Notch signaling and Notch signaling modifiers

Originally discovered nearly a century ago, the Notch signaling pathway is critical for virtually all developmental programs and modulates an astounding variety of pathogenic processes. The DSL (Delta, Serrate, LAG-2 family) proteins have long been considered canonical activators of the core Notch pathway. More recently, a wide and expanding network of non-canonical extracellular factors has also been shown to modulate Notch signaling, conferring newly appreciated complexity to this evolutionarily conserved signal transduction system. Here, I review current concepts in Notch signaling, with a focus on work from the last decade elucidating novel extracellular proteins that up- or down-regulate signal potency.     

The double-edged sword of Notch signaling in cancer

Recent deep sequencing of cancer genomes has produced an explosion of new data implicating Notch signaling in several human cancers. Unlike most other pathways, these data indicate that Notch signaling can be either oncogenic or tumor suppressive, depending on the cellular context. In some instances, these relationships were predicted from mouse models or presaged by developmental roles for Notch, but in other cases were unanticipated. This review discusses the pathogenic and translational significance of these new findings.     

Multiple functions of Notch signaling in self-renewing organs and cancer

In recent years a substantial body of evidence has accumulated to support the notion that signaling pathways known to be important during embryonic development play important roles in regulating self-renewing tissues. Moreover, the same pathways are often deregulated during tumorigenesis due to mutations of key elements of these pathways. The Notch signaling cascade meets all of the above-mentioned criteria. We discuss here the pleiotropic roles of the Notch signaling pathway in three different self-renewing organs (intestine, hematopoietic system and skin) and how its deregulation is involved in tumorigenesis.     

Notch signaling genes

Notch intercellular signaling is critical for diverse developmental pathways and for homeostasis in various types of stem cells and progenitor cells. Because Notch gene products need to be precisely regulated spatially and temporally, epigenetics is likely to help control expression of Notch signaling genes. Reduced representation bisulfite sequencing (RRBS) indicated significant hypomethylation in myoblasts, myotubes, and skeletal muscle vs. many nonmuscle samples at intragenic or intergenic regions of the following Notch receptor or ligand genes: NOTCH1, NOTCH2, JAG2, and DLL1. An enzymatic assay of sites in or near these genes revealed unusually high enrichment of 5-hydroxymethylcytosine (up to 81%) in skeletal muscle, heart, and cerebellum. Epigenetics studies and gene expression profiles suggest that hypomethylation and/or hydroxymethylation help control expression of these genes in heart, brain, myoblasts, myotubes, and within skeletal muscle myofibers. Such regulation could promote cell renewal, cell maintenance, homeostasis, and a poised state for repair of tissue damage.     

Notch signaling in diabetic nephropathy

Notch signaling is an evolutionarily conserved cell-cell signaling system that controls the fate of cells during development. In this review, we will summarize the literature that notch signaling during development controls nephron number and segmentation and therefore could influence kidney disease susceptibility. We will also review the evidence that Notch is reactivated in adult-onset diabetic kidney disease where it promotes the development of nephropathy including glomerulopathy, tubulointerstitial fibrosis and possibly arteriopathy and inflammation. Finally, we will review the evidence that blockade of pathogenic Notch signaling alters the natural history of diabetic nephropathy and thus could represent a novel therapeutic approach to the management of diabetic kidney disease.     

Notch1 signaling modulates hypoxia-induced multidrug resistance in human laryngeal cancer cells

Molecular Biology Reports - Laryngeal carcinoma is one of the common malignant tumors of the head and neck. Multidrug resistance (MDR) remains a critical problem in the chemotherapy of patients...     

Curcumin induces cell death in esophageal cancer cells through modulating Notch signaling

Background

Curcumin inhibits the growth of esophageal cancer cell lines; however, the mechanism of action is not well understood. It is becoming increasingly clear that aberrant activation of Notch signaling has been associated with the development of esophageal cancer. Here, we have determined that curcumin inhibits esophageal cancer growth via a mechanism mediated through the Notch signaling pathway.

Methodology/Principal Findings

In this study, we show that curcumin treatment resulted in a dose and time dependent inhibition of proliferation and colony formation in esophageal cancer cell lines. Furthermore, curcumin treatment induced apoptosis through caspase 3 activation, confirmed by an increase in the ratio of Bax to Bcl2. Cell cycle analysis demonstrated that curcumin treatment induced cell death and down regulated cyclin D1 levels. Curcumin treatment also resulted in reduced number and size of esophagospheres. Furthermore, curcumin treatment led to reduced Notch-1 activation, expression of Jagged-1 and its downstream target Hes-1. This reduction in Notch-1 activation was determined to be due to the down-regulation of critical components of the γ-secretase complex proteins such as Presenilin 1 and Nicastrin. The combination of a known γ-secretase inhibitor DAPT and curcumin further decreased proliferation and induced apoptosis in esophageal cancer cells. Finally, curcumin treatment down-regulate the expressions of Notch-1 specific microRNAs miR-21 and miR-34a, and upregulated tumor suppressor let-7a miRNA.

Conclusion/Significance

Curcumin is a potent inhibitor of esophageal cancer growth that targets the Notch-1 activating γ-secretase complex proteins. These data suggest that Notch signaling inhibition is a novel mechanism of action for curcumin during therapeutic intervention in esophageal cancers.     

Significance of glycosylation in Notch signaling

Notch signaling is essential for cell-fate specification in metazoans, and dysregulation of the pathway leads to a variety of human diseases including heart and vascular defects as well as cancer. Glycosylation of the Notch extracellular domain has emerged as an elegant means for regulating Notch activity, especially since the discovery that Fringe is a glycosyltransferase that modifies O-fucose in 2000. Since then, several other O-glycans on the extracellular domain have been demonstrated to modulate Notch activity. Here we will describe recent results on the molecular mechanisms by which Fringe modulates Notch activity, summarize recent work on how O-glucose, O-GlcNAc, and O-GalNAc glycans affect Notch, and discuss several human genetic disorders resulting from defects in Notch glycosylation.     

Targeting Notch signaling pathway to overcome drug resistance for cancer therapy

Chemotherapy is an important therapeutic strategy for cancer treatment and remains the mainstay for the management of human malignancies; however, chemotherapy fails to eliminate all tumor cells because of intrinsic or acquired drug resistance, which is the most common cause of tumor recurrence. Recently, emerging evidences suggest that Notch signaling pathway is one of the most important signaling pathways in drug-resistant tumor cells. Moreover, down-regulation of Notch pathway could induce drug sensitivity, leading to increased inhibition of cancer cell growth, invasion, and metastasis. This article will provide a brief overview of the published evidences in support of the roles of Notch in drug resistance and will further summarize how targeting Notch by “natural agents” could become a novel and safer approach for the improvement of tumor treatment by overcoming drug resistance.     

Notch signaling in leukemias and lymphomas

Aberrant Notch activation is linked to cancer since 1991 when mammalian Notch1 was first identified as part of the translocation t(7;9) in a subset of human T-cell acute lymphoblastic leukemias (T-ALL). Since then oncogenic Notch signaling has been found in many solid and hematopoietic neoplasms. Depending on tumor type Notch interferes with differentiation, proliferation, survival, cell-cycle progression, angiogenesis, and possibly self-renewal. In hematopoietic neoplasms, recent findings indicate an important role of Notch for T-ALL induction and progression and the pathogenesis of human T- and B-cell-derived lymphomas. Notch signaling has been identified as a potential new therapeutic target in these hematopoietic neoplasms. This review will focus on the most recent findings on Notch signaling in leukemias and lymphomas and its potential role in the maintenance of malignant stem cells.     

Targeting Notch signaling cross-talk with estrogen receptor and ErbB-2 in breast cancer

The Notch signaling pathway is receiving considerable interest because of its pervasive importance in developmental biology and more recently, in the post-natal functions of the immune system and in cancer biology.Our observations, together with those of other laboratories, support a context-dependent role for Notch signaling in breast cancer.Targeting Notch signaling paves the way to new therapeutic strategy.     

Notch signaling inhibits axon regeneration

Many neurons have limited capacity to regenerate their axons after injury. Neurons in the mammalian central nervous system do not regenerate, and even neurons in the peripheral nervous system often fail to regenerate to their former targets. This failure is likely due in part to pathways that actively restrict regeneration; however, only a few factors that limit regeneration are known. Here, using single-neuron analysis of regeneration in?vivo, we show that Notch/lin-12 signaling inhibits the regeneration of mature C.?elegans neurons. Notch signaling suppresses regeneration by acting autonomously in the injured cell to prevent growth cone formation. The metalloprotease and gamma-secretase cleavage events that lead to Notch activation during development are also required for its activity in regeneration. Furthermore, blocking Notch activation immediately after injury improves regeneration. Our results define a postdevelopmental role for the Notch pathway as a repressor of axon regeneration in?vivo.     

Notch signaling and neural connectivity

The cell surface receptor Notch contributes to the development of nearly every tissue in most metazoans by controlling the fates and differentiation of cells. Recent results have now established that Notch also regulates the connectivity of the nervous system, and does so at a variety of levels, including specification of neuronal identity, division, survival and migration, as well as axon guidance, morphogenesis of dendritic arbors and weighting of synapse strength. To these ends, Notch engages at least two signal transduction pathways, one that controls nuclear gene expression and another that directly targets the cytoskeleton. Coordinating the many functions of Notch to produce neural structure is thus a pivotal aspect of building and maintaining the nervous system.     

Activin-like signaling activates Notch signaling during mesodermal induction

Both activin-like signaling and Notch signaling play fundamental roles during early development. Activin-like signaling is involved in mesodermal induction and can induce a broad range of mesodermal genes and tissues from prospective ectodermal cells (animal caps). On the other hand, Notch signaling plays important roles when multipotent precursor cells achieve a specific cell fate. However, the relationship between these two signal pathways is not well understood. Here, we show that activin A induces Delta-1, Delta-2 and Notch expression and then activates Notch signaling in animal caps. Also, in vivo, ectopic activin-like signaling induced the ectopic expression of Delta-1 and Delta-2, whereas inhibition of activin-like signaling abolished the expression of Delta-1 and Delta-2. Furthermore, we show that MyoD, which is myogenic gene induced by activin A, can induce Delta-1 expression. However, MyoD had no effect on Notch expression, and inhibited Delta-2 expression. These results indicated that activin A induces Delta-1, Delta-2 and Notch by different cascades. We conclude that Notch signaling is activated when activin-like signaling induces various tissues from homogenous undifferentiated cells.     

Notch signaling in vascular development and physiology

Notch signaling is an ancient intercellular signaling mechanism that plays myriad roles during vascular development and physiology in vertebrates. These roles include regulation of artery/vein differentiation in endothelial and vascular smooth muscle cells, regulation of blood vessel sprouting and branching during both normal development and tumor angiogenesis, and the differentiation and physiological responses of vascular smooth muscle cells. Defects in Notch signaling also cause inherited vascular and cardiovascular diseases. In this review, I summarize recent findings and discuss the growing relevance of Notch pathway modulation for therapeutic applications in disease.