Characterization of tissue specific expression of Notch-1 in human tissues

Baldi, Alfonso; Falco, Maria De; Luca, Luca De; Cottone, Giuliano; Paggi, Marco G.; Nickoloff, Brian J.; Miele, Lucio; Luca, Antonio De

doi:10.1016/j.biolcel.2004.01.005

Cited by 23 publications

(14 citation statements)

References 64 publications

(73 reference statements)

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“…Finally, an RMS tissue microarray containing human eRMS, aRMS, and normal skeletal muscle cores was probed for activated Notch1 protein expression, using standard immunohistochemistry, as a surrogate for Hey1 protein expression. As expected in tissues of skeletal muscle origin (19), there was diffuse membrane and cytoplasmic staining of Notch1 in all samples. However, nuclear Notch1 staining, which represents the transcriptionally active form of Notch1, while absent in skeletal muscle and moderately expressed in aRMS, was highly expressed in eRMS (Fig.1C).…”

Section: Resultssupporting

confidence: 84%

Inhibition of the Notch-Hey1 Axis Blocks Embryonal Rhabdomyosarcoma Tumorigenesis

Belyea

Naini

Bentley

et al. 2011

Clinical Cancer Research

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Purpose Rhabdomyosarcoma (RMS) is the most common soft tissue sarcoma of childhood and remains refractory to combined-modality therapy in patients with high risk disease. In skeletal myogenesis, Notch signaling prevents muscle differentiation and promotes proliferation of satellite cell progeny. Given its physiologic role in myogenesis and oncogenic role in other human cancers, we hypothesized that aberrant Notch signaling may contribute to RMS tumorigenesis and present novel therapeutic opportunities. Experimental Design Human RMS cell lines and tumors were evaluated by immunoblot, IHC, and RT-PCR to measure Notch ligand, receptor, and target gene expression. Manipulation of Notch signaling was accomplished using genetic and pharmacologic approaches. In vitro cell growth, proliferation, and differentiation were assessed using colorimetric MTT and BrdU assays, and biochemical/morphologic changes after incubation in differentiation-promoting media, respectively. In vivo tumorigenesis was assessed using xenograft formation in SCID/beige mice. Results Notch signaling is upregulated in human RMS cell lines and tumors compared to primary skeletal muscle, especially in the embryonal (eRMS) subtype. Inhibition of Notch signaling using Notch1 RNAi or γ-secretase inhibitors reduced eRMS cell proliferation in vitro. Hey1 RNAi phenocopied Notch1 loss and permitted modest myogenic differentiation, while over-expression of an activated Notch moiety, ICN1, promoted eRMS cell proliferation and rescued pharmacologic inhibition. Finally, Notch inhibition using RNAi or γ-secretase inhibitors blocked tumorigenesis in vivo. Conclusions Aberrant Notch-Hey1 signaling contributes to eRMS by impeding differentiation and promoting proliferation. The efficacy of Notch pathway inhibition in vivo supports the development of Notch-Hey1 axis inhibitors in the treatment of eRMS.

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Section: Resultssupporting

confidence: 84%

Inhibition of the Notch-Hey1 Axis Blocks Embryonal Rhabdomyosarcoma Tumorigenesis

Belyea

Naini

Bentley

et al. 2011

Clinical Cancer Research

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“…Staining for the NICD, however, was not restricted to fibroblasts and was also prominent in keratinocytes, endothelial cells, pericytes, VSMCs and T cells as described before (figure 1A). 20 Consistent with increased Notch signalling, the mRNA levels of the Notch target gene hes-1 were elevated by 392 ± 33% in skin biopsy samples of patients with SSc as compared with similar samples from healthy individuals (p < 0.05) (figure 1B). To investigate the mechanisms that activate Notch signalling in SSc, we analysed the expression of Notch ligands and observed an upregulation of Jag-1 mRNA levels by 608 ± 86% in SSc skin compared with control skin samples (p < 0.05) (figure 1C).…”

Section: Resultsmentioning

confidence: 75%

Notch signalling regulates fibroblast activation and collagen release in systemic sclerosis

Dees

Tomčík

Zerr

et al. 2011

Annals of the Rheumatic Diseases

124

106

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BACKGROUND: Dermal fibroblasts from patients with systemic sclerosis (SSc) release excessive amounts of collagen resulting in tissue fibrosis. The molecular mechanisms underlying this pathological activation are incompletely understood. OBJECTIVE: To investigate whether Notch signalling contributes to the uncontrolled activation of fibroblasts in SSc. METHODS: Activation of the Notch pathway was assessed by immunohistochemistry or Western blot for the Notch intracellular domain and the Notch ligand Jagged-1 (Jag-1) and real-time PCR for the target gene hes-1. Differentiation of resting dermal fibroblasts into myofibroblasts was assessed by staining for -smooth muscle actin. The synthesis of collagen was quantified by real-time PCR and Sircol assays. RESULTS: Notch signalling was activated in lesional skin of patients with SSc. The activation persisted in cultured dermal SSc fibroblasts. Stimulation of healthy dermal fibroblasts with recombinant human Jag-1-Fc chimera resulted in an SSc-like phenotype with increased release of collagen and differentiation of resting fibroblasts into myofibroblasts. Consistent with the selective activation of the Notch pathway in dermal SSc fibroblasts, DAPT or siRNA against Notch strongly reduced the basal collagen expression in SSc fibroblasts, but not in fibroblasts from healthy volunteers. CONCLUSION: It was shown that Notch signalling is activated in SSc and plays an important role in fibroblast activation and collagen release. Inhibition of Notch signalling might be an effective strategy to selectively prevent the aberrant activation of SSc fibroblasts. Conclusion:We demonstrated that Notch signaling is activated in SSc and plays an important role in fibroblast activation and collagen release. Inhibition of Notch signaling might be an effective strategy to selectively prevent the aberrant activation of SSc fibroblasts.

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“…An important exception to this general rule is the epidermal keratinocyte, because we and others have clearly demonstrated that activation of Notch signaling promotes epidermal keratinocyte differentiation (Lowell et al, 2000;Rangarajan et al, 2001b;Nickoloff et al, 2002). Characterizing expression patterns for Notch-1 in human tissues has revealed that in the skin, Notch-1 was expressed by hair follicles, sebaceous glands, and sweat glands (Baldi et al, 2004). In the epidermis, Notch-1 appears to first become apparent in the suprabasal layers corresponding to the cells undergoing initial differentiation (Nickoloff et al, 2002).…”

Section: Notch Signaling As a Proto-oncogene Or Tumor Suppressormentioning

confidence: 95%

Notch and NOXA-Related Pathways in Melanoma Cells

Nickoloff

Hendrix

Pollock

et al. 2005

Journal of Investigative Dermatology Symposium Proceedings

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Notch receptor-mediated intracellular events represent an ancient cell signaling system, and alterations in Notch expression are associated with various malignancies in which Notch may function as an oncogene or less commonly as a tumor suppressor. Notch signaling regulates cell fate decisions in the epidermis, including influencing stem cell dynamics and growth/differentiation control of cells in skin. Because of increasing evidence that the Notch signaling network is deregulated in human malignancies, Notch receptors have become attractive targets for selective killing of malignant cells. Compared with proliferating normal human melanocytes, melanoma cell lines are characterized by markedly enhanced levels of activated Notch-1 receptor. By using a small molecule gamma-secretase inhibitor (GSI) consisting of a tripeptide aldehyde, N-benzyloxycarbonyl-Leu-Leu-Nle-CHO, which can block processing and activation of all four different Notch receptors, we identified a specific apoptotic vulnerability in melanoma cells. GSI triggers apoptosis in melanoma cells, but only G2/M growth arrest in melanocytes without subsequent cell death. Moreover, GSI treatment induced a pro-apoptotic BH3-only protein, NOXA, in melanoma cells but not in normal melanocytes. The use of GSI to induce NOXA induction overcomes the apoptotic resistance of melanoma cells, which commonly express numerous cell survival proteins such as Mcl-1, Bcl-2, and survivin. Taken together, these results highlight the concept of synthetic lethality in which exposure to GSI, in combination with melanoma cells overexpressing activated Notch receptors, has lethal consequences, producing selective killing of melanoma cells, while sparing normal melanocytes. By identifying signaling pathways that contribute to the transformation of melanoma cells (e.g. Notch signaling), and anti-cancer agents that achieve tumor selectivity (e.g., GSI-induced NOXA), this experimental approach provides a useful framework for future therapeutic strategies in cutaneous oncology.

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Characterization of tissue specific expression of Notch-1 in human tissues

Cited by 23 publications

References 64 publications

Inhibition of the Notch-Hey1 Axis Blocks Embryonal Rhabdomyosarcoma Tumorigenesis

Inhibition of the Notch-Hey1 Axis Blocks Embryonal Rhabdomyosarcoma Tumorigenesis

Notch signalling regulates fibroblast activation and collagen release in systemic sclerosis

Notch and NOXA-Related Pathways in Melanoma Cells

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