Ricerc@Sapienza

Reactive oxygen species (ROS) are mutagenic and may thereby promote cancer. However, ROS play an important role in apoptosis induction under both physiologic and pathologic conditions. Moreover, there is growing evidence that ROS may also act as chemical messenger. The balance between the pro-tumorigenic and pro-apoptotic functions of ROS is likely to involve a complex interplay between pathways that enhanced ROS detoxification and other pathway that acting as sensor of ROS level mediate the pro-apoptotic function of ROS. In our preliminary work, we have found that calcium induced differentiation is associated with increased oxidative-stress mediated induction of Ask1 activity in primary keratinocytes. Additionally, the expression of a Notch1-constitutively active mutant in primary mouse keratinocytes is sufficient to suppress differentiation and this is correlated with ASK1 inhibition. The main working hypothesis of this proposal is that Notch signaling plays an important role in the molecular control of ROS toxicology and tumorigenesis. Both human and mouse primary keratinocytes are used as a prototype model system. Mouse primary keratinocytes provide an ideal experimental system to study the switch between epithelial cell growth and differentiation. Our studies on the role on the link between Notch1 and oxidative stress in keratinocytes are likely to generate entirely novel insights into how this protein is functionally connected with other critical signaling molecules such as Ask1, in the coordinate control of keratinocyte differentiation and transformation. While focused on keratinocytes, our work is likely to be of great relevance for a better understanding of other non keratinocyte-derived tumors.