The continuously growing rodent incisor is an emerging model for the study of renewal of mineralized tissues by adult stem cells. Although the Bmp, Fgf, Shh, and Wnt pathways have been studied in this organ previously, relatively little is known about the role of Notch signaling during incisor renewal. Notch signaling components are expressed in enamel-forming ameloblasts and the underlying stratum intermedium (SI), which suggested distinct roles in incisor renewal and enamel mineralization. Here, we injected adult mice with inhibitory antibodies against several components of the Notch pathway. This blockade led to defects in the interaction between ameloblasts and the SI cells, which ultimately affected enamel formation. Furthermore, Notch signaling inhibition led to the downregulation of desmosome-specific proteins such as PERP and desmoplakin, consistent with the importance of desmosomes in the integrity of ameloblast-SI attachment and enamel formation. Together, our data demonstrate that Notch signaling is critical for proper enamel formation during incisor renewal, in part by regulating desmosome-specific components, and that the mouse incisor provides a model system to dissect Jag-Notch signaling mechanisms in the context of mineralized tissue renewal.

• Klíčová slova
• AMELOBLAST, AMELOGENESIS, JAG, NOTCH, STRATUM INTERMEDIUM, TOOTH DEVELOPMENT,
• MeSH
• ameloblasty metabolismus   patologie   MeSH
• desmozomy metabolismus   patologie   MeSH
• myši MeSH
• nemoci zubů MeSH
• receptory Notch * MeSH
• řezáky metabolismus   patologie   MeSH
• signální transdukce * MeSH
• zubní sklovina metabolismus   patologie   MeSH
• zvířata MeSH
• Check Tag
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• Research Support, N.I.H., Extramural MeSH
• Názvy látek
• receptory Notch * MeSH

Cardiac fibroblast-myofibroblast transformation (CMT) is a critical event in the initiation of myocardial fibrosis. Notch signaling has been shown to regulate myofibroblast transformation from other kinds of cells. However, whether Notch signaling is also involved in CMT remains unclear. In the present study, expressions of Notch receptors in cardiac fibroblasts (CFs) were examined, effects of Notch signaling inhibitor N-[N-(3,5-difluorophenacetyl)-l-alanyl]-S-phenylglycine t-butyl ester (DAPT) and transforming growth factor-beta1 (TGF-beta1) on CMT were determined by increasing alpha-smooth muscle actin (alpha-SMA) expression and collagen synthesis, and Notch signaling was examined by analyzing expressions of Notch receptors. The results showed that: (1) Notch receptor 1, 2, 3 and 4 were all expressed in CFs; (2) DAPT promoted CMT in a time-dependent manner; (3) During the period of CMT induced by TGF-beta1, expressions of Notch receptor 1, 3 and 4 in CFs were down-regulated, whereas there was no change for Notch receptor 2. Moreover, the downtrends of Notch 1, 3 and 4 were corresponding to the trend growth of alpha-SMA expression and collagen synthesis. These results suggested that inhibiting of Notch signaling might promote CMT. The down-regulations of Notch receptor 1, 3 and 4 induced by TGF-beta1 may facilitate CMT. In conclusion, inhibition of Notch signaling might be a novel mechanism of CMT in myocardial fibrosis.

• MeSH
• buněčná diferenciace MeSH
• down regulace MeSH
• fibroblasty cytologie   metabolismus   MeSH
• kardiomyocyty cytologie   metabolismus   MeSH
• krysa rodu Rattus MeSH
• kultivované buňky MeSH
• myofibroblasty cytologie   metabolismus   MeSH
• novorozená zvířata MeSH
• potkani Sprague-Dawley MeSH
• receptory Notch metabolismus   MeSH
• signální transdukce fyziologie   MeSH
• zvířata MeSH
• Check Tag
• krysa rodu Rattus MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• receptory Notch MeSH

Notch and gp130 signaling are involved in the regulation of multiple cellular processes across various tissues during animal ontogenesis. In the developing nervous system, both signaling pathways intervene at many stages to determine cell fate-from the first neural lineage commitment and generation of neuronal precursors, to the terminal specification of cells as neurons and glia. In most cases, the effects of Notch and gp130 signaling in these processes are similar. The aim of the current review was to summarize the knowledge regarding the roles of Notch and gp130 signaling in the maintenance of neural stem and progenitor cells during animal ontogenesis, from early embryo to adult. Recent data show a direct crosstalk between these signaling pathways that seems to be specific for a particular type of neural progenitors.

• MeSH
• cytokinový receptor gp130 metabolismus   MeSH
• interakce mezi receptory a ligandy MeSH
• lidé MeSH
• nervové kmenové buňky metabolismus   MeSH
• neurogeneze MeSH
• receptory Notch metabolismus   MeSH
• signální transdukce * MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• přehledy MeSH
• Názvy látek
• cytokinový receptor gp130 MeSH
• receptory Notch MeSH

Previous studies have suggested that the Notch signaling pathway plays a very important role in the proliferation and differentiation of pulmonary microvascular endothelial cells (PMVECs). Therefore, we aimed to investigate the expression level of Notch-related signaling molecules in PMVECs in bleomycin (BLM)-induced rat pulmonary fibrosis. Immunohistochemistry, immunofluorescence, Western blotting, and real-time PCR were used to analyze the differences in protein and mRNA expression levels of Notch-related signaling molecules, i.e. Notch1, Jagged1, Delta-like ligand 4 (Dll4), and hairy and enhancer of split homolog 1 (Hes1), between a control group treated with intratracheal instillation of saline and a study group treated with intratracheal instillation of BLM solution. Expression levels of the receptor Notch1 and one of its ligands, Jagged1, were upregulated, while the expression levels of the ligand Dll4 and the target molecule of the Notch signaling pathway, Hes1, were downregulated. The differences in protein and mRNA expression levels between the control and study groups were significant (p<0.001). The Jagged1/Notch1 signaling pathway is activated in the pathogenesis of BLM-induced rat pulmonary fibrosis, while the Dll4/Notch1 signaling pathway is inhibited, which inhibits the suppressive effect of Dll4/Notch1 signaling on PMVEC overproliferation, further causing PMVEC dysfunction in cell sprouting and maturation as well as abnormal differentiation of the cell phenotype. Conversely, the down-expression of Hes1 indicates that the Jagged1/Notch1 signaling pathway could be a non-canonical Notch signaling pathway independent of Hes1 activation, which differs from the canonical Dll4/Notch1 signaling pathway.

• MeSH
• arteria pulmonalis účinky léků   metabolismus   MeSH
• bleomycin MeSH
• endoteliální buňky účinky léků   metabolismus   MeSH
• krysa rodu Rattus MeSH
• kultivované buňky MeSH
• mezibuněčné signální peptidy a proteiny metabolismus   MeSH
• mikrocévy metabolismus   MeSH
• plicní fibróza chemicky indukované   metabolismus   MeSH
• receptory Notch metabolismus   MeSH
• zvířata MeSH
• Check Tag
• krysa rodu Rattus MeSH
• mužské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• bleomycin MeSH
• mezibuněčné signální peptidy a proteiny MeSH
• receptory Notch MeSH

The Wnt, TGF-β, and Notch signaling pathways are essential for the regulation of cellular polarity, differentiation, proliferation, and migration. Differential activation and mutual crosstalk of these pathways during animal development are crucial instructive forces in the initiation of the body axis and the development of organs and tissues. Due to the ability to initiate cell proliferation, these pathways are vulnerable to somatic mutations selectively producing cells, which ultimately slip through cellular and organismal checkpoints and develop into cancer. The architecture of the Wnt, TGF-β, and Notch signaling pathways is simple. The transmembrane receptor, activated by the extracellular stimulus, induces nuclear translocation of the transcription factor, which subsequently changes the expression of target genes. Nevertheless, these pathways are regulated by a myriad of factors involved in various feedback mechanisms or crosstalk. The most prominent group of regulators is the ubiquitin-proteasome system (UPS). To open the door to UPS-based therapeutic manipulations, a thorough understanding of these regulations at a molecular level and rigorous confirmation in vivo are required. In this quest, mouse models are exceptional and, thanks to the progress in genetic engineering, also an accessible tool. Here, we reviewed the current understanding of how the UPS regulates the Wnt, TGF-β, and Notch pathways and we summarized the knowledge gained from related mouse models.

• Klíčová slova
• cancer, gene inactivation, mouse model, ubiquitin–proteasome system,
• MeSH
• beta-katenin metabolismus   MeSH
• buněčná diferenciace fyziologie   MeSH
• homeostáza genetika   MeSH
• ligasy metabolismus   MeSH
• myši embryologie   genetika   MeSH
• proliferace buněk fyziologie   MeSH
• proteiny Wnt metabolismus   MeSH
• receptory Notch metabolismus   MeSH
• signální dráha Wnt fyziologie   MeSH
• transformující růstový faktor beta metabolismus   MeSH
• transkripční faktory metabolismus   MeSH
• ubikvitin metabolismus   MeSH
• ubikvitinligasy metabolismus   fyziologie   MeSH
• vývojová regulace genové exprese genetika   MeSH
• zvířata MeSH
• Check Tag
• myši embryologie   genetika   MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• přehledy MeSH
• Názvy látek
• beta-katenin MeSH
• ligasy MeSH
• proteiny Wnt MeSH
• receptory Notch MeSH
• transformující růstový faktor beta MeSH
• transkripční faktory MeSH
• ubikvitin MeSH
• ubikvitinligasy MeSH

The silent information regulator 1 (Sirt1) has been shown to have negative effects on the Notch pathway in several contexts. We bring evidence that Sirt1 has a positive effect on Notch activation in Drosophila, in the context of sensory organ precursor specification and during wing development. The phenotype of Sirt1 mutant resembles weak Notch loss-of-function phenotypes, and genetic interactions of Sirt1 with the components of the Notch pathway also suggest a positive role for Sirt1 in Notch signalling. Sirt1 is necessary for the efficient activation of enhancer of split [E(spl)] genes by Notch in S2N cells. Additionally, the Notch-dependent response of several E(spl) genes is sensitive to metabolic stress caused by 2-deoxy-d-glucose treatment, in a Sirt1-dependent manner. We found Sirt1 associated with several proteins involved in Notch repression as well as activation, including the cofactor exchange factor Ebi (TBL1), the RLAF/LAF histone chaperone complex and the Tip60 acetylation complex. Moreover, Sirt1 participates in the deacetylation of the CSL transcription factor Suppressor of Hairless. The role of Sirt1 in Notch signalling is, therefore, more complex than previously recognized, and its diverse effects may be explained by a plethora of Sirt1 substrates involved in the regulation of Notch signalling.

• Klíčová slova
• Drosophila melanogaster, acetylation/deacetylation, metabolic regulation, notch signalling pathway, sirtuins,
• MeSH
• buněčné linie MeSH
• deoxyglukosa farmakologie   MeSH
• Drosophila MeSH
• hmotnostní spektrometrie MeSH
• imunoprecipitace MeSH
• messenger RNA antagonisté a inhibitory   MeSH
• proteiny Drosophily genetika   metabolismus   MeSH
• receptory Notch genetika   metabolismus   MeSH
• represorové proteiny genetika   metabolismus   MeSH
• RNA interference fyziologie   MeSH
• signální transdukce účinky léků   genetika   MeSH
• sirtuin 1 genetika   metabolismus   MeSH
• transkripční faktory bHLH genetika   metabolismus   MeSH
• vazba proteinů MeSH
• zvířata MeSH
• Check Tag
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• deoxyglukosa MeSH
• E(spl)m7-HLH protein, Drosophila MeSH Prohlížeč
• messenger RNA MeSH
• proteiny Drosophily MeSH
• receptory Notch MeSH
• represorové proteiny MeSH
• sirtuin 1 MeSH
• transkripční faktory bHLH MeSH

Notch signalling is critical for the development of the nervous system. In the zebrafish mindbomb mutants, disruption of E3 ubiquitin ligase activity inhibits Notch signalling. In these mutant embryos, precocious development of primary neurons leading to depletion of neural progenitor cells results in a neurogenic phenotype characterized by defects in neural patterning and brain development. Cyclin-dependent kinase 5 (Cdk5), a predominant neuronal kinase, is involved in a variety of essential functions of the nervous system. Most recently, mammalian studies on Notch and Cdk5 regulating each other's function have been emerging. The status of Cdk5 in the mindbomb mutant embryos with excessive primary neurons is not known. In situ hybridization of the zebrafish mindbomb mutant embryos uncovered a robust upregulation in Cdk5 expression but with a reduced Cdk5 activity. The implications of these findings in both the mammalian system and zebrafish are discussed in this mini-review to provide a glimpse into the relationship between Notch and Cdk5 that may explain certain neurodevelopmental defects associated with either mutations in ubiquitin ligase or altered expression of Cdk5.

• MeSH
• biologické modely MeSH
• cyklin-dependentní kinasa 5 metabolismus   MeSH
• dánio pruhované metabolismus   MeSH
• mutace genetika   MeSH
• proteiny dánia pruhovaného genetika   MeSH
• receptory Notch metabolismus   MeSH
• upregulace genetika   MeSH
• zvířata MeSH
• Check Tag
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH
• Názvy látek
• cyklin-dependentní kinasa 5 MeSH
• proteiny dánia pruhovaného MeSH
• receptory Notch MeSH

Glycolytic shift is a characteristic feature of rapidly proliferating cells, such as cells during development and during immune response or cancer cells, as well as of stem cells. It results in increased glycolysis uncoupled from mitochondrial respiration, also known as the Warburg effect. Notch signalling is active in contexts where cells undergo glycolytic shift. We decided to test whether metabolic genes are direct transcriptional targets of Notch signalling and whether upregulation of metabolic genes can help Notch to induce tissue growth under physiological conditions and in conditions of Notch-induced hyperplasia. We show that genes mediating cellular metabolic changes towards the Warburg effect are direct transcriptional targets of Notch signalling. They include genes encoding proteins involved in glucose uptake, glycolysis, lactate to pyruvate conversion and repression of the tricarboxylic acid cycle. The direct transcriptional upregulation of metabolic genes is PI3K/Akt independent and occurs not only in cells with overactivated Notch but also in cells with endogenous levels of Notch signalling and in vivo. Even a short pulse of Notch activity is able to elicit long-lasting metabolic changes resembling the Warburg effect. Loss of Notch signalling in Drosophila wing discs as well as in human microvascular cells leads to downregulation of glycolytic genes. Notch-driven tissue overgrowth can be rescued by downregulation of genes for glucose metabolism. Notch activity is able to support growth of wing during nutrient-deprivation conditions, independent of the growth of the rest of the body. Notch is active in situations that involve metabolic reprogramming, and the direct regulation of metabolic genes may be a common mechanism that helps Notch to exert its effects in target tissues.

• Klíčová slova
• Notch targets, Warburg effect, glycolytic shift, metabolism, tissue growth,
• MeSH
• aktivace transkripce MeSH
• biologické modely MeSH
• buněčné linie MeSH
• citrátový cyklus genetika   MeSH
• energetický metabolismus genetika   MeSH
• exprese genu MeSH
• glykolýza genetika   MeSH
• lidé MeSH
• promotorové oblasti (genetika) MeSH
• proteiny Drosophily genetika   metabolismus   MeSH
• receptory Notch genetika   metabolismus   MeSH
• regulace genové exprese * MeSH
• regulační oblasti nukleových kyselin MeSH
• reportérové geny MeSH
• represorové proteiny genetika   metabolismus   MeSH
• vazba proteinů MeSH
• vazebná místa MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• proteiny Drosophily MeSH
• receptory Notch MeSH
• represorové proteiny MeSH
• Su(H) protein, Drosophila MeSH Prohlížeč

Mitochondrial dysfunctions belong amongst the most common metabolic diseases but the signalling networks that lead to the manifestation of a disease phenotype are often not well understood. We identified the subunits of respiratory complex I, III and IV as mediators of major signalling changes during Drosophila wing disc development. Their downregulation in larval wing disc leads to robust stimulation of TOR activity, which in turn orchestrates a complex downstream signalling network. Specifically, after downregulation of the complex I subunit ND-49 (mammalian NDUFS2), TOR activates JNK to induce cell death and ROS production essential for the stimulation of compensatory apoptosis-induced proliferation within the tissue. Additionally, TOR upregulates Notch and JAK/STAT signalling and it directs glycolytic switch of the target tissue. Our results highlight the central role of TOR signalling in mediating the complex response to mitochondrial respiratory dysfunction and they provide a rationale why the disease symptoms associated with respiratory dysfunctions are often alleviated by mTOR inhibitors.

• MeSH
• down regulace MeSH
• Drosophila MeSH
• Janus kinasy metabolismus   MeSH
• křídla zvířecí růst a vývoj   metabolismus   MeSH
• proteiny Drosophily genetika   metabolismus   MeSH
• reaktivní formy kyslíku metabolismus   MeSH
• receptory Notch metabolismus   MeSH
• respirační komplex I genetika   metabolismus   MeSH
• signální transdukce * MeSH
• transkripční faktory STAT metabolismus   MeSH
• tyrosinkinasové receptory metabolismus   MeSH
• zvířata MeSH
• Check Tag
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• Janus kinasy MeSH
• N protein, Drosophila MeSH Prohlížeč
• proteiny Drosophily MeSH
• reaktivní formy kyslíku MeSH
• receptory Notch MeSH
• respirační komplex I MeSH
• tor protein, Drosophila MeSH Prohlížeč
• transkripční faktory STAT MeSH
• tyrosinkinasové receptory MeSH

Intestinal homeostasis is a complex and tightly regulated process governed by a variety of signalling pathways that balance cell proliferation and differentiation. As revealed by extensive use of defined mouse models, perturbations within the signalling circuitry trigger initial expansion of premalignant cells. In this review, we attempt to summarise recent advances in the knowledge of the cellular signalling mechanisms that drive tumorigenesis in the human and mouse intestine.

• MeSH
• erbB receptory fyziologie   MeSH
• homeostáza * MeSH
• lidé MeSH
• nádorová transformace buněk * MeSH
• proteiny hedgehog fyziologie   MeSH
• receptory Notch fyziologie   MeSH
• rodina receptorů Eph fyziologie   MeSH
• signální dráha Wnt fyziologie   MeSH
• signální transdukce fyziologie   MeSH
• střevní nádory etiologie   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• přehledy MeSH
• Názvy látek
• erbB receptory MeSH
• proteiny hedgehog MeSH
• receptory Notch MeSH
• rodina receptorů Eph MeSH