Dr. Dotto's main research interest has been control of epithelial tissue homeostasis and carcinogenesis, using skin as model system. His earlier work focused on the biochemical and cell-cell communication events underlying the onset of keratinocyte differentiation. His group was the first to implicate the cyclin/CDK inhibitor p21WAF1/Cip1 in control of keratinocyte differentiation and cancer formation, showing that this molecule can directly impact on gene transcription independently of the cell cycle. Notch activation in mammalian cells is commonly thought to enhance stem cell potential and promote tumorigenesis. Dr. Dotto showed instead that in keratinocytes Notch signaling is an important determinant of differentiation and tumor suppression, with p21 WAF1/Cip1 and p63 as critical targets. Little is known on control of Notch1 gene expression. His laboratory established this gene as a direct p53 target in antagonism to EGFR signaling, validating these findings for cancer development in the clinical setting. They also discovered a novel pro-differentiation and tumor suppressing function of calcineurin signaling in keratinocytes, with the ATF3 transcription factor as a critical target. This is of major clinical significance for the many patients under treatment with calcineurin inhibitors as immunosuppressants, who develop squamous cell carcinoma as a very frequent and often deadly complication. Epithelial-mesenchymal interactions play a key role in epithelial organ morphogenesis and homeostasis. In this context, the Dotto's group has pioneered research on an entirely novel and unexpected role of the Notch pathway in the mesenchymal compartment of the skin. His group showed that this pathway is critically required in dermal papilla cells for control and maintenance of the hair follicle cell fate. More recently, they showed that dermal fibroblast alterations can play a primary role in cutaneous field cancerization, with loss of Notch/CSL signaling and associated AP1 activation as underlying mechanisms.