The dual nature of Notch in tissue homeostasis and carcinogenesis

The Notch pathway is an evolutionarily conserved signaling system that plays a critical pleiotropic role in regulating stem cell self-renewal and differentiation. The functional outcome of Notch signaling is highly dependent on cellular context and signal dosage. For example, distinct levels of Notch activity can either promote or suppress proliferation of mammary gland epithelial cells. In addition, Notch activation increases the self-renewal capacity of hematopoietic, neural and muscle stem cells but induces differentiation of stem cells in skin, breast, lung and thymic epithelia. Our recent study showed that Notch activation in different cell lineages within the same tissue system can result in completely opposite biological consequences. In prostate basal cells, Notch activation suppresses proliferation and induces differentiation, while in prostate luminal cells, the same signaling instead enhances proliferation. The mechanisms through which Notch directs distinct biological outcomes have not been definitively determined. One prevailing hypothesis is that crosstalk between Notch and other signaling transduction pathways affects where Notch binds, hence influencing transcriptional output. A plethora of studies have shown that transcription factors such as β-catenin, Smad3 and NFκB can directly interact with Notch intracellular domain (NICD) to modulate its transcriptional activity. In addition, an interesting observation is that Notch usually suppresses the proliferation of epithelial stem cells that express P63, a transcription factor belonging to the P53 superfamily. Crosstalk between P63 and Notch at various regulatory levels may also influence the The dual nature of Notch in tissue homeostasis and carcinogenesis