The emerging role of Notch pathway in ageing: Focus on the related mechanisms in age-related diseases

Notch signaling is an evolutionarily conserved pathway, which is fundamental for the development of all tissues, organs and systems of human body. Recently, a considerable and still growing number of studies have highlighted the contribution of Notch signaling in various pathological processes of the adult life, such as age-related diseases. In particular, the Notch pathway has emerged as major player in the maintenance of tissue specific homeostasis, through the control of proliferation, migration, phenotypes and functions of tissue cells, as well as in the cross-talk between inflammatory cells and the innate immune system, and in onset of inflammatory age-related diseases. However, until now there is a confounding evidence about the related mechanisms. Here, we discuss mechanisms through which Notch signaling acts in a very complex network of pathways, where it seems to have the crucial role of hub. Thus, we stress the possibility to use Notch pathway, the related molecules and pathways constituting this network, both as innovative (predictive, diagnostic and prognostic) biomarkers and targets for personalised treatments for age-related diseases.     

Notch signaling and its integration with other signaling mechanisms

An improved understanding of stem cell differentiation is critical for progress in regenerative medicine. It is an emerging view that a relatively small number of intracellular signaling mechanisms play particularly important roles in differentiation control. As one may expect, these pathways are highly evolutionarily conserved, used in many tissues and iteratively during differentiation of a particular tissue. The Notch signaling system is one pathway meeting these criteria. In many cases, Notch signaling keeps stem/progenitor cells undifferentiated, although it can in some cellular contexts be instructive for differentiation toward a particular fate. Here, we review our current understanding of how Notch controls cellular differentiation in various organs and how Notch integrates with other major signaling pathways, primarily focusing on Notch signaling in mammals. Given the importance of Notch in many stem cell fate decisions, the possibility of experimentally manipulating Notch signaling opens up new avenues to control stem cell differentiation.     

Coordinate regulation of ribosome biogenesis and function by the ribosomal protein S6 kinase, a key mediator of mTOR function

Current understanding of the mechanisms by which cell growth is regulated lags significantly behind our knowledge of the complex processes controlling cell cycle progression. Recent studies suggest that the mammalian target of rapamycin (mTOR) pathway is a key regulator of cell growth via the regulation of protein synthesis. The key mTOR effectors of cell growth are eukaryotic initiation factor 4E-binding protein 1 (4EBP-1) and the ribosomal protein S6 kinase (S6K). Here we will review the current models for mTOR dependent regulation of ribosome function and biogenesis as well as its role in coordinating growth factor and nutrient signaling to facilitate homeostasis of cell growth and proliferation. We will place particular emphasis on the role of S6K1 signaling and will highlight the points of cross talk with other key growth control pathways. Finally, we will discuss the impact of S6K signaling and the consequent feedback regulation of the PI3K/Akt pathway on disease processes including cancer.     

Coordinate regulation of ribosome biogenesis and function by the ribosomal protein S6 kinase,a key mediator of mTOR function

Current understanding of the mechanisms by which cell growth is regulated lags significantly behind our knowledge of the complex processes controlling cell cycle progression. Recent studies suggest that the mammalian target of rapamycin (mTOR) pathway is a key regulator of cell growth via the regulation of protein synthesis. The key mTOR effectors of cell growth are eukaryotic initiation factor 4E-binding protein 1 (4EBP-1) and the ribosomal protein S6 kinase (S6K). Here we will review the current models for mTOR dependent regulation of ribosome function and biogenesis as well as its role in coordinating growth factor and nutrient signaling to facilitate homeostasis of cell growth and proliferation. We will place particular emphasis on the role of S6K1 signaling and will highlight the points of cross talk with other key growth control pathways. Finally, we will discuss the impact of S6K signaling and the consequent feedback regulation of the PI3K/Akt pathway on disease processes including cancer.     

The love-hate relationship between Ras and Notch

The Ras and Notch signaling pathways are used over and over again during development to control many different biological processes. Frequently, these two signaling pathways intersect to influence common processes, but sometimes they cooperate and sometimes they antagonize each other. The Caenorhabditis elegans vulva and the Drosophila eye are two classic paradigms for understanding how Ras and Notch affect cell fates, and how the two pathways work together to control biological pattern. Recent advances in these systems reveal some of the mechanisms by which Ras and Notch can interact. Similar types of interactions in mammals may be important for determining whether and how alterations in Ras or Notch lead to cancer.     

调控骨肉瘤及干细胞的相关信号通路

文题释义： 骨肉瘤：是多发于儿童和青少年的原发恶性骨肿瘤,恶性程度高,容易发生转移,预后不良。骨肉瘤的复发、转移及多药耐药,是制约骨肉瘤治疗效果的主要问题。 信号通路：是指能将细胞外的分子信号经细胞膜传入细胞内发挥效应的一系列酶促反应通路,在骨肉瘤的发生、增殖和侵袭中发挥重要作用。 背景：骨肉瘤是儿童和青少年中最常见的原发性骨源性恶性肿瘤,过去30年骨肉瘤患者的预后几乎没有大的进步,迫切需要开发新的策略和创新疗法,以进一步提高骨肉瘤患者的生存率。 目的：阐述骨肉瘤进展和转移的分子机制和信号传导网络的最新进展,为治疗骨肉瘤提供一定的理论基础。 方法：以“骨肉瘤,信号通路,预后,转移,耐药,Notch,Wnt/β-catenin,Hedgehog,PI3K/Akt/mTOR,BMPs”为中文检索词,以“osteosarcoma,signaling pathway,prognosis,metastasis,drug resistance,Notch,Wnt/β-catenin,Hedgehog,PI3K/Akt/mTOR,BMPs”为英文检索词,应用计算机在CNKI、PubMed 数据库检索1999年2月至2019年2月相关文献共586篇。通过阅读文献标题和摘要进行筛选,按排除标准剔除不相关的文献,最后共纳入40篇文献进行综述。 结果与结论：信号通路在骨肉瘤的形成和增殖调控方面非常重要,研究发现Notch、Wnt/β-catenin、Hedgehog、PI3K/Akt/mTOR和BMP等信号通路在骨肉瘤及骨肉瘤干细胞中均有表达,对骨肉瘤的发生发展产生重要影响。 ORCID: 0000-0003-4489-9647(陶海) 中国组织工程研究杂志出版内容重点：干细胞;骨髓干细胞;造血干细胞;脂肪干细胞;肿瘤干细胞;胚胎干细胞;脐带脐血干细胞;干细胞诱导;干细胞分化;组织工程     

胶质母细胞瘤信号通路的研究

胶质母细胞瘤（GBM）是胶质瘤中恶性程度最高的脑部肿瘤,其死亡率和复发率较高。目前GBM发生发展机制尚不明确,无特效治疗手段。常见的治疗方法有手术切除、放疗及化疗等,但其预后差,因此寻找GBM相关信号通路可为了解其发病机制、靶向治疗提供指引。目前,研究发现p53途径、MAPK途径、PI3K/AKT途径以及Notch途径是参与GBM的重要通路;除此之外,还有其他的信号通路也陆续被发现。本文通过对p53信号通路、MAPK信号通路、PI3K/AKT信号通路、Notch信号通路以及其他信号通路在GBM中的作用进行综述,旨在为临床治疗GBM提供参考。     

Notch signaling pathway and human placenta

Notch signaling was evolutionarily conserved and critical for cell-fate determination, differentiation and many other biological processes. Growing evidences suggested that Notch signaling pathway played an important role in the mammalian placental development. All of the mammalian Notch family proteins had been identified in human placenta except Delta-like 3, which appeared to affect the axial skeletal system. However the molecular mechanisms that regulated the Notch signaling pathway remained largely unknown in human placenta. Therefore, additional research was needed to investigate expression pattern of Notch family members and the mechanisms for activation of Notch signaling pathway in human placenta, which might help elucidate the roles of Notch signaling pathway in human placentation. This review would focus on the roles of Notch receptors and ligands in the human placental trophoblasts function and placental angiogenesis. It might hopefully provide perspectives for future research about human placentation of pregnancy complicated by preeclampsia and other placenta associated diseases.     

The Notch ligand, Delta-1, reduces TNF-alpha-induced growth suppression and apoptosis by decreasing activation of caspases in U937 cells

The Notch signaling pathway plays an important role in the regulation of self-renewal and differentiation of hematopoietic progenitors. Tumor necrosis factor (TNF)-alpha induces apoptosis through activation of caspase pathway. A monoblastic leukemia cell line, U937, undergoes apoptosis following stimulation with TNF-alpha. We found that Notch activation induced by a recombinant Notch ligand, Delta-1, reduced the TNF-alpha-induced growth suppression and apoptosis in U937 cells. As the molecular mechanism involved, we showed Delta-1 stimulation partially suppressed the sequential activation of caspase-8, caspase-3, and, PARP induced by TNF-alpha. The TNF-alpha-induced activation of c-Jun N-terminal kinase (JNK), p38, and NF-kappaB was not affected by Delta-1 stimulation. The cells needed to be exposed to Delta-1 prior to TNF-alpha stimulation to reduce the suppressive effect of TNF-alpha. Therefore, we thought that Delta-1 stimulation might reduce the expression of TNF-receptor (R) 1 and proteins to modulate the activation of caspases such as FLIP and XIAP. However, Delta-1 stimulation did not affect their expression. The precise mechanism by which Notch signaling suppresses caspase activation has yet to be determined. This is the first report to show the relationship between Notch activation and TNF-R1 signaling. The findings suggest possible mechanisms by which Notch activation supports cell survival.     

Age-related changes in gene expression in tissues of the sea urchin Strongylocentrotus purpuratus

The life history of sea urchins is fundamentally different from that of traditional models of aging and therefore they provide the opportunity to gain new insight into this complex process. Sea urchins grow indeterminately, reproduce throughout their life span and some species exhibit negligible senescence. Using a microarray and qRT-PCR, age-related changes in gene expression were examined in three tissues (muscle, esophagus and nerve) of the sea urchin species Strongylocentrotus purpuratus. The results indicate age-related changes in gene expression involving many key cellular functions such as the ubiquitin-proteasome pathway, DNA metabolism, signaling pathways and apoptosis. Although there are tissue-specific differences in the gene expression profiles, there are some characteristics that are shared between tissues providing insight into potential mechanisms that promote lack of senescence in these animals. As an example, there is an increase in expression of genes encoding components of the Notch signaling pathway with age in all three tissues and a decrease in expression of the Wnt1 gene in both muscle and nerve. The interplay between the Notch and Wnt pathways may be one mechanism that ensures continued regeneration of tissues with advancing age contributing to the general lack of age-related decline in these animals.     

Notch3, another Notch in T cell development

Different members of the Notch family have been described to play a critical role in T cell lineage commitment and T cell development and functions. Nevertheless, whether they act as redundant molecules, by affecting the same molecular mechanisms, or play distinct roles in T cell differentiation and/or functions is not clear. Altered Notch3 signaling impairs the developmentally regulated interplay between pre-TCR and NF-kappaB signaling and allows the disruption of early thymocyte differentiation and the development of T cell leukemia, thus identifying the crucial role of Notch3 receptor in the coordination of T cell differentiation and growth control.     

Alternative and classical NF-kappa B signaling retain autoreactive B cells in the splenic marginal zone and result in lupus-like disease

Expression of B cell-activating factor (BAFF), a critical B cell survival factor, is elevated in autoimmune and lymphoproliferative disorders. Mice overproducing BAFF develop systemic lupus erythematosus (SLE)-like disease and exhibit B cell activation of classical and alternative NF-kappaB-signaling pathways. We used a genetic approach and found that both NF-kappaB-signaling pathways contributed to disease development but act through distinct mechanisms. Whereas BAFF enhanced long-term B cell survival primarily through the alternative, but not the classical, NF-kappaB pathway, it promoted immunoglobulin class switching and generation of pathogenic antibodies through the classical pathway. Activation of the alternative NF-kappaB pathway resulted in integrin upregulation, thereby retaining autoreactive B cells in the splenic marginal zone, a compartment that contributes to their survival. Thus, both classical and alternative NF-kappaB signaling are important for development of lupus-like disease associated with BAFF overproduction. The same mechanisms may be involved in the pathogenesis of human SLE.     

Curcumin inhibits the survival and metastasis of prostate cancer cells via the Notch‐1 signaling pathway

Prostate cancer is one of the most common malignancies in men, and it urgently demands precise interventions that target the signaling pathways implicated in its initiation, progression, and metastasis. The Notch‐1 signaling pathway is closely associated with the pathophysiology of prostate cancer. This study investigated the antitumor effects and mechanisms of curcumin, which is a well‐known natural compound from curcuminoids, in prostate cancer cells. Viability, proliferation, and migration were analyzed in two prostate cancer cell lines, DU145 and PC3, after curcumin treatment. Whether the Notch‐1 signaling pathway is involved in the antitumor effects of curcumin was examined. Curcumin inhibited the survival and proliferation of PC3 and DU145 cells in a dose‐ and time‐dependent manner and inhibited DU145 migration. Curcumin did not affect the expression of Notch‐1 or its active product NICD, but it did inhibit the expression of MT1‐MMP and MMP2 proteins in DU145 cells. We found that curcumin inhibited the DNA‐binding ability of NICD in DU145 cells. In conclusion, curcumin inhibited the survival and metastasis of prostate cancer cells via the Notch‐1 signaling pathway.     

Cross-linking of MHC class II molecules interferes with phorbol 12,13-dibutyrate-induced differentiation of resting B cells by inhibiting Rac-associated ROS-dependent ERK/p38 MAP kinase pathways leading to NF-kappaB activation

In addition to their essential role in antigen presentation, major histocompatibility complex (MHC) class II molecules have been described as the receptor associated with signal transduction regulating B-cell function. In previous experiments, we found that cross-linking of MHC class II molecules with corresponding anti-MHC class II antibodies inhibited NF-kappaB-activated signaling pathways associated with the proliferation and differentiation of the LPS-stimulated primary and resting B-cell line, 38B9. We also found that exposure to the anti-MHC class II antibody reduced the production of ROS, which function as secondary signal transducers, in the phorbol 12,13-dibutyrate (PDBU)-treated (but not in the LPS-treated) resting B-cell line. In this study, we investigated the molecular mechanisms in the ROS-associated signaling pathway leading to PDBU-induced NF-kappaB activation that results in B-cell differentiation and speculated that the signaling pathway was inhibited by exposure to the anti-MHC class II antibody. We also found that this inhibition was mediated through down-regulation of the activated Rac/ROS-associated ERK/p38 MAPK signaling pathway in PDBU-treated 38B9 cells. Collectively, these findings suggest that ROS-associated molecules are involved in MHC class II-associated negative signal transduction in resting B cells.