Figure 1: A hypothesis on Notch–p53 and Wnt interplay derived from signalling network analysis.

Green and grey arrows indicate an activating effect, red arrows depict an inhibiting effect and dotted line indicates an indirect effect. (a) Schematic view of three signalling pathways (Wnt, Notch and p53) and the phenotypes of apoptosis, proliferation and EMT induction, showing crosstalk between each other. (b) Schematic view at a molecular level showing the involvement of Notch and Wnt pathways, p53 family and microRNAs in activating EMT inducers. The p53 family members (p53, p63 and p73) can be activated by DNA damage and can induce transcription of miRNAs (for example, miR34, miR200 and miR203). These miRNAs target mRNAs coding for β-catenin (Wnt pathway), Notch and the EMT inducers (Snail, Twist, Slug, Zeb1 and Zeb2). Those EMT inducers activate the Wnt pathway that, in turn, activates the Notch pathway, resulting in the activation of Notch (NICD). NICD activates the gene expression of EMT inducers, but can also inhibit transcription of p63 and p73, but not p53. Various signals from tumour microenvironment as extracellular matrix (ECM) components, hormones, growth factors, inflammatory factors and so on (collectively denoted as ‘Tumour microenvironment’ node) can sensitize the activation of EMT programme only in those cells that are in contact with microenvironmental signals.