Notch Intracellular Domain Expression in Various Skin Fibroproliferative Diseases

Kim, Jung Eun; Lee, Juhyun; Jeong, Kwan; Kim, Gyong Moon; Kang, Hoon

doi:10.5021/ad.2014.26.3.332

Cited by 16 publications

(15 citation statements)

References 23 publications

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“…Notch signalling plays an important role in the fibrotic phenotype of SSc fibroblasts and in scleroderma animal models 11 12 34. HOTAIR has previously been shown to enhance Notch expression and signalling in keratinocytes and retinoblastoma tissue 35–37.…”

Section: Resultsmentioning

confidence: 99%

Long non-coding RNA HOTAIR drives EZH2-dependent myofibroblast activation in systemic sclerosis through miRNA 34a-dependent activation of NOTCH

et al. 2020

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BackgroundSystemic sclerosis (SSc) is characterised by autoimmune activation, tissue and vascular fibrosis in the skin and internal organs. Tissue fibrosis is driven by myofibroblasts, that are known to maintain their phenotype in vitro, which is associated with epigenetically driven trimethylation of lysine 27 of histone 3 (H3K27me3).MethodsFull-thickness skin biopsies were surgically obtained from the forearms of 12 adult patients with SSc of recent onset. Fibroblasts were isolated and cultured in monolayers and protein and RNA extracted. HOX transcript antisense RNA (HOTAIR) was expressed in healthy dermal fibroblasts by lentiviral induction employing a vector containing the specific sequence. Gamma secretase inhibitors were employed to block Notch signalling. Enhancer of zeste 2 (EZH2) was blocked with GSK126 inhibitor.ResultsSSc myofibroblasts in vitro and SSc skin biopsies in vivo display high levels of HOTAIR, a scaffold long non-coding RNA known to direct the histone methyltransferase EZH2 to induce H3K27me3 in specific target genes. Overexpression of HOTAIR in dermal fibroblasts induced EZH2-dependent increase in collagen and α-SMA expression in vitro, as well as repression of miRNA-34A expression and consequent NOTCH pathway activation. Consistent with these findings, we show that SSc dermal fibroblast display decreased levels of miRNA-34a in vitro. Further, EZH2 inhibition rescued miRNA-34a levels and mitigated the profibrotic phenotype of both SSc and HOTAIR overexpressing fibroblasts in vitro.ConclusionsOur data indicate that the EZH2-dependent epigenetic phenotype of myofibroblasts is driven by HOTAIR and is linked to miRNA-34a repression-dependent activation of NOTCH signalling.

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Section: Resultsmentioning

confidence: 99%

Long non-coding RNA HOTAIR drives EZH2-dependent myofibroblast activation in systemic sclerosis through miRNA 34a-dependent activation of NOTCH

et al. 2020

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“…Notch reporters undergo successive cleavages, leading to the release of their activated form, the Notch intracellular domain (NID). The NID translocates to the nucleus and forms a complex with DNA-binding proteins, thereby activating transcription 22 23 . This interaction results in the expression of various target genes, including HES and HES-related repressor protein ( HEY ) 24 .…”

Section: Discussionmentioning

confidence: 99%

Interaction of Wnt5a with Notch1 is Critical for the Pathogenesis of Psoriasis

et al. 2016

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BackgroundPsoriasis is characterized by uncontrolled hyperproliferation, aberrant differentiation, and dermal infiltration of immune cells. Recent studies have reported that Wnt5a and Notch1 signaling are altered in psoriatic skin lesions.ObjectiveWe aimed to investigate the interaction of Wnt5a with Notch 1 with respect to inflammation-mediated epidermal hyperproliferation in psoriasis.MethodsExpression of Wnt5a and Notch1 signaling-related proteins were examined in psoriatic skin biopsies. Wnt5a was upregulated in human keratinocytes by treating the cells with its recombinant form (rWnt5a).ResultsIn psoriatic lesions, expression of Wnt5a increased while that of Notch1 decreased when compared to that in non-lesional and normal skin. Treatment with rWnt5a increased the proliferation of keratinocytes and increased their secretion of interleukin (IL)-23, IL-12, and tumor necrosis factor (TNF)-α. Further, exposure of keratinocytes to IL-1α, TNF-α, transforming growth factor-α, and interferon-γ downregulated Notch1 as well as HES 1, which is downstream to Notch1, but increased the Wnt5a levels. The upregulated Wnt5a in keratinocytes downregulated both Notch1 and HES1.ConclusionOur data suggest that Wnt5a and Notch1 signaling exert counteracting influences on each other and are involved, in part, in the pathomechanism of psoriasis.

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“…Notch signaling regulates late-stage epidermal differentiation and maintains postnatal hair cycle homeostasis [101-103]. In fibroproliferative skin diseases, the NICD is highly expressed in fibroblasts of keloids and moderately to highly expressed in hypertrophic scars and dermatofibromas, whereas low or no expression is detected in the fibroblasts of normal skin specimens and morpheas [101]. In hypertrophic scar, more Notch1 and Jagged1 positive keratinocytes were found than in normal skin [100].…”

Section: Notch and Skin Fibrosismentioning

confidence: 99%

Notch in fibrosis and as a target of anti-fibrotic therapy

Phan

2016

Pharmacological Research

112

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The Notch pathway represents a highly conserved signaling network with essential roles in regulation of key cellular processes and functions, many of which are critical for development. Accumulating evidence indicates that it is also essential for fibrosis and thus the pathogenesis of chronic fibroproliferative diseases in diverse organs and tissues. Different effects of Notch activation are observed depending on cellular and tissue context as well as in both physiologic and pathologic states. Close interactions of Notch signaling pathway with other signaling pathways have been identified. In this review, current knowledge on the role of the Notch signaling with special focus on fibrosis and its potential as a therapeutic target is summarized.

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Notch Intracellular Domain Expression in Various Skin Fibroproliferative Diseases

Cited by 16 publications

References 23 publications

Long non-coding RNA HOTAIR drives EZH2-dependent myofibroblast activation in systemic sclerosis through miRNA 34a-dependent activation of NOTCH

Long non-coding RNA HOTAIR drives EZH2-dependent myofibroblast activation in systemic sclerosis through miRNA 34a-dependent activation of NOTCH

Interaction of Wnt5a with Notch1 is Critical for the Pathogenesis of Psoriasis

Notch in fibrosis and as a target of anti-fibrotic therapy

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