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[Notch signaling pathway and new strategies in cancer treatment].

The Notch signaling pathway plays a crucial role at different stages of cell development, such as proliferation, growth, differentiation, and apoptosis. Recent studies demonstrate that depending on the expression level and cellular context, the Notch receptors play a role in apoptosis resistance in malignant cells. These findings suggest that Notch signaling components may be a potential target in the development of new cancer therapies. This review describes the function of the Notch pathway and new strategies in the modulation of its signal.

Apoptosis↗
PubMed2000

Notch signaling enhances survival and alters differentiation of 32D myeloblasts.

The Notch transmembrane receptors play important roles in precursor survival and cell fate specification during hematopoiesis. To investigate the function of Notch and the signaling events activated by Notch in myeloid development, we expressed truncated forms of Notch1 or Notch2 proteins that either can or cannot activate the core binding factor 1 (CBF1) in 32D (clone 3) myeloblasts. 32D cells proliferate as blasts in the presence of the cytokines, GM-CSF or IL-3, but they initiate differentiation and undergo granulopoiesis in the presence of granulocyte CSF (G-CSF). 32D cells expressing constitutively active forms of Notch1 or Notch2 proteins that signal through the CBF1 pathway maintained significantly higher numbers of viable cells and exhibited less cell death during G-CSF induction compared with controls. They also displayed enhanced entry into granulopoiesis, and inhibited postmitotic terminal differentiation. In contrast, Notch1 constructs that either lacked sequences necessary for CBF1 binding or that failed to localize to the nucleus had little effect. Elevated numbers of viable cells during G-CSF treatment were also observed in 32D cells overexpressing the basic helix-loop-helix protein (bHLH), HES1, consistent with activation of the CBF1 pathway. Taken together, our data suggest that Notch signaling enhances 32D cell survival, promotes entry into granulopoiesis, and inhibits postmitotic differentiation through a CBF1-dependent pathway.

Animals↗
PubMed2004

Obligatory role for cooperative signaling by pre-TCR and Notch during thymocyte differentiation.

The first checkpoint during T cell development, known as beta selection, requires the successful rearrangement of the TCR-beta gene locus. Notch signaling has been implicated in various stages during T lymphopoiesis. However, it is unclear whether Notch receptor-ligand interactions are necessary during beta selection. Here, we show that pre-TCR signaling concurrent with Notch receptor and Delta-like-1 ligand interactions are required for the survival, proliferation, and differentiation of mouse CD4(-)CD8(-) thymocytes to the CD4(+)CD8(+) stage. Furthermore, we address the minimal signaling requirements underlying beta selection and show a hierarchical positioning of key proximal signaling molecules. Collectively, our results demonstrate an essential role for Notch receptor-ligand interactions in enabling the autonomous signaling capacity of the pre-TCR complex.

Animals↗
PubMed2006

Lunatic fringe controls T cell differentiation through modulating notch signaling.

T cells differentiate from bone marrow-derived stem cells by expressing developmental stage-specific genes. We here searched arrays of genes that are highly expressed in mature CD4-CD8+ (CD8 single-positive (SP)) T cells but little in CD4+CD8+ (double-positive (DP)) cells by cDNA subtraction. Lunatic fringe (Lfng), a modulator of Notch signaling, was identified to be little expressed in DP cells and highly expressed in CD8SP T cell as well as in CD4-CD8- (double-negative (DN)) and mature CD4+CD8- (CD4SP) T cells. Thus, we examined whether such change of expression of Lfng plays a role in T cell development. We found that overexpression of Lfng in Jurkat T cells strengthened Notch signaling by reporter gene assay, indicating that Lfng is a positive regulator for Notch signaling in T cells. The enforced expression of Lfng in thymocytes enhanced the development of immature CD8SP cells but decreased mature CD4SP and CD8SP cells. In contrast, the down-regulation of Lfng in thymocytes suppressed DP cells development due to the defective transition from CD44+CD25- stage to subsequent stage in DN cells. The overexpression of Lfng in fetal liver-derived hemopoietic stem cells enhanced T cell development, whereas its down-regulation suppressed it. These results suggested that the physiological high expression of Lfng in DN cells contributes to enhance T cell differentiation through strengthening Notch signaling. Shutting down the expression of Lfng in DP cells may have a physiological role in promoting DP cells differentiation toward mature SP cells.

Animals↗
PubMed2006

Evolutionary origins of Notch signaling in early development.

Notch signaling is known to play key roles in early embryonic development and in the specification or patterning of germ layers in several lower organisms. Thus it is surprising that the removal of maternal and zygotic protein O-fucosyltransferase 1 (Pofut1), an essential component of the canonical Notch signaling pathway, does not affect early embryogenesis in the mouse. Mouse embryos lacking Pofut1 develop normally through blastogenesis to E8.0 when all three germ layers have formed. Here we summarize roles for Notch signaling in early embryonic development of several species, and discuss the potential evolutionary origins of these roles. We propose that Notch signaling might have first been used in the common ancestor of the metazoa for certain advanced developmental processes such as segmentation, and only later in evolution been coopted for use at early stages of embryogenesis in some organisms.

Animals↗
PubMed2001

Transcription factor expression and Notch-dependent regulation of neural progenitors in the adult rat spinal cord.

Recent studies have demonstrated that neural stem cells and other progenitors are present in the adult CNS. Details of their properties, however, remain poorly understood. Here we examined the properties and control mechanisms of neural progenitors in the adult rat spinal cord at the molecular level. Adult and embryonic progenitors commonly expressed various homeodomain-type (Pax6, Pax7, Nkx2.2, and Prox1) and basic helix-loop-helix (bHLH)-type (Ngn2, Mash1, NeuroD1, and Olig2) transcriptional regulatory factors in vitro. Unlike their embryonic counterparts, however, adult progenitors could not generate specific neurons that expressed markers appropriate for spinal motoneurons or interneurons, including Islet1, Lim1, Lim3, and HB9. Cells expressing the homeodomain factors Pax6, Pax7, and Nkx2.2 also emerged in vivo in response to injury and were distributed in unique patterns in the lesioned spinal cord. However, neither the expression of the neurogenic bHLH factors including Ngn2, Mash1, and NeuroD1 nor subsequent generation of new neurons could be detected in injured tissue. Our results suggest that signaling through the cell-surface receptor Notch is involved in this restriction. The expression of Notch1 in vivo was enhanced in response to injury. Furthermore, activation of Notch signaling in vitro inhibited differentiation of adult progenitors, whereas attenuation of Notch signals and forced expression of Ngn2 significantly enhanced neurogenesis. These results suggest that both the intrinsic properties of adult progenitors and local environmental signals, including Notch signaling, account for the limited regenerative potential of the adult spinal cord.

Animals↗
PubMed2004

Regulation of notch signaling activity.

Cell-cell signalling mediated by the receptor Notch is used widely across the metazoans to determine cell fate and regulate pattern formation. Notch signals via a conserved regulated intramembrane proteolysis. Recent analyses of the cell biology of the Notch receptor have identified several fundamental mechanisms that contribute to regulate Notch signaling activity in space and time.

Amyloid Precursor Protein Secretases↗
PubMed2004

[Characterization of Notch gene involved in genetic regulatory networks in dental pulp stem cells].

OBJECTIVE: To investigate the characterization of Notch gene involved in genetic regulatory networks in dental pulp stem cells. METHODS: The pulp tissue was separated from mouse teeth and digested by collagenase type I. Single-cell suspensions of dental pulp were seeded into 6-well plates with alpha modification of Eagle's medium supplemented with ES cell qualified Fetal Bovine Serum. Colony-forming efficiency was assessed in 14ds culture. Transcripts for Notch were detected by reverse transcription-PCR by using total RNA isolated from cells. RESULTS: There were clonogenic cells in dental pulp cell and the incidence of colony-forming cells derived from mouse dental pulp cells was 1.6-2.5 colonies/10(4) plate. Mouse-specific Notch mRNA expressed in colony-forming cells. CONCLUSION: Notch mRNA expressing in colony-forming cells provided a more detailed understanding of mouse dental pulp stem cell biology.

Animals↗
PubMed2006

[Notch signaling in chondrogenesis].

Notch is a signaling molecule which plays a critical role in the determination of multiple cellular differentiation pathways and morphogenesis in various biological systems, such as neurogenesis, immune system, and hematopoiesis. However, roles of Notch signaling in osteo/chondrogenesis have not been well studied. We will present our recent progress in investigating roles of Notch signaling in chondrogenesis using in vitro chondrogenic system. We will also discuss about the recent reports which used conditional knockout mice to investigate roles of Notch signaling molecules in vivo .

Animals↗
PubMed1997

Diverse roles for the Notch receptor in the development of D. melanogaster.

Notch proteins appear to be involved in cell fate commitments with deep evolutionary roots. Homologues have been shown to play key roles in the development of nematodes, insects, amphibia, and mammals. Activity of the Notch receptor has been observed in the patterning of ectoderm, mesoderm, and endoderm, indicating an origin prior to the functional differentiation of these germ layers. To understand how a single receptor can participate so widely in development, we have been examining the role of specific extracellular segments of Notch. Early studies of mutations affecting widely separated EGF-like elements of Notch first raised the possibility for interaction with multiple ligands. Biochemical approaches, and exhaustive structure function studies in transgenic Drosophila are beginning to reveal how this receptor is activated, and point to a range of physical interactions with other proteins.

Animals↗
PubMed1998

Notch and neurogenesis.

The Notch signaling pathway has during the last few years emerged as an important signaling mechanism for communication between neighboring cells. Many of the components in the Notch signaling pathway have been identified and the pathway is important for cellular differentiation in various organs, including the nervous system. The Notch pathway is pivotal for a process called lateral inhibition, which ensures that cells differentiate to distinct fates from an initially homogenous cell population. The aim of this review is to describe our current understanding of the molecular aspects of the Notch signaling pathway and to discuss its importance for nervous system development and disease.

Animals↗
PubMed2005

Cruciate ligament laxity and femoral intercondylar notch narrowing in early-stage knee osteoarthritis.

OBJECTIVE: The influence of the cruciate ligaments in spontaneous osteoarthritis (OA) is not understood, although ligament rupture is known to cause secondary OA. Additionally, femoral notch narrowing at the anterior cruciate ligament (ACL) insertion site is associated with disease severity, but it is unknown whether ligament deterioration precedes or follows osteophyte formation. We examined cruciate ligament mechanics and metabolism and the intercondylar notch width in OA-prone Dunkin-Hartley (DH) guinea pigs at ages up to and including the age at OA onset (24 weeks), and compared the data with those in age-matched controls (Bristol strain 2 [BS2] guinea pigs). METHODS: Guinea pigs were assessed at 3, 6, 9, 12, 16, 20, 24, and 36 weeks of age. ACLs were mechanically tested, and the intercondylar notch width index (NWI) was determined. Cruciate ligament metabolism was determined by measuring the following markers of collagen turnover: matrix metalloproteinase 2 (MMP-2), tissue inhibitor of metalloproteinases 2, C-terminal type I procollagen propeptide (PICP), and the immature collagen-derived crosslink dihydroxylysinonorleucine (DHLNL). RESULTS: DH guinea pigs had significantly laxer ACLs than did BS2 guinea pigs, at 12, 16, and 24 weeks. We observed elevated levels of pro and active MMP-2, PICP, and DHLNL in the cruciate ligaments of DH animals at most ages, compared with BS2 guinea pigs. The NWI in DH animals was significantly lower than that in BS2 guinea pigs at 24 and 36 weeks. CONCLUSION: In DH guinea pigs, laxer ACLs, which are associated with increased collagen turnover, may cause joint instability and predispose these animals to the early onset of OA. Decreased intercondylar notch width in the DH animals indicates that bone remodeling at the ACL insertion site is a response to elevated ACL laxity.

Animals↗
PubMed2001

Does a 'notched' nuchal translucency indicate Down syndrome fetuses or other adverse pregnancy outcome?

The aim of the present study was to assess the sonographic contour of the increased nuchal translucency (NT) and to correlate this with pregnancy outcome. Fifty sonographic images of fetuses with increased NT [> 95th centile thickness of the normal range for crown-rump length (CRL) between 38 and 84 mm] were retrospectively assessed. In all the cases a complete pregnancy and even infancy follow-up (< 36 months) was available. The NT appearances were subdivided into two forms: a 'notched' or 'uniform' appearance. The images were correlated with karyotype results [trisomy 21 (DS) vs euploid cases] and pregnancy outcome. Complicated outcomes were classified as being either DS fetuses, miscarriage or termination of pregnancy because of structural anomaly. Thus 30/35 (86%) of the euploid fetuses had a 'uniformly' increased NT, whereas 8/13 DS cases (62%) had a 'notched' appearance (Fisher's exact test, p = 0.004). Additionally, 27/29 fetuses (93%) which had an uneventful pregnancy outcome had a 'uniform' increased NT, whereas 12/26 (57%) of the fetuses which had adverse pregnancy outcome had a 'notched' appearance of their NT (Fisher's exact test, p < 0.001). Although it was not possible to correlate the sonographic data with post-evacuation microdissection findings, it is possible that a uniformly shaped, increased NT may be more representative of a developmental delay in a normal fetus. Conversely, a 'notched' nuchal surface may represent abnormal lymphatic or cardiovascular development more commonly seen in DS fetuses.

Adult↗
PubMed2005

[Frequency specific auditory evoked responses. Experiments on stimulus polarity, sweep frequency, stimulus duration, notched-noise masking level, and threshold estimation in volunteers with normal hearing].

Auditory evoked responses to tone-pips in notched-noise provide frequency specific estimations of thresholds. Most often, test frequencies are 0.5-4 kHz. Thresholds are expected to match with a high degree to behavioral thresholds. However, only few studies are available containing data on stimulus and averaging parameters, especially at a test frequency of 0.25 kHz. In order to find "optimal" parameters for a widely used device (Nicolet Spirit Version 1.6), we designed five experiments on stimulus polarity (Exp.I), sweep frequency (Exp.II), stimulus duration (Exp.III), notched noise level (Exp.IV), and threshold estimation (Exp.V). The experiments also included a low test frequency of 0.25 kHz. These experiments were applied to 29 healthy volunteers (n=29, aged 20-41 years with normal hearing and no history of illness of the ear). We found that alternating stimulus polarity and a sweep frequency of 43.5/s evoked responses that were highest with respect to amplitudes (0.2-0.4 mV) and correlations (0.49-0.91). A novel finding of the study was that the highest amplitudes and correlations could be achieved if stimulus durations and notched-noise-levels were specifically adjusted to the test frequencies (stimulus durations 0.25 kHz: 4 ms, 0.5 Hz: 2 ms, 1-4 kHz: 1 ms, notched-noise-levels 0.25-0.5 Hz: +10 dB, 1-4 kHz: +/-0 dB). Deviations from behavioral thresholds did not exceed +/-5 dB in 93% of the measures. The results indicate that frequency specific auditory evoked responses provide reliable threshold estimations. Future experiments are required to confirm the threshold deviations for hard of hearing individuals.

Acoustic Stimulation↗
PubMed2003

Is there any effect of suprascapular notch type in iatrogenic suprascapular nerve lesions? An anatomical study.

This anatomical study, which is aimed at assessing the effect of suprascapular notch type in iatrogenic suprascapular nerve lesions in surgical interventions, was conducted in two stages. A hundred dry scapulas and 20 scapulas of 11 cadavera were classified according to Rengachary. The point of measurement was determined medially as the deepest point of suprascapular notch and laterally as supraglenoid tubercle in dry scapulas and anchor of biceps in cadavera. It was found that in the measurements made in dry scapulas, notch Type-IV scapulas, despite not being statistically significant, had the lowest average (2.35 cm), with minimum and maximum values of 2.1 cm and 2.78 cm respectively, when compared to other scapula types. It was found in the cadavera study that the measurements of one Type-IV scapula and one Type-V scapula were lower than the other types. Determination of the notch type in the rotator-cuff tears--especially in massive and retracted tears where supraspinatus has to be released from the fossa--may be helpful in avoiding iatrogenic nerve lesion.

Adult↗
PubMed2000

Diagnosing CADASIL using MRI: evidence from families with known mutations of Notch 3 gene.

Clinical data and MRI findings are presented on 18 subjects from two families with neuropathologically confirmed CADASIL. DNA analysis revealed mutations in exon 4 of Notch 3 gene in both families. All family members with mutations in Notch 3 gene had extensive abnormalities on MRI, principally lesions in the white matter of the frontal lobes and in the external capsules. Of several family members in whom a diagnosis of CADASIL was suspected on the basis of minor symptoms, one had MRI changes consistent with CADASIL; none of these cases carried a mutation in the Notch 3 gene. MRI and clinical features that may alert the radiologist to the diagnosis of CADASIL are reviewed. However, a wide differential diagnosis exists for the MRI appearances of CADASIL, including multiple sclerosis and small-vessel disease secondary to hypertension. The definitive diagnosis cannot be made on MRI alone and requires additional evidence, where available, from a positive family history and by screening DNA for mutations of Notch 3 gene.

Adult↗
PubMed2003

Evaluating the hilar bifurcation territory in the human liver caudate lobe to obtain critical information for delimiting reliable margins during caudate lobe surgery: anatomic study of livers with and without the external caudate notch.

The hilar bifurcation (HB), a wedged portion between the left and right portal vein origins, often issues the caudate branch. However, the HB territory in the caudate lobe has not been well recognized during liver surgery. In 50% of 48 human livers (25 usual livers and 23 with the external caudate notch), the HB gave off thick portal branches (> 1 mm) to supply the caudate lobe. Using minute dissections, we identified four cross-sectional configurations of three subdivisions of the caudate lobe (i.e., left, right, and HB portal territories). The HB territory was consistently located in the paracaval portion, although it sometimes (29.2%: type A) extended slightly or deeply into Spiegel's lobe. This leftward HB territorial extension was seen more frequently in livers with the notch (43.6%) than in those without it ("usual" livers) (16.0%). Moreover, in livers with the notch the caudate lobe (usually its right portal territory) tended to extend upward and rightward to attach or surround the terminal portion of the right hepatic vein. Our results suggested that in many cases subdivisions of the caudate lobe cannot be divided simply into right and left portions. The HB branch or territory should be examined to determine the real principal border as well as the subdivisional configuration of the caudate lobe. Combined evaluation of the HB branch(es) and external notch could provide critical information for anatomically sophisticated caudate lobe surgery.

Hepatectomy↗
PubMed1984

Echographic early systolic partial closure (notching) of the aortic valve in congestive cardiomyopathy.

We investigated the prevalence and significance of aortic valve early systolic partial closure (notching) in congestive cardiomyopathy by reviewing clinical and M-mode echocardiographic findings in 33 patients. We also compared their echocardiographic aortic root and valve findings to those in 17 aortic regurgitation patients and 24 normal subjects. Thirteen cardiomyopathy patients (39%) exhibited aortic valve partial closure--similar to the prevalence in the aortic regurgitation (41%) and normal (33%) groups. However, patients with dilated cardiomyopathy and aortic valve notching exhibited a higher mean percentage of partial closure (18% +/- 10) than those with notching in either the aortic regurgitation (8% +/- 9) or normal (5% +/- 2) group. There was no significant difference in age, body surface area, left ventricular dimension, systolic function, or presence of mitral regurgitation between cardiomyopathy patients with and without aortic valve notching, but the former had slightly greater aortic root dimensions and maximal aortic leaflet separation. Although the reason for this difference is unknown, a wider aortic root may result in low-pressure areas bordering the aortic flow stream during early systole, which may favor partial aortic valve closure.

Adult↗