The Experts below are selected from a list of 37341 Experts worldwide ranked by ideXlab platform
Raphael Kopan - One of the best experts on this subject based on the ideXlab platform.
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Notch Signaling regulates akap12 expression and primary cilia length during renal tubule morphogenesis
The FASEB Journal, 2020Co-Authors: Malini Mukherjee, Ishara Ratnayake, Madhusudhana R Janga, Eric Fogarty, Shania Scheidt, Justin J Grassmeyer, Jennifer Deriso, Indra Chandrasekar, Phil Ahrenkiel, Raphael KopanAbstract:Alagille syndrome patients present with loss of function mutations in either JAG1 or Notch2. About 40%-50% of patients have kidney abnormalities, and frequently display multicystic, dysplastic kidneys. Additionally, gain-of-function mutations in Notch2 are associated with cystic kidneys in Hajdu-Cheney syndrome patients. How perturbations in Notch Signaling cause renal tubular cysts remains unclear. Here, we have determined that reduced Notch Signaling mediated transcription by ectopic expression of dominant-negative mastermind-like (dnMaml) peptide in the nephrogenic epithelia from after the s-shaped body formation and in the developing collecting ducts results in proximal tubular and collecting duct cysts, respectively. An acute inhibition of Notch Signaling for two days during kidney development is sufficient to disrupt tubule formation, and significantly increases Akap12 expression. Ectopic expression of Akap12 in renal epithelia results in abnormally long primary cilia similar to that observed in Notch-Signaling-deficient epithelia. Both loss of Notch Signaling and elevated Akap12 expression disrupt the ability of renal epithelial cells to form spherical structures with a single lumen when grown embedded in matrix. Interestingly, Akap12 can inhibit Notch Signaling mediated transcription, which likely explains how both loss of Notch Signaling and ectopic expression of Akap12 result in similar renal epithelial abnormalities. We conclude that Notch Signaling regulates Akap12 expression while also ensuring normal primary cilia length and renal epithelial morphogenesis, and suggest that one aspect of diseases associated with defective Notch Signaling, such as Alagille syndrome, maybe mechanistically related to ciliopathies.
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Notch Signaling regulates akap12 expression and primary cilia length during renal tubule morphogenesis
bioRxiv, 2019Co-Authors: Malini Mukherjee, Ishara Ratnayake, Madhusudhana R Janga, Eric Fogarty, Shania Scheidt, Justin J Grassmeyer, Jennifer Deriso, Indra Chandrasekar, Phil Ahrenkiel, Raphael KopanAbstract:Abstract Alagille syndrome patients present with loss of function mutations in either JAG1 or Notch2. About 40-50% of patients have kidney abnormalities, with multi-cystic, dysplastic kidneys being one of the more frequent kidney defects. Additionally, gain-of-function mutations in Notch2 are associated with cystic kidneys in Hajdu-Cheney syndrome patients. Conditional inactivation of Notch1, Notch2, or RBPJ within the nephrogenic lineage impairs nephrogenesis and produces proximal tubule cysts in mice. How perturbations in Notch Signaling cause renal tubular cysts remains unclear. Here we have determined that inhibition of Notch Signaling in the kidney increases Akap12 expression. Ectopic expression of Akap12 in renal epithelia results in abnormally long primary cilia similar to those observed in Notch-signal-deficiency. Both loss of Notch Signaling and elevated Akap12 expression disrupt the ability of renal epithelial cells to form spherical structures with a single lumen when grown embedded in matrix. We conclude that Notch Signaling regulates Akap12 expression to ensure normal primary cilia length and renal epithelial morphogenesis, and suggest that diseases associated with defective Notch Signaling, such as Alagille syndrome, maybe mechanistically related to ciliopathies. Translational Statement The current study examines how a reduction in Notch Signaling results in abnormal renal tubule formation, as occurs in Alagille Syndrome patients with mutations in JAG1 or Notch2. The finding that reduced Notch Signaling results in abnormally long cilia is suggestive that some of the clinical manifestations in Alagille Syndrome, such as small cystic kidneys, may originate due to defective cilia function. Linking Notch to primary cilia also opens up the possibility that coinheritance of mutations in ciliopathy genes along with a mutation in JAG1 or Notch2 may enhance the severity of the clinical phenotypes such as cystic kidney disease and may explain the variable occurrence and onset of kidney disease among Alagille Syndrome patients.
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the canonical Notch Signaling pathway unfolding the activation mechanism
Cell, 2009Co-Authors: Raphael Kopan, Ma Xenia G IlaganAbstract:Notch Signaling regulates many aspects of metazoan development and tissue renewal. Accordingly, the misregulation or loss of Notch Signaling underlies a wide range of human disorders, from developmental syndromes to adult-onset diseases and cancer. Notch Signaling is remarkably robust in most tissues even though each Notch molecule is irreversibly activated by proteolysis and signals only once without amplification by secondary messenger cascades. In this Review, we highlight recent studies in Notch Signaling that reveal new molecular details about the regulation of ligand-mediated receptor activation, receptor proteolysis, and target selection.
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Notch Signaling maintains bone marrow mesenchymal progenitors by suppressing osteoblast differentiation
Nature Medicine, 2008Co-Authors: Matthew J Hilton, Raphael Kopan, Xiaolin Tu, Ximei Wu, Haibo Zhao, Tatsuya Kobayashi, Henry M Kronenberg, Steven L Teitelbaum, Patrick F Ross, Fanxin LongAbstract:Postnatal bone marrow houses mesenchymal progenitor cells that are osteoblast precursors. These cells have established therapeutic potential, but they are difficult to maintain and expand in vitro, presumably because little is known about the mechanisms controlling their fate decisions. To investigate the potential role of Notch Signaling in osteoblastogenesis, we used conditional alleles to genetically remove components of the Notch Signaling system during skeletal development. We found that disruption of Notch Signaling in the limb skeletogenic mesenchyme markedly increased trabecular bone mass in adolescent mice. Notably, mesenchymal progenitors were undetectable in the bone marrow of mice with high bone mass. As a result, these mice developed severe osteopenia as they aged. Moreover, Notch Signaling seemed to inhibit osteoblast differentiation through Hes or Hey proteins, which diminished Runx2 transcriptional activity via physical interaction. These results support a model wherein Notch Signaling in bone marrow normally acts to maintain a pool of mesenchymal progenitors by suppressing osteoblast differentiation. Thus, mesenchymal progenitors may be expanded in vitro by activating the Notch pathway, whereas bone formation in vivo may be enhanced by transiently suppressing this pathway.
Warren S Pear - One of the best experts on this subject based on the ideXlab platform.
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Notch Signaling is an important regulator of type 2 immunity
Journal of Experimental Medicine, 2005Co-Authors: Terry C Fang, Ivan Maillard, David Artis, Olga Shestova, Seth E Pross, Warren S PearAbstract:Notch ligands and receptors have been implicated in helper T cell (Th cell) differentiation. Whether Notch signals are involved in differentiation of T helper type 1 (Th1) cells, Th2 cells, or both, however, remains unresolved. To clarify the role of Notch in Th cell differentiation, we generated mice that conditionally inactivate Notch Signaling in mature T cells. Mice that lack Notch Signaling in CD4+ T cells fail to develop a protective Th2 cell response against the gastrointestinal helminth Trichuris muris. In contrast, they exhibit effective Th1 cell responses and are able to control Leishmania major infection. These data demonstrate that Notch Signaling is a regulator of type 2 immunity.
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Notch Signaling represses myocardin induced smooth muscle cell differentiation
Journal of Biological Chemistry, 2005Co-Authors: Aaron Proweller, Warren S Pear, Michael S ParmacekAbstract:Abstract Notch Signaling is essential for vascular patterning and response of the vasculature to injury and growth factor stimulation. Despite these findings, the molecular basis of Notch Signaling in the vasculature is poorly understood. Here we report that activation of Notch Signaling mediated through members of the HRT family of basic helix-loop-helix transcription factors represses smooth muscle cell (SMC) differentiation and expression of genes encoding smooth muscle cell contractile markers. Activation of Notch receptors by Jagged1 or forced expression of the constitutively active Notch1 intracellular domain in C3H10T1/2 fibroblasts inhibited myocardin-dependent transcription of SMC-restricted genes and activity of multiple SMC-restricted transcriptional regulatory elements. Consistent with these findings, forced expression of HRT2 inhibited myocardin-induced expression of SMC-restricted genes and activity of SMC-restricted transcriptional regulatory elements. Moreover, forced expression of HRT2 repressed transcription of multiple SMC-restricted transcriptional regulatory elements in A10 SMCs. The repressive function of HRT2 was not mediated via the capacity of HRT2 to bind SMC CArG elements or by disruption of myocardin-SRF protein complexes. Structure-function analyses of HRT2 indicated that repression required the basic DNA binding domain and additional C-terminal sequence. Taken together, these results demonstrate that Notch Signaling represses myocardin-dependent SMC transcription. These data are consistent with a model wherein Notch Signaling represses SMC differentiation and maintenance of the contractile SMC phenotype.
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Notch Signaling in hematopoiesis and early lymphocyte development
Immunological Reviews, 2002Co-Authors: David Allman, Jon C Aster, Warren S PearAbstract:Notch signals regulate multiple cell fate decisions during metazoan development. During hematopoiesis, Notch affects both hematopoietic stem cells and committed progenitors. In hematopoietic stem cells, Notch Signaling has the propensity to expand the stem cells, promote their self-renewal, and influence their survival. In committed progenitors, Notch Signaling plays a key role in determining lymphoid cell fates. This review focuses on recent developments to understand the role of Notch Signaling in early events in hematopoiesis.
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Notch Signaling in cancer
Cancer Biology & Therapy, 2002Co-Authors: Eric J Allenspach, Ivan Maillard, Jon C Aster, Warren S PearAbstract:Notch Signaling plays a key role in the normal development of many tissues and cell types, through diverse effects on differentiation, survival, and/or proliferation that are highly dependent on signal strength and cellular context. Because perturbations in the regulation of differentiation, survival, and/or proliferation underlie malignant transformation, pathophysiologic Notch signals potentially contribute to cancer development in several different ways. Notch Signaling was first linked to tumorigenesis through identification of a recurrent t(7;9)(q34;q34.3) chromosomal translocation involving the human Notch1 gene that is found in a small subset of human pre-T-cell acute lymphoblastic leukemias (T-ALL).1 Since this discovery, aberrant Notch Signaling has been suggested to be involved in a wide variety of human neoplasms. In this review, we will focus on recent studies linking aberrant Notch Signaling with cancer. First, we discuss various mechanisms through which Notch Signaling may influence cellular...
Fazlul H Sarkar - One of the best experts on this subject based on the ideXlab platform.
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regulation of emt by Notch Signaling pathway in tumor progression
Current Cancer Drug Targets, 2013Co-Authors: Xiujuan Qian, Jun Xia, Lucio Miele, Fazlul H Sarkar, Zhiwei WangAbstract:Notch Signaling pathway has been reported to play critical roles in the development and progression of human cancers because Notch Signaling pathway is critically involved in many cellular processes including cell proliferation, survival, apoptosis, migration, invasion, angiogenesis, and metastasis. Emerging evidence suggests that Notch regulates EMT (Epithelial-to-Mesenchymal Transition), leading to tumor invasion and metastasis. Thus, this mini-review is focused on discussing the novel role of Notch Signaling pathway in the regulation of EMT. Moreover, we summarized that Notch Signaling pathway could be down-regulated by its inhibitors or natural compounds, resulting in the reversal of EMT to MET (Mesenchymal-to-Epithelial Transition), which could be a promising strategy for achieving better treatment outcome in patients diagnosed with cancer.
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Notch Signaling proteins legitimate targets for cancer therapy
Current Protein & Peptide Science, 2010Co-Authors: Zhiwei Wang, Fazlul H SarkarAbstract:Proteins and small peptides (growth factors and hormones) are key molecules in maintaining cellular homeostasis. To that end, Notch Signaling pathway proteins are known to play critical roles in maintaining the balance between cell proliferation, differentiation and apoptosis, and thus it has been suggested that Notch may be responsible for the development and progression of human malignancies. Therefore, the Notch Signaling pathway proteins may present novel therapeutic targets, which could have promising therapeutic impact on eradicating human malignancies. This review describes the role of Notch Signaling pathway proteins in cancer and how its deregulation is involved in tumor development and progression leading to metastasis and the ultimate demise of patients diagnosed with cancer. Further, we summarize the role of several Notch inhibitors especially “natural agents” that could represent novel therapeutic strategies targeting Notch Signaling toward better treatment outcome of patients diagnosed with cancer.
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the role of Notch Signaling pathway in epithelial mesenchymal transition emt during development and tumor aggressiveness
Current Drug Targets, 2010Co-Authors: Zhiwei Wang, Dejuan Kong, Fazlul H SarkarAbstract:The Notch Signaling pathway maintains a balance between cell proliferation and apoptosis, and thus it is believed that Notch Signaling pathway may play an important role in the development and progression of several malignancies. However, the functions of Notch Signaling in EMT are largely unknown. This mini review describes the role of Notch Signaling pathway in EMT, and cataloging how its deregulation is involved in EMT and tumor aggressiveness. Further attempts have been made to summarize the role of several chemopreventive agents that could be useful for targeted inactivation of Notch Signaling, and thus it may cause reversal of EMT, which could become a novel approach for cancer prevention and treatment.
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exploitation of the Notch Signaling pathway as a novel target for cancer therapy
Anticancer Research, 2008Co-Authors: Zhiwei Wang, Sanjeev Banerjee, Fazlul H SarkarAbstract:The Notch Signaling pathway appears to be responsible for maintaining a balance between cell proliferation and apoptosis and thus it has been suggested that Notch may play an important role in species development and in the development and progression of several malignancies. Therefore, the Notch Signaling pathway may represent a novel therapeutic target, which could have the highest therapeutic impact in modern medicine. This review describes the mechanisms of signal transduction of the Notch Signaling pathway and provides emerging evidence in support of its role in the development of human malignancies. Further attempts have been made to summarize the role of several chemopreventive agents that could be useful for targeted inactivation of Notch Signaling, which could become a novel approach for cancer prevention and treatment.
Zhiwei Wang - One of the best experts on this subject based on the ideXlab platform.
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regulation of emt by Notch Signaling pathway in tumor progression
Current Cancer Drug Targets, 2013Co-Authors: Xiujuan Qian, Jun Xia, Lucio Miele, Fazlul H Sarkar, Zhiwei WangAbstract:Notch Signaling pathway has been reported to play critical roles in the development and progression of human cancers because Notch Signaling pathway is critically involved in many cellular processes including cell proliferation, survival, apoptosis, migration, invasion, angiogenesis, and metastasis. Emerging evidence suggests that Notch regulates EMT (Epithelial-to-Mesenchymal Transition), leading to tumor invasion and metastasis. Thus, this mini-review is focused on discussing the novel role of Notch Signaling pathway in the regulation of EMT. Moreover, we summarized that Notch Signaling pathway could be down-regulated by its inhibitors or natural compounds, resulting in the reversal of EMT to MET (Mesenchymal-to-Epithelial Transition), which could be a promising strategy for achieving better treatment outcome in patients diagnosed with cancer.
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Notch Signaling proteins legitimate targets for cancer therapy
Current Protein & Peptide Science, 2010Co-Authors: Zhiwei Wang, Fazlul H SarkarAbstract:Proteins and small peptides (growth factors and hormones) are key molecules in maintaining cellular homeostasis. To that end, Notch Signaling pathway proteins are known to play critical roles in maintaining the balance between cell proliferation, differentiation and apoptosis, and thus it has been suggested that Notch may be responsible for the development and progression of human malignancies. Therefore, the Notch Signaling pathway proteins may present novel therapeutic targets, which could have promising therapeutic impact on eradicating human malignancies. This review describes the role of Notch Signaling pathway proteins in cancer and how its deregulation is involved in tumor development and progression leading to metastasis and the ultimate demise of patients diagnosed with cancer. Further, we summarize the role of several Notch inhibitors especially “natural agents” that could represent novel therapeutic strategies targeting Notch Signaling toward better treatment outcome of patients diagnosed with cancer.
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the role of Notch Signaling pathway in epithelial mesenchymal transition emt during development and tumor aggressiveness
Current Drug Targets, 2010Co-Authors: Zhiwei Wang, Dejuan Kong, Fazlul H SarkarAbstract:The Notch Signaling pathway maintains a balance between cell proliferation and apoptosis, and thus it is believed that Notch Signaling pathway may play an important role in the development and progression of several malignancies. However, the functions of Notch Signaling in EMT are largely unknown. This mini review describes the role of Notch Signaling pathway in EMT, and cataloging how its deregulation is involved in EMT and tumor aggressiveness. Further attempts have been made to summarize the role of several chemopreventive agents that could be useful for targeted inactivation of Notch Signaling, and thus it may cause reversal of EMT, which could become a novel approach for cancer prevention and treatment.
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exploitation of the Notch Signaling pathway as a novel target for cancer therapy
Anticancer Research, 2008Co-Authors: Zhiwei Wang, Sanjeev Banerjee, Fazlul H SarkarAbstract:The Notch Signaling pathway appears to be responsible for maintaining a balance between cell proliferation and apoptosis and thus it has been suggested that Notch may play an important role in species development and in the development and progression of several malignancies. Therefore, the Notch Signaling pathway may represent a novel therapeutic target, which could have the highest therapeutic impact in modern medicine. This review describes the mechanisms of signal transduction of the Notch Signaling pathway and provides emerging evidence in support of its role in the development of human malignancies. Further attempts have been made to summarize the role of several chemopreventive agents that could be useful for targeted inactivation of Notch Signaling, which could become a novel approach for cancer prevention and treatment.
Hua Han - One of the best experts on this subject based on the ideXlab platform.
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Notch Signaling pathway and cancer metastasis
Advances in Experimental Medicine and Biology, 2012Co-Authors: Minhua Zheng, Rui Zhang, Yingmin Liang, Hua HanAbstract:Cancer metastasis is the leading cause of cancer-related deaths all over the world at present. Accumulated researches have demonstrated that cancer metastasis is composed of a series of successive incidents, mainly including epithelial-mesenchymal transition (EMT), malignant cell migration, resistance to anoikis, and angiogenesis and lymphangiogenesis processes. However, the complicated cellular and molecular mechanisms underlying and modulating these processes have not been well elucidated. Thus, studies on cancer metastasis mechanism may propose possibilities to therapeutically interfere with Signaling pathways required for each step of cancer metastasis, therefore inhibiting the outgrowth of distant metastasis of tumors. Recent insights have linked the Notch Signaling pathway, a critical pathways governing embryonic development and maintaining tumor stemness, to cancer metastasis. This chapter highlights the current evidence for aberration of the Notch Signaling in metastasis of tumors such as osteosarcoma, breast cancer, prostate cancer, and melanoma. In these studies, Notch activity seems to participate in cancer metastasis by modulating the EMT, tumor angiogenesis processes, and the anoikis-resistance of tumor cells. Therefore, manipulating Notch Signaling may represent a promising alternative/ complement therapeutic strategy targeting cancer metastasis besides cancer stemness.
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Notch Signaling determines the m1 versus m2 polarization of macrophages in antitumor immune responses
Cancer Research, 2010Co-Authors: Yaochun Wang, Minhua Zheng, Yingmin Liang, Fan Feng, Xiaowei Liu, Guangying Dong, Hongyan Qin, Liang Liang, Lei Feng, Hua HanAbstract:Macrophages are important tumor-infiltrating cells and play pivotal roles in tumor growth and metastasis. Macrophages participate in immune responses to tumors in a polarized manner: classic M1 macrophages produce interleukin (IL) 12 to promote tumoricidal responses, whereas M2 macrophages produce IL10 and help tumor progression. The mechanisms governing macrophage polarization are unclear. Here, we show that the M2-like tumor-associated macrophages (TAM) have a lower level of Notch pathway activation in mouse tumor models. Forced activation of Notch Signaling increased M1 macrophages which produce IL12, no matter whether M1 or M2 inducers were applied. When Notch Signaling was blocked, the M1 inducers induced M2 response in the expense of M1. Macrophages deficient in canonical Notch Signaling showed TAM phenotypes. Forced activation of Notch Signaling in macrophages enhanced their antitumor capacity. We further show that RBP-J-mediated Notch Signaling regulates the M1 versus M2 polarization through SOCS3. Therefore, Notch Signaling plays critical roles in the determination of M1 versus M2 polarization of macrophages, and compromised Notch pathway activation will lead to the M2-like TAMs. These results provide new insights into the molecular mechanisms of macrophage polarization and shed light on new therapies for cancers through the modulation of macrophage polarization through the Notch Signaling.
