Ann Dermatol.  2019 Aug;31(4):365-371. 10.5021/ad.2019.31.4.365.

The Significance of NOTCH Pathway in the Development of Fibrosis in Systemic Sclerosis

Affiliations
  • 1Department of Cancer Genetics with Cytogenetic Laboratory, Medical University of Lublin, Poland. s.zmorzynski@gmail.com
  • 2Chair and Department of Dermatology, Venerology and Paediatric Dermatology, Medical University of Lublin, Poland.

Abstract

Systemic sclerosis (SSc) is an autoimmune disorder characterized by the fibrosis of skin, heart, lung, and kidney as well. Excessive activation of fibroblasts is associated with higher expression of Notch1 and/or Notch3 genes. The constitutive expression of NOTCH genes was described in epithelial cells: epidermal keratinocytes, hair follicle cells and sebaceous glands. The NOTCH signalling pathway may be involved in the development of fibrosis, myofibroblast formation and the process of epithelial-mesenchymal transition. Activation of the NOTCH pathway leads to morphological, phenotypic and functional changes in epithelial cells. Furthermore, inhibition of Notch signalling prevent the development of fibrosis in different models, among them, bleomycin-induced fibrosis and in the Task-1 mause model. Molecular mechanisms, including the role of NOTCH signaling pathway, associated with fibrosis in SSc have not been completely recognized.

Keyword

Fibrosis; NOTCH genes; NOTCH pathway; Scleroderma; systemic; Transforming growth factor beta

MeSH Terms

Epithelial Cells
Epithelial-Mesenchymal Transition
Fibroblasts
Fibrosis*
Hair Follicle
Heart
Keratinocytes
Kidney
Lung
Myofibroblasts
Scleroderma, Systemic*
Sebaceous Glands
Skin
Transforming Growth Factor beta
Transforming Growth Factor beta

Figure

  • Fig. 1 Cross-talk between NOTCH and transforming growth factor β (TGF-β) pathways. Activation of NOTCH receptors by ligand binding causes the cleavage by an A Digestirn and Metalloproteinase 17 (ADAM) metalloprotease (α-secretase) producing the Notch extracellular truncation fragment. Another cleavage by γ-secretase of transmembrane fragment releases the NOTCH intracellular domain (NICD). It translocates to the nucleus and acts as a co-transcription factor in association with the CSL (C-repeat/DRE binding factor 1/suppressor of hairless/Lag1) and other transcription factors including SMAD3. This protein translocates to the nulceus in the phosphorylated form as a result of TGF-β receptor activation.


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