the ECG because of the limited notch bandwidth.

Computers↗
PubMed1990

Derivation of auditory filter shapes from notched-noise data.

A well established method for estimating the shape of the auditory filter is based on the measurement of the threshold of a sinusoidal signal in a notched-noise masker, as a function of notch width. To measure the asymmetry of the filter, the notch has to be placed both symmetrically and asymmetrically about the signal frequency. In previous work several simplifying assumptions and approximations were made in deriving auditory filter shapes from the data. In this paper we describe modifications to the fitting procedure which allow more accurate derivations. These include: 1) taking into account changes in filter bandwidth with centre frequency when allowing for the effects of off-frequency listening; 2) correcting for the non-flat frequency response of the earphone; 3) correcting for the transmission characteristics of the outer and middle ear; 4) limiting the amount by which the centre frequency of the filter can shift in order to maximise the signal-to-masker ratio. In many cases, these modifications result in only small changes to the derived filter shape. However, at very high and very low centre frequencies and for hearing-impaired subjects the differences can be substantial. It is also shown that filter shapes derived from data where the notch is always placed symmetrically about the signal frequency can be seriously in error when the underlying filter is markedly asymmetric. New formulae are suggested describing the variation of the auditory filter with frequency and level. The implication of the results for the calculation of excitation patterns are discussed and a modified procedure is proposed. The appendix list FORTRAN computer programs for deriving auditory filter shapes from notched-noise data and for calculating excitation patterns. The first program can readily be modified so as to derive auditory filter shapes from data obtained with other types of maskers, such as rippled noise.

Acoustic Stimulation↗
PubMed1993

A zebrafish homologue of the Drosophila neurogenic gene Notch and its pattern of transcription during early embryogenesis.

We describe here the primary structure of a zebrafish homologue of the Drosophila neurogenic gene Notch and its pattern of mRNA accumulation during embryogenesis. The gene produces a 8.5 kb transcript encoding a putative transmembrane protein with a high degree of sequence similarity to members of the Notch family, comprising 36 EGF-like repeats, three lin-12/Notch repeats, six cdc10/SWI6 repeats, OPA repeats and a PEST sequence. Transcription of the zebrafish Notch gene is spatially and temporally regulated. A high density of transcripts, most probably of maternal origin, can already be detected in the 2-cell stage. During pregastrulation stages, RNA is present in all cells. However, following gastrulation, transcripts accumulate in specific regions of the embryo following a rapidly changing pattern. In some of these regions, cell divisions take place at the time of Notch expression, in others processes of cell differentiation. This holds true for various mesodermal derivatives, such as the prospective notochord, and for different neural primordia, such as the neural plate and the brain vesicles. This pattern of transcript accumulation suggests a role for the zebrafish Notch homologue in processes of regionalization and cell diversification.

Amino Acid Sequence↗
PubMed2006

Arthroscopic suprascapular nerve decompression at the suprascapular notch.

The suprascapular notch is a common location for entrapment of the suprascapular nerve. Open surgical procedures for excision of the transverse scapular ligament are associated with pain relief and functional improvement. Arthroscopic procedures have been described for decompressing ganglion cysts, which compress the nerve at the spinoglenoid notch. However, there is no description of an arthroscopic procedure for decompression of the nerve at the suprascapular notch, and this is probably related to unfamiliarity with the complex anatomy of the region. The technique described herein is based on standard anatomic landmarks and utilization of these as reference points for arthroscopic orientation and reproducibility. The acromioclavicular joint, conoid ligament, and coracoid process are stepwise reference landmarks leading to the suprascapular notch. Arthroscopic identification of structures around the notch is necessary before ligament resection. A new suprascapular portal, in combination with an accessory portal, is described for retraction, blunt dissection, nerve stimulation, and ligament resection. Key instruments include a 4-mm arthroscope of standard length (160 mm), with a 70 degree angled lens for adequate visualization and a calibrated probe to guide and limit dissection.

Arthroscopy↗
PubMed2005

CSL: a notch above the rest.

CSL (CBF1, Suppressor of Hairless, Lag-1) is a transcription factor that is responsible for activating the genes downstream of the Notch signalling pathway, a pathway that is essential for the development of the nervous system and the differentiation of the haematopoietic system among others. In the absence of Notch signalling, CSL represses transcription of Notch target genes, and following activation by Notch, CSL is converted into a transcriptional activator and activates transcription of the same genes. These two opposing functions of CSL are mediated through interactions with distinct protein complexes. The Notch signalling pathway and its crucial cofactor CSL can maintain cells in an undifferentiated state, and have therefore been associated with a growing list of cancers. In addition, CSL has been co-opted by Epstein-Barr virus to mediate viral and host gene transcription following infection.

Amino Acid Sequence↗
PubMed2006

Delta-4 Notch ligand promotes erythroid differentiation of human umbilical cord blood CD34+ cells.

OBJECTIVE: Important roles of Notch signaling have been demonstrated in hematopoiesis. In many cases, activation of the Notch pathway leads to the inhibition of differentiation of immature precursors, suggesting a potential role in self-renewal promotion. However, the function of Notch and Notch ligands is not so straightforward because it is considerably dependent on cytokine context. In this study, we analyzed effects of one Notch ligand, Delta-4, whose function is less clear than others, such as Delta-1 and Jagged-1 and -2. METHODS: CD34(+) cells isolated from human umbilical cord blood were cocultured with a Delta-4-expressing murine stromal cell line, SC9-19, and induced to erythroid differentiation by adding stem cell factor and erythropoietin. To examine the involvement of Delta-4, we utilized stromal cell subclones expressing Delta-4 protein at higher or lower level than parental SC9-19 by plasmid transfection. Erythroid maturation was examined by surface phenotype (CD34 and glycophorin A) and cytospin morphology. Recombinant human Delta-4 protein was prepared to analyze direct effects of Delta-4. RESULTS: Under erythroid lineage-inducing conditions, we found that the increase in Delta-4 expression of SC9-19 promoted erythroid differentiation whereas the decrease in Delta-4 expression inhibited it. Morphologic examination as well as colony formation analysis supported this observation. Moreover, the experiment using recombinant Delta-4 provided direct evidence of the Delta-4 activity found in coculture system. CONCLUSIONS: By modifying Delta-4 expression of the stromal cells and using the recombinant protein, we demonstrated that Delta-4 had a differentiation promoting activity for human primitive hematopoietic cells into erythroid lineage.

Animals↗
PubMed2006

Short exposure to Notch ligand Delta-4 is sufficient to induce T-cell differentiation program and to increase the T cell potential of primary human CD34+ cells.

OBJECTIVE: The Notch pathway plays a key role in cell fate choices and in T-cell development. The goal of our study was to evaluate whether a short in vitro stimulation of the Notch pathway may alter human progenitor cell behavior. METHODS: CD34+ cord blood progenitors were exposed for 4 days to either immobilized Notch ligand Delta-4 or in control conditions. Phenotypic and molecular changes induced by the short stimulation were assessed at day 4. Next, long-term alteration of the fate of these progenitors was assessed in culture conditions suitable for B (coculture with MS5 stromal cells) and T (FTOC and OP9 stromal cells expressing Delta-4 systems) cell differentiation. RESULTS: Notch activation was sufficient to trigger immunophenotypic and molecular changes consistent with early T-cell lineage differentiation. Delta-4 induced, in 4 days, CD7+cytCD3epsilon+ cells. This paralleled at the gene-transcription level with de novo expression of several T cell-related transcription factors and TCRgamma rearrangement, while B cell transcripts were simultaneous silenced. As compared to non-Delta-4 primed cells, these early changes translated to long-term alteration of the potential of cells. Delta-4 priming led to an acceleration of T-cell development, including a completion of the TCR rearrangement, when cells were cultured in systems suitable for T-cell development while B-cell development was inhibited. CONCLUSION: A transient Notch activation is sufficient to promote T-cell differentiation from cord blood CD34+ cells. This system may be a useful tool for the amplification and the quantification of the T potential of CD34+ cells in various disease conditions.

Adaptor Proteins, Signal Transducing↗
PubMed1983

The electrogenesis of terminal QRS notches in normal subjects.

This study was undertaken to explore the mechanisms responsible for the low amplitude, low frequency notches commonly recorded at the end of the QRS complex. Such waves were registered in tracings from twenty-three of fifty normal volunteers evaluated. In fourteen cases, notches were localized to the lateral precordial leads (V3-6), in six they were limited to right precordial leads (V1-2) and in three, notches were found in both right and lateral lead records. Isopotential maps were constructed from potentials registered from one-hundred-fifty torso electrodes. Results demonstrated that: 1) notches in lateral precordial leads (V3-V6) were due to either movement of or changes in potential of early ventricular repolarization effects; and 2) notches in right precordial leads (V1-V2) were caused by migration of terminal ventricular activation currents. These findings document the necessity for study of factors that determine the spatial as well as the temporal and magnitude parameters of electrocardiographic waveforms.

Adult↗
PubMed1997

Intracellular cleavage of Notch leads to a heterodimeric receptor on the plasma membrane.

Previous models for signal transduction via the Notch pathway have depicted the full-length Notch receptor expressed at the cell surface. We present evidence demonstrating that the Notch receptor on the plasma membrane is cleaved. This cleavage is an evolutionarily conserved, general property of Notch and occurs in the trans-Golgi network as the receptor traffics toward the plasma membrane. Although full-length Notch is detectable in the cell, it does not reach the surface. Cleavage results in a C-terminal fragment, N(TM), that appears to be cleaved N-terminal to the transmembrane domain, and an N-terminal fragment, N(EC), that contains most of the extracellular region. We provide evidence that these fragments are tethered together on the plasma membrane by a link that is sensitive to reducing conditions, forming a heterodimeric receptor.

Blotting, Western↗