The Notch3 Receptor and Its Intracellular Signaling-Dependent Oncogenic Mechanisms

Bellavia, Diana; Checquolo, Saula; Palermo, Rocco; Screpanti, Isabella

doi:10.1007/978-3-319-89512-3_10

Cited by 8 publications

(5 citation statements)

References 115 publications

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“…For example, HOXB5 and HOXB6 code for proteins belonging to the Antp homeobox family and encode nuclear proteins with homeobox DNA-binding domains, participating in development of lung and gut (HOXB5), and lung and skin (HOXB6), respectively [29,30]. NOTCH3 encodes Notch Receptor 3, which is involved in various developmental processes, including vasculogenesis neural development [31]. Expression of the abovementioned genes is significantly changed in some MPS types (Table 4), and changes in lung, gut, skin, vascular system, and central nervous system are evident in MPS patients.…”

Section: Discussionmentioning

confidence: 99%

Underestimated Aspect of Mucopolysaccharidosis Pathogenesis: Global Changes in Cellular Processes Revealed by Transcriptomic Studies

Gaffke

Pierzynowska

Podlacha

et al. 2020

IJMS

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Mucopolysaccharidoses (MPS), a group of inherited metabolic disorders caused by deficiency in enzymes involved in degradation of glycosaminoglycans (GAGs), are examples (and models) of monogenic diseases. Accumulation of undegraded GAGs in lysosomes was supposed to be the major cause of MPS symptoms; however, their complexity and variability between particular types of the disease can be hardly explained by such a simple storage mechanism. Here we show that transcriptomic (RNA-seq) analysis of the material derived from fibroblasts of patients suffering from all types and subtypes of MPS, supported by RT-qPCR results, revealed surprisingly large changes in expression of genes involved in various cellular processes, indicating complex mechanisms of MPS. Although each MPS type and subtype was characterized by specific changes in gene expression profile, there were genes with significantly changed expression relative to wild-type cells that could be classified as common for various MPS types, suggesting similar disturbances in cellular processes. Therefore, both common features of all MPS types, and differences between them, might be potentially explained on the basis of changes in certain cellular processes arising from disturbed regulations of genes’ expression. These results may shed a new light on the mechanisms of genetic diseases, indicating how a single mutation can result in complex pathomechanism, due to perturbations in the network of cellular reactions. Moreover, they should be considered in studies on development of novel therapies, suggesting also why currently available treatment methods fail to correct all/most symptoms of MPS. We propose a hypothesis that disturbances in some cellular processes cannot be corrected by simple reduction of GAG levels; thus, combined therapies are necessary which may require improvement of these processes.

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Section: Discussionmentioning

confidence: 99%

Underestimated Aspect of Mucopolysaccharidosis Pathogenesis: Global Changes in Cellular Processes Revealed by Transcriptomic Studies

Gaffke

Pierzynowska

Podlacha

et al. 2020

IJMS

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“…There are numerous published review articles on the effects of Notch signaling in cancer treatment ( Giovannini et al, 2016 ; Bellavia et al, 2018 ; Giuli et al, 2019 ; Katoh and Katoh, 2020 ). By contrast, this review mainly focuses on the underlying Notch3-related molecular mechanisms that regulate cancer stemness and chemoresistance.…”

Section: Introductionmentioning

confidence: 99%

The Role of Notch3 Signaling in Cancer Stemness and Chemoresistance: Molecular Mechanisms and Targeting Strategies

Xiu

Wang

et al. 2021

Front. Mol. Biosci.

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Aberrant Notch signaling profoundly affects cancer progression. Especially the Notch3 receptor was found to be dysregulated in cancer, where its expression is correlated with worse clinicopathological features and poor prognosis. The activation of Notch3 signaling is closely related to the activation of cancer stem cells (CSCs), a small subpopulation in cancer that is responsible for cancer progression. In addition, Notch3 signaling also contributes to tumor chemoresistance against several drugs, including doxorubicin, platinum, taxane, epidermal growth factor receptor (EGFR)–tyrosine kinase inhibitors (TKIs) and gemcitabine, through complex mechanisms. In this review, we mainly focus on discussing the molecular mechanisms by which Notch3 modulates cancer stemness and chemoresistance, as well as other cancer behaviors including metastasis and angiogenesis. What’s more, we propose potential treatment strategies to block Notch3 signaling, such as non-coding RNAs, antibodies and antibody-drug conjugates, providing a comprehensive reference for research on precise targeted cancer therapy.

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“…[ 15 , 16 ] Mutations not only affect the formation of disulfide bonds in the EGFR region and destroy the stability of the extracellular segment of the transmembrane protein, [ 17 ] but also affect the intracellular signal transduction of NOTCH3 protein. [ 18 ] Therefore, mutations at different NOTCH3 gene loci can lead to different clinical symptoms.…”

Section: Discussionmentioning

confidence: 99%

Case report: Mild leukoencephalopathy caused by a new mutation of NOTCH3 gene

2023

Medicine

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Background: Cerebral autosomal dominant arteriosis with subcortical infarction and leukoencephalopathy (CADASIL) is a single-gene small-vessel disease of the brain characterized by migraine, recurrent ischemic stroke, psychiatric disorders, progressive cognitive decline, and occasional intracerebral hemorrhage. [ 1 ] NOTCH3 was identified as a pathogenic gene for CADASIL. [ 2 ] The NOTCH3 gene encodes a membrane-bound receptor protein, and to date, several different NOTCH3 gene mutations have been identified. [ 3 ] Here, we report a case of CADASIL with a heterozygous mutation c.931T > G (thymine > guanine) on the exon region of the NOTCH3 gene, resulting in an amino acid change p.C311G (cysteine > glycine). Case report: We report a case of a female patient with CADASIL whose genetic sequencing revealed a mutation in the NOTCH3 gene. However, this patient did not exhibit any of the typical clinical findings of CADASIL but the patient’s cerebral magnetic resonance imaging was consistent with the characteristic findings of CADASIL. Conclusions: This case reminds us that mutations caused by different mutation sites present different clinical symptoms.

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The Notch3 Receptor and Its Intracellular Signaling-Dependent Oncogenic Mechanisms

Cited by 8 publications

References 115 publications

Underestimated Aspect of Mucopolysaccharidosis Pathogenesis: Global Changes in Cellular Processes Revealed by Transcriptomic Studies

Underestimated Aspect of Mucopolysaccharidosis Pathogenesis: Global Changes in Cellular Processes Revealed by Transcriptomic Studies

The Role of Notch3 Signaling in Cancer Stemness and Chemoresistance: Molecular Mechanisms and Targeting Strategies

Case report: Mild leukoencephalopathy caused by a new mutation of NOTCH3 gene

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