Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 420.107
Filtrar
1.
Adv Exp Med Biol ; 1287: 105-122, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-33034029

RESUMEN

The NOTCH pathway is critical for the development of many cell types including the squamous epithelium lining of cutaneous and mucosal surfaces. In genetically engineered mouse models, Notch1 acts as one of the first steps to commit basal keratinocytes to terminally differentiate. Similarly, in human head and neck squamous cell cancers (HNSCCs), NOTCH1 is often lost consistent with its essential tumor-suppressive role for initiating keratinocyte differentiation. However, constitutive NOTCH1 activity in the epithelium results in expansion of the spinous keratinocyte layers and impaired terminal differentiation is consistent with the role of NOTCH1 as an oncogene in other cancers, especially in T-cell acute lymphoblastic leukemia. We have previously observed that NOTCH1 plays a dual role as both a tumor suppressor and oncogene, depending on the mutational context of the tumor. Namely, gain or loss or NOTCH1 activity promotes the development of human papillomavirus (HPV)-associated cancers. The additional HPV oncogenes likely disrupt the tumor-suppressive activities of NOTCH and enable the oncogenic pathways activated by NOTCH to promote tumor growth. In this review, we detail the role of NOTCH pathway in head and neck cancers with a focus on HPV-associated cancers.


Asunto(s)
Carcinogénesis , Neoplasias de la Boca/metabolismo , Neoplasias de la Boca/virología , Papillomaviridae/patogenicidad , Infecciones por Papillomavirus/metabolismo , Receptores Notch/metabolismo , Transducción de Señal , Animales , Carcinoma de Células Escamosas/metabolismo , Carcinoma de Células Escamosas/virología , Humanos , Infecciones por Papillomavirus/virología
2.
Sci Total Environ ; 753: 141962, 2021 Jan 20.
Artículo en Inglés | MEDLINE | ID: mdl-32890875

RESUMEN

Arsenic (As) is a known human carcinogen with a hitherto unknown mechanism of action. Dimethylarsinic acid (DMAV) is a methylated metabolite of arsenicals found in most mammals, and long-term exposure to DMAV can lead to bladder cancer in rats. Human epidermal growth factor receptor 2 (HER2) is an oncogenic factor that is overexpressed in bladder cancer, but its role in the initiation and progression of As-induced bladder cancer has not been elucidated. We found that HER2 was up-regulated in human uroepithelial cells treated with arsenite as well as in the bladder tissues of DMAV-exposed rats. HER2 overexpression correlated to increased cell proliferation, epithelial-to-mesenchymal transition (EMT), migration and angiogenesis in vitro. The anti-HER2 monoclonal antibody trastuzumab significantly decreased serum vascular endothelial-derived growth factor (VEGF) levels and that of proliferation-related proteins in the bladder tissues of DMAV-exposed rats. Furthermore, inhibition of HER2, as well as that of the MAPK, AKT and STAT3 pathways, attenuated arsenite-induced proliferation, migration and angiogenesis of human uroepithelial cells, and increased apoptosis rates in vitro. These findings indicate that HER2 mediates the oncogenic effects of As on bladder epithelial cells by activating the MAPK, PI3K/AKT and Src/STAT3 signaling pathways, and is therefore a promising biomarker.


Asunto(s)
Arsénico , Animales , Arsénico/toxicidad , Proliferación Celular , Células Epiteliales , Humanos , Fosfatidilinositol 3-Quinasas , Ratas , Receptor ErbB-2 , Transducción de Señal
3.
Gene ; 764: 145082, 2021 Jan 05.
Artículo en Inglés | MEDLINE | ID: mdl-32858176

RESUMEN

Melatonin functions as a plant growth regulator in a concentration-dependent manner. In this study, we investigated the effects of melatonin on root growth and dissected underlined mechanisms. The results showed that melatonin up to 1000 µM inhibited primary root growth, but promoted lateral root development. Through RNA sequencing analysis, functions of differentially expressed genes were mainly involved in stress response, signaling transduction, transport, hormone metabolism and amino acid metabolism. Genes involving in jasmonate (JA), brassinosteroid (BR) and cytokinin (CK) biosynthesis were inhibited, but these in ethylene (ET), strigolactone (SL) and gibberellins (GA) biosynthetic pathways were activated after melatonin treatment. The majority of zinc finger proteins (ZFPs), Calmodulin-like (CMLs), NAM, ATAF1/2, and CUC2 (NACs) and ubiquitination related genes (RING/U-box and F-box) were upregulated, which possibly acted downstream of integrated hormone signals to mediate root growth. This study characterized melatonin modulated networks in regulating root growth.


Asunto(s)
Arabidopsis/fisiología , Regulación del Desarrollo de la Expresión Génica , Regulación de la Expresión Génica de las Plantas , Melatonina/metabolismo , Reguladores del Crecimiento de las Plantas/metabolismo , Raíces de Plantas/crecimiento & desarrollo , Proteínas de Arabidopsis/genética , Proteínas de Arabidopsis/metabolismo , Vías Biosintéticas/genética , RNA-Seq , Transducción de Señal/genética , Factores de Transcripción/metabolismo , Transcriptoma/genética
4.
Gene ; 766: 145113, 2021 Jan 15.
Artículo en Inglés | MEDLINE | ID: mdl-32891771

RESUMEN

Breast cancer remains the most common malignancy in women worldwide. Circular RNAs (circRNAs) are a newly validated type of endogenous non-coding RNAs and accumulating evidence suggests that aberrant circRNAs are involved in disease pathogenesis. However, the function of circRNAs in breast cancer remains largely unknown. This study is aimed to characterize the potential role and mechanism of hsa_circ_0000442 (circ_0000442) in breast cancer. The human breast epithelial cell line (MCF-10A), breast cancer cell lines (MCF-7, T47D, BT474, SK-BR-3, MDA-MB-231, SUM-1315) and the Balb/C Nude mice were used for exploration, and the qRT-PCR, western blot, dual-luciferase reporter assay, glo assay, colony formation assay, and tumor xenograft were carried out for investigation. In this study, the results showed a lower expression of circ_0000442 in breast cancer tumor tissues compared with the adjacent normal tissues. Subsequently, circ_0000442 was found to acted as the sponge of miR-148b-3p in breast cancer cells, thus exerting the tumor-suppressive effects. In the subsequent mechanism study, results showed that miR-148b-3p directly targeted PTEN, a well-known tumor suppressor which negatively regulats PI3K/Akt pathway, thus promoting tumor growth in breast cancer. Overall, this study for the first time identified the tumor-suppressive role of circ_0000442 in breast cancer and found PTEN as a novel direct target of miR-148b-3p. The regulatory role of circ_0000442/miR-148b-3p/PTEN/PI3K/Akt axis was preliminarily confirmed in breast cancer cells and mouse models. These findings suggest an important progress in our standing of breast cancer and lay the foundation for the further function, diagnosis, therapy and prognosis research of circular RNAs in breast cancer.


Asunto(s)
Neoplasias de la Mama/genética , Fosfohidrolasa PTEN/genética , Fosfatidilinositol 3-Quinasas/genética , Proteínas Proto-Oncogénicas c-akt/genética , ARN Circular/genética , Transducción de Señal/genética , Animales , Línea Celular , Línea Celular Tumoral , Proliferación Celular/genética , Femenino , Regulación Neoplásica de la Expresión Génica/genética , Humanos , Células MCF-7 , Ratones , Ratones Endogámicos BALB C , Ratones Desnudos , MicroARNs/genética , Pronóstico
5.
Gene ; 766: 145134, 2021 Jan 15.
Artículo en Inglés | MEDLINE | ID: mdl-32898605

RESUMEN

BACKGROUND: Artesunate (ART) has been used extensively as anti-malarial drugs worldwide. Besides, it has also been reported to have anti-cancer activities. This study was aimed to explore the anti-cancer activity of ART in combination with cisplatin (CIS) on A549 cells. METHODS: Cells were cultured with different concentrations of ART and/or CIS for 24, 48, or 72 h to test the anti-proliferative effects by CCK-8 assay. Colony formation assay and EdU staining were also performed. TUNEL staining was used to illustrate the morphologic changes. Cell cycle and apoptosis were determined by flow cytometry assay, and Western blot analysis was conducted to detect the expression of apoptosis- and proliferation-related proteins. Caspase activities were determined by colorimetric assay kit. Moreover, the synergistic effect of ART with CIS in A549 cell xenograft model was also determined. RESULTS: ART significantly inhibited cell proliferation in dose- and time-dependent manners. Collectively, the combination treatment remarkably decreased colony formation rates and increased the rates of TUNEL-positive cells compared with mono-treatment. Mechanistically, the combination treatment influenced the expression of Bcl-2, Bax, p-P53, Caspase-3/7, Caspase-9, CyclinB1, P34, P21, and synergistically regulated the activity of P38/JNK/ERK1/2 MAPK pathway. In mice A549 xenograft tumors, the combination strategy significantly increased the anti-cancer efficacy of ART and CIS alone, consistent with the in vitro observations. CONCLUSIONS: ART exhibited significant anti-tumor effect on A549 cells and this efficiency could be enhanced by combination with CIS.


Asunto(s)
Antineoplásicos/farmacología , Artesunato/farmacología , Cisplatino/farmacología , Neoplasias Pulmonares/tratamiento farmacológico , Sistema de Señalización de MAP Quinasas/efectos de los fármacos , Transducción de Señal/efectos de los fármacos , Células A549 , Animales , Apoptosis/efectos de los fármacos , Ciclo Celular/efectos de los fármacos , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Sinergismo Farmacológico , Femenino , Humanos , Neoplasias Pulmonares/metabolismo , Ratones , Ratones Desnudos , Inhibidores de Proteínas Quinasas/farmacología
6.
Gene ; 766: 145128, 2021 Jan 15.
Artículo en Inglés | MEDLINE | ID: mdl-32911026

RESUMEN

BACKGROUND: The pathogenesis of osteonecrosis of the femoral head (ONFH) is unclear. Our previous study demonstrated that upregulated miR-335 in bone microvascular endothelial cells (BMECs) might be associated with the disease of steroid-induced ONFH. Here, we study the preventive effect of ICA on steroid-induced ONFH in rats. METHOD: 90 rats were separated into three groups: control group, methylprednisolone (MPS) group, and MPS + Icariin (ICA) group. Four weeks later, histological analyses were performed. Thrombomodulin (TM) and vascular endothelial growth factor (VEGF) were tested. MiRNA-335 expression was screened in the three groups using Agilent Gene Spring GX software. Target genes of miRNA-335 were detected by bioinformatics analysis. The functions of BMECs were analyzed by scratch, angiogenesis and cell survival rate. RESULTS: ICA can prevent the occurrence of steroid-associated ONFH in rats and reduce the amount of TM and VEGF in serum induced by glucocorticoids. ICA could regulate the overexpression of miRNA-335 induced by glucocorticoids. We predicted the Gene ontology (GO) and signaling pathways of target genes. At 24 hours, we found that ICA significantly promoted BMECs migration abilities. We also found that ICA could promote the angioplasty ability of BMECs. ICA could improve the survival rate of BMECs after steroid-induced injury. CONCLUSIONS: ICA is effective to prevent the occurrence of steroidinduced ONFH. ICA has a protective effect against steroid-induced BMECs injury. ICA regulated the imbalance of miRNA-335 expression induced by the glucocorticoid in BMECs, which provides a new viewpoint to explore the mechanism of ICA in preventing steroid-induced ONFH.


Asunto(s)
Células Endoteliales/efectos de los fármacos , Necrosis de la Cabeza Femoral/tratamiento farmacológico , Cabeza Femoral/efectos de los fármacos , Flavonoides/farmacología , MicroARNs/metabolismo , Neovascularización Patológica/tratamiento farmacológico , Sustancias Protectoras/farmacología , Adipogénesis/efectos de los fármacos , Animales , Movimiento Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Células Endoteliales/metabolismo , Femenino , Cabeza Femoral/metabolismo , Necrosis de la Cabeza Femoral/inducido químicamente , Necrosis de la Cabeza Femoral/metabolismo , Glucocorticoides/metabolismo , Metilprednisolona/farmacología , Neovascularización Patológica/metabolismo , Osteocitos/efectos de los fármacos , Osteogénesis/efectos de los fármacos , Ratas , Ratas Sprague-Dawley , Transducción de Señal/efectos de los fármacos , Esteroides/farmacología , Factor A de Crecimiento Endotelial Vascular/metabolismo
7.
Gene ; 766: 145142, 2021 Jan 15.
Artículo en Inglés | MEDLINE | ID: mdl-32911027

RESUMEN

Rootstocks are among the primary factors that influence fruit yield and quality as well as melon development. To understand the differences in the molecular mechanisms and gene expression networks of fruit development between grafted and nongrafted plants in oriental melon, we performed a comprehensive analysis of the transcriptome and proteome dynamic gene/protein expression profiles during fruit development in oriental melon (Cucumis melo L. var. makuwa). Using pairwise comparisons between grafted and nongrafted samples by transcriptome analysis, we identified a large number of candidate genes involved in hormonal signaling pathways, transcription factors, resistance-related biosynthetic pathways and photosynthesis-related metabolic pathways. Many transcription factor-encoded genes were significantly more strongly expressed in the grafted samples, for example, AP2/ERF, C2H2, MYB, bHLH, and AUX/IAA, which are well-known participants in the regulation of developmental processes and hormonal signaling metabolism. Some differentially expressed genes (DEGs) were enriched in flavonoid biosynthesis and phenylpropanoid biosynthesis and determined plant resistance. In addition, some differentially expressed proteins (DEPs) were enriched in photosynthesis-related pathways, which could improve fruit quality and yield. Moreover, through weighted gene coexpression network analyses, we identified modules of coexpressed genes and hub genes specifically related to grafting for different fruit developmental stages. The results suggested that graft-related modules and hub genes were primarily associated with photosynthate metabolism and hormonal signaling pathways. The results obtained in this study provide a valuable resource for dissecting the role of candidate genes governing graft-related metabolism in oriental melon fruit, suggesting an interesting correlation with the effects of rootstock on fruit development.


Asunto(s)
Cucumis melo/genética , Cucurbitaceae/crecimiento & desarrollo , Cucurbitaceae/genética , Frutas/crecimiento & desarrollo , Frutas/genética , Regulación de la Expresión Génica de las Plantas/genética , Perfilación de la Expresión Génica/métodos , Redes Reguladoras de Genes/genética , Fotosíntesis/genética , Raíces de Plantas/genética , RNA-Seq/métodos , Transducción de Señal/genética , Transcriptoma/genética
8.
Gene ; 766: 145150, 2021 Jan 15.
Artículo en Inglés | MEDLINE | ID: mdl-32949695

RESUMEN

There are a few studies indicating that small molecular compounds affect the proliferation, differentiation, apoptosis, and autophagy of female germline stem cells (FGSCs). However, whether small molecular compound 28 (C28) affect development of FGSCs remains unknown. In this study, we found that C28 reduced the viability and proliferation of FGSCs, respectively. Additionally, western blotting showed that the expression of autophagy marker light chain 3 beta II (LC3B-II) was significantly increased and expression of sequestosome-1 (SQSTM1) was significantly reduced in C28-treated groups. Immunofluorescence showed that, in C28-treated groups, the number of LC3B-II-positive puncta was increased significantly. These results indicated that C28 induced autophagy of FGSCs in vitro. Furthermore, data from Chromatin Immunoprecipitation Sequencing for H3K27ac showed that autophagy-related biological processes such as regulation of mitochondrial membrane potential, Golgi vesicle transport, and cellular response to reactive oxygen species were different after C28-treated. In addition, RNA-Seq showed that the expression of genes (Trib3, DDIT3, and ATF4) related to endoplasmic reticulum (ER) stress was enhanced by C28. These results suggest that the changes of H3K27ac and ER stress might be associated with C28-induced FGSC autophagy.


Asunto(s)
Acetilación/efectos de los fármacos , Autofagia/efectos de los fármacos , Histonas/genética , Células Madre Oogoniales/efectos de los fármacos , Bibliotecas de Moléculas Pequeñas/farmacología , Transcriptoma/efectos de los fármacos , Animales , Proliferación Celular/efectos de los fármacos , Estrés del Retículo Endoplásmico/efectos de los fármacos , Femenino , Aparato de Golgi/efectos de los fármacos , Aparato de Golgi/genética , Potencial de la Membrana Mitocondrial/efectos de los fármacos , Ratones , Ratones Endogámicos C57BL , Células Madre Oogoniales/metabolismo , Especies Reactivas de Oxígeno/metabolismo , Transducción de Señal/efectos de los fármacos
9.
Gene ; 766: 145154, 2021 Jan 15.
Artículo en Inglés | MEDLINE | ID: mdl-32949699

RESUMEN

CircRNA serves a crucial role in the development of heart failure (HF). Nevertheless, the regulatory mechanisms of circ_0062389 in HF are unknown. This study aims to examine the effect and mechanism of circ_0062389 on cardiomyocyte apoptosis in HF rats and H9C2 cells. Rats were divided into 5 groups (n = 8/group): the Control group, Sham group, HF group, HF + si-NC group, and HF + si-circRNA group. The echocardiography was used to examine the cardiac function, including LVIDd, LVIDs, IVSd, and IVSs. The apoptosis of myocardial tissue was detected through TUNEL method. H9C2 cells were randomly assigned into Control group (untransfected H9C2 cells), H/R group (untransfected H/R H9C2 cells), H/R + si-NC group (transfected si-NC) and H/R + si-circRNA group (transfect si-circ_0062389). Cell apoptosis was assessed through flow cytometry. The expression of circ_0062389 in myocardial tissues of HF rats was significantly higher than that of Control group and Sham group. Silencing circ_0062389 significantly reduced the levels of LVIDd, LVIDs, IVSd, and IVSs. Additionally, silencing circ_0062389 could significantly reduce the apoptosis rate of rat cardiomyocytes. Besides, silencing circ_0062389 significantly reduced the expression of TGF-ß1 and Smad3 protein. Silencing circ_0062389 could alleviate cardiomyocyte apoptosis in HF rats via modulating TGF-ß1/Smad3 signaling pathway, which might be a promising target for the treatment of HF.


Asunto(s)
Apoptosis/genética , Insuficiencia Cardíaca/genética , Miocitos Cardíacos/patología , Interferencia de ARN/fisiología , ARN Circular/genética , Transducción de Señal/genética , Proteína smad3/genética , Factor de Crecimiento Transformador beta1/genética , Animales , Línea Celular , Corazón/fisiología , Insuficiencia Cardíaca/patología , Masculino , Miocardio/patología , Ratas , Ratas Sprague-Dawley
10.
Gene ; 766: 145152, 2021 Jan 15.
Artículo en Inglés | MEDLINE | ID: mdl-32979431

RESUMEN

OBJECTIVE: Cerebrovascular disease is one of the major diseases that seriously harm human health currently. The purpose of this study is to find an effective treatment and clarify its mechanism of action to provide a new idea and drug target for the clinical treatment of ischemic cerebrovascular disease. METHODS: The microglia cell line (BV2 cell line) was cultured in vitro. Prepare a hypoxia ischemia cell model by OGD and simulate the pathophysiological process of ischemic cerebrovascular disease in vivo. According to the techniques of LDH Cytotoxicity Assay Kit, flow cytometry of Annexin V-FITC Apoptosis Detection Kit, Laser Confocal Fluorescence Immunostaining (Double staining method), enzyme-linked immunosorbent assay (ELISA), and Western blotting, BV2 cells are observed through morphology and function changes induced by OGD. Moreover, these techniques were used to analyze changes in key proteins expression of signal transduction pathway in ischemic cerebrovascular disease, to explore the mechanism of gastrodin on ischemic cerebrovascular disease, and to elucidate the available ways for cell protection following ischemia and hypoxia. RESULTS: Gastrodin has no obvious toxic effect on BV-2 cells under physiological conditions. The death rate of BV-2 cells increases as the time of hypoxia increase. In the absence of oxygen, Gastrodin has a protective effect on the survival of BV-2 cells. This protective effect is related to the reduction of apoptosis rate. It can also improve the hypoxic tolerance of BV-2 cells, and there is no obvious Gastrodin dose-dependence. Moreover, Gastrodin has dual effects on BV-2 cells. The dual role of Gastrodin is closely related to the expression of several proteins which can affect the MAPK signal transduction pathway. CONCLUSION: Gastrodin has a dual effect on microglia with OGD. On the one hand, Gastrodin can inhibit the inflammatory cytokines secreted by microglia and aggravate the inflammatory response; on the other hand, Gastrodin can promote the secretion of protective cytokines from microglia to reduce the inflammatory response.


Asunto(s)
Alcoholes Bencílicos/farmacología , Glucosa/metabolismo , Glucósidos/farmacología , Oxígeno/metabolismo , Animales , Apoptosis/efectos de los fármacos , Hipoxia de la Célula/efectos de los fármacos , Línea Celular , Ratones , Microglía/efectos de los fármacos , Microglía/metabolismo , Neuroprotección/efectos de los fármacos , Transducción de Señal/efectos de los fármacos
11.
Food Chem ; 335: 127513, 2021 Jan 15.
Artículo en Inglés | MEDLINE | ID: mdl-32745838

RESUMEN

Zhenjiang aromatic vinegar is a famous traditional fermented cooking ingredient in China, with multiple nutritional and medicinal applications. Zhenjiang aromatic vinegar extract (100-400 µg/mL) is rich in polyphenols increased the glucose uptake and glucose consumption in high glucose-induced insulin resistant HepG2 (IR-HepG2) cells. Zhenjiang aromatic vinegar extract enhanced glycogen synthesis and attenuated gluconeogenesis by regulating key enzymes in IR-HepG2 cells. In addition, Zhenjiang aromatic vinegar extract ameliorated high glucose-induced IR by inhibiting phosphorylated insulin receptor substrate-1 (IRS-1) expression and activating phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt) pathway in IR-HepG2 cells. Moreover, Zhenjiang aromatic vinegar extract reduced reactive oxygen species generation and phosphorylated c-Jun NH2 terminal kinase (JNK) expression in IR-HepG2 cells. The attenuation of the high glucose is owned to the PI3K/Akt pathway activation, glycogen synthesis induction and gluconeogenesis suppression in IR-HepG2 cells.


Asunto(s)
Ácido Acético/farmacología , Glucosa/farmacología , Resistencia a la Insulina , Polifenoles/análisis , Transducción de Señal/efectos de los fármacos , Ácido Acético/química , Relación Dosis-Respuesta a Droga , Células Hep G2 , Humanos , Proteínas Sustrato del Receptor de Insulina/metabolismo , Proteínas Quinasas JNK Activadas por Mitógenos/metabolismo , Fosfatidilinositol 3-Quinasas/metabolismo , Fosforilación/efectos de los fármacos , Proteínas Proto-Oncogénicas c-akt/metabolismo
12.
Adv Exp Med Biol ; 1287: 1-7, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-33034022

RESUMEN

The evolutionary conserved Notch pathway that first developed in metazoans and that was first discovered in fruit flies (Drosophila melanogaster) governs fundamental cell fate decisions and many other cellular key processes not only in embryonic development but also during initiation, promotion, and progression of cancer. On a first look, the Notch pathway appears remarkably simple, with its key feature representing a direct connection between an extracellular signal and transcriptional output without the need of a long chain of protein intermediaries as known from many other signaling pathways. However, on a second, closer look, this obvious simplicity exerts surprising complexity. There is no doubt that the enormous scientific progress in unraveling the functional mechanisms that underlie this complexity has recently greatly increased our knowledge about the role of Notch signaling for pathogenesis and progression of many types of cancer. Moreover, these new scientific findings have shown promise in opening new avenues for cancer prevention and therapy, although this goal is still challenging. Vol. III of the second edition of the book Notch Signaling in Embryology and Cancer, entitled Notch Signaling in Cancer, summarizes important recent developments in this fast-moving and fascinating field. Here, we give an introduction to this book and a short summary of the individual chapters that are written by leading scientists, covering the latest developments in this intriguing research area.


Asunto(s)
Neoplasias/prevención & control , Neoplasias/terapia , Receptores Notch/metabolismo , Transducción de Señal , Animales , Diferenciación Celular , Humanos , Neoplasias/patología
13.
Adv Exp Med Biol ; 1287: 9-30, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-33034023

RESUMEN

The Notch signal transduction cascade requires cell-to-cell contact and results in the proteolytic processing of the Notch receptor and subsequent assembly of a transcriptional coactivator complex containing the Notch intracellular domain (NICD) and transcription factor RBPJ. In the absence of a Notch signal, RBPJ remains at Notch target genes and dampens transcriptional output. Like in other signaling pathways, RBPJ is able to switch from activation to repression by associating with corepressor complexes containing several chromatin-modifying enzymes. Here, we focus on the recent advances concerning RBPJ-corepressor functions, especially in regard to chromatin regulation. We put this into the context of one of the best-studied model systems for Notch, blood cell development. Alterations in the RBPJ-corepressor functions can contribute to the development of leukemia, especially in the case of acute myeloid leukemia (AML). The versatile role of transcription factor RBPJ in regulating pivotal target genes like c-MYC and HES1 may contribute to the better understanding of the development of leukemia.


Asunto(s)
Regulación de la Expresión Génica , Proteína de Unión a la Señal Recombinante J de las Inmunoglobulinas/metabolismo , Receptores Notch/metabolismo , Cromatina/genética , Cromatina/metabolismo , Humanos , Transducción de Señal
14.
Adv Exp Med Biol ; 1287: 31-46, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-33034024

RESUMEN

The endosomal pathway plays a pivotal role upon signal transduction in the Notch pathway. Recent work on lethal (2) giant discs (lgd) points to an additional critical role in avoiding uncontrolled ligand-independent signalling during trafficking of the Notch receptor through the endosomal pathway to the lysosome for degradation. In this chapter, we will outline the journey of Notch through the endosomal system and present an overview of the current knowledge about Lgd and its mammalian orthologs Lgd1/CC2D1b and Lgd2/CC2D1a. We will then discuss how Notch is activated in the absence of lgd function in Drosophila and ask whether there is evidence that a similar ligand-independent activation of the Notch pathway can also happen in mammals if the orthologs are inactivated.


Asunto(s)
Proteínas de Unión al ADN/metabolismo , Proteínas de Drosophila/metabolismo , Neoplasias/metabolismo , Receptores Notch/metabolismo , Proteínas Represoras/metabolismo , Transducción de Señal , Proteínas Supresoras de Tumor/metabolismo , Animales , Endosomas/metabolismo , Humanos
15.
Adv Exp Med Biol ; 1287: 47-57, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-33034025

RESUMEN

The human endometrium is a unique, highly dynamic tissue that undergoes cyclic changes of cell proliferation, differentiation, and death. Endometrial cancer is the most common malignancy among women in developed countries. Importantly, the incidence of endometrial cancer is rising in high-income countries. Currently histological classification is used for subtyping of endometrial cancer, while ongoing research is evaluating markers for more accurate molecular classification. Evolutionary conserved Notch signaling pathway regulates diverse cellular processes such as proliferation, differentiation, and cell invasion. Accumulating evidence links aberrant Notch signaling with diseases such as hyperplasia and endometrial cancer. This chapter summarizes the current state of Notch signaling investigations in the endometrium, endometriosis, and endometrial cancer.


Asunto(s)
Neoplasias Endometriales , Endometriosis , Receptores Notch/metabolismo , Neoplasias Endometriales/metabolismo , Neoplasias Endometriales/patología , Endometriosis/metabolismo , Endometriosis/patología , Endometrio/metabolismo , Endometrio/patología , Femenino , Humanos , Transducción de Señal
16.
Adv Exp Med Biol ; 1287: 59-68, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-33034026

RESUMEN

Esophageal squamous cell carcinoma (ESCC) is a deadly disease that requires extensive research on its mechanisms, prevention, and therapy. Recent studies have shown that NOTCH mutations are commonly seen in human ESCC. This chapter summarizes our current understanding of the NOTCH pathway in normal esophagus and in ESCC. In normal esophagus, NOTCH pathway regulates the development of esophageal squamous epithelium, in particular, squamous differentiation. Exposure to extrinsic and intrinsic factors, such as gastroesophageal reflux, alcohol drinking, and inflammation, downregulates the NOTCH pathway and thus inhibits squamous differentiation of esophageal squamous epithelial cells. In ESCC, NOTCH plays a dual role as both a tumor suppressor pathway and an oncogenic pathway. In summary, further studies are warranted to develop NOTCH activators for the prevention of ESCC and NOTCH inhibitors for targeted therapy of a subset of ESCC with activated NOTCH pathway.


Asunto(s)
Neoplasias Esofágicas , Carcinoma de Células Escamosas de Esófago , Receptores Notch/metabolismo , Carcinogénesis , Neoplasias Esofágicas/metabolismo , Neoplasias Esofágicas/patología , Carcinoma de Células Escamosas de Esófago/metabolismo , Carcinoma de Células Escamosas de Esófago/patología , Humanos , Transducción de Señal
17.
Adv Exp Med Biol ; 1287: 69-80, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-33034027

RESUMEN

Interactions between liver cells are closely regulated by Notch signaling. Notch signaling has been reported clinically related to bile duct hypogenesis in Alagille syndrome, which is caused by mutations in the Jagged1 gene. Notch activation and hepatocarcinogenesis are closely associated since cancer signaling is affected by the development of liver cells and cancer stem cells. Gene expression and genomic analysis using a microarray revealed that abnormalities in Notch-related genes were associated with the aggressiveness of liver cancer. This pattern was also accompanied with α-fetoprotein- and EpCAM-expressing phenotypes in vitro, in vivo, and in clinical tissues. Hepatitis B or C virus chronic infection or alcohol- or steatosis-related liver fibrosis induces liver cancer. Previous reports demonstrated that HBx, a hepatitis B virus protein, was associated with Jagged1 expression. We found that the Jagged1 and Notch1 signaling pathways were closely associated with the transcription of covalently closed circular hepatitis B virus DNA, which regulated cAMP response element-binding protein, thereby affecting Notch1 regulation by the E3 ubiquitin ligase ITCH. This viral pathogenesis in hepatocytes induces liver cancer. In conclusion, Notch signaling exerts various actions and is a clinical signature associated with hepatocarcinogenesis and liver context-related developmental function.


Asunto(s)
Neoplasias Hepáticas , Receptores Notch/metabolismo , Transducción de Señal , Hepatitis/metabolismo , Hepatitis/virología , Virus de la Hepatitis B/patogenicidad , Humanos , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/virología , Proteínas Represoras/metabolismo , Ubiquitina-Proteína Ligasas/metabolismo
18.
Adv Exp Med Biol ; 1287: 81-103, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-33034028

RESUMEN

Head and neck cancer is a group of neoplastic diseases affecting the facial, oral, and neck region. It is one of the most common cancers worldwide with an aggressive, invasive evolution. Due to the heterogeneity of the tissues affected, it is particularly challenging to study the molecular mechanisms at the basis of these tumors, and to date we are still lacking accurate targets for prevention and therapy. The Notch signaling is involved in a variety of tumorigenic mechanisms, such as regulation of the tumor microenvironment, aberrant intercellular communication, and altered metabolism. Here, we provide an up-to-date review of the role of Notch in head and neck cancer and draw parallels with other types of solid tumors where the Notch pathway plays a crucial role in emergence, maintenance, and progression of the disease. We therefore give a perspective view on the importance of the pathway in neoplastic development in order to define future lines of research and novel therapeutic approaches.


Asunto(s)
Neoplasias de Cabeza y Cuello , Receptores Notch , Neoplasias de Cabeza y Cuello/metabolismo , Neoplasias de Cabeza y Cuello/terapia , Humanos , Transducción de Señal , Microambiente Tumoral
19.
Adv Exp Med Biol ; 1287: 123-154, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-33034030

RESUMEN

Since many decades, nonmelanoma skin cancer (NMSCs) is the most common malignancy worldwide. Basal cell carcinomas (BCC) and squamous cell carcinomas (SCC) are the major types of NMSCs, representing approximately 70% and 25% of these neoplasias, respectively. Because of their continuously rising incidence rates, NMSCs represent a constantly increasing global challenge for healthcare, although they are in most cases nonlethal and curable (e.g., by surgery). While at present, carcinogenesis of NMSC is still not fully understood, the relevance of genetic and molecular alterations in several pathways, including evolutionary highly conserved Notch signaling, has now been shown convincingly. The Notch pathway, which was first developed during evolution in metazoans and that was first discovered in fruit flies (Drosophila melanogaster), governs cell fate decisions and many other fundamental processes that are of high relevance not only for embryonic development, but also for initiation, promotion, and progression of cancer. Choosing NMSC as a model, we give in this review a brief overview on the interaction of Notch signaling with important oncogenic and tumor suppressor pathways and on its role for several hallmarks of carcinogenesis and cancer progression, including the regulation of cancer stem cells, tumor angiogenesis, and senescence.


Asunto(s)
Carcinogénesis , Células Madre Neoplásicas/patología , Neovascularización Patológica , Receptores Notch/metabolismo , Transducción de Señal , Neoplasias Cutáneas/metabolismo , Neoplasias Cutáneas/patología , Animales , Carcinoma Basocelular/metabolismo , Carcinoma Basocelular/patología , Carcinoma de Células Escamosas/metabolismo , Carcinoma de Células Escamosas/patología , Humanos , Neoplasias Cutáneas/irrigación sanguínea
20.
Adv Exp Med Biol ; 1287: 155-168, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-33034031

RESUMEN

Thyroid cancer is the most common malignancy of the endocrine system with a steadily rising incidence. The term "thyroid cancer" encompasses a spectrum of subtypes, namely papillary thyroid cancer, follicular thyroid cancer, anaplastic thyroid cancer, and medullary thyroid cancer. Each subtype differs histopathologically and in degrees of cellular differentiation, which may be in part due to signaling of the Notch pathway. The Notch pathway is an evolutionarily conserved signal transduction mechanism that regulates cell proliferation, differentiation, survival, stem cell maintenance, embryonic and adult development, epithelial-mesenchymal transition, and angiogenesis. Its role in cancer biology is controversial, as it has been shown to play both an oncogenic and tumor-suppressive role in many different types of cancers. This discordance holds true for each subtype of thyroid cancer, indicating that Notch signaling is likely cell type and context dependent. Whether oncogenic or not, Notch signaling has proven to be significantly involved in the tumorigenesis of thyroid cancer and has thus earned interest as a therapeutic target. Advancement in the understanding of Notch signaling in thyroid cancer holds great promise for the development of novel treatment strategies to benefit patients.


Asunto(s)
Receptores Notch/metabolismo , Transducción de Señal , Neoplasias de la Tiroides/metabolismo , Humanos , Oncogenes , Neoplasias de la Tiroides/genética , Neoplasias de la Tiroides/patología
SELECCIÓN DE REFERENCIAS
DETALLE DE LA BÚSQUEDA