Calcineurin (PP2B) is the only known serine/threonine phosphatase under calcium/calmodulin control and a key mediator of intracellular calcium signaling. The biochemical and biological functions of Calcineurin in epithelial cells have been mostly unexplored. In recent work, we have shown that Calcineurin plays a key role in keratinocyte growth/differentiation control and the hair cycle. The present studies are designed to test the hypothesis that Calcineurin plays a similarly important role in the response of keratinocytes to UVB exposure, impinging on intrinsic regulation of these cells as well as their capability to modulate other cell types in the skin. Our approach will be based on a keratinocyte-specific genetic deletion of the Calcineurin B1 gene (CnB1), which is essential for Calcineurin activity in these cells. By a combination of functional and biochemical assays, we will test the further hypothesis that Calcineurin functions in concert with the p53 and Notch signaling pathways in the intrinsic decision of keratinocytes to enter cell cycle withdrawal, apoptosis and/or differentiation. Finally, by a combination of in vivo and in vitro assays, we will test the hypothesis that Calcineurin plays an important role for the long-term consequences of UVB exposure in maintenance of keratinocyte stem cell populations and/or carcinogenesis. Narrative Calcineurin is the only known serine/threonine phosphatase under calcium/calmodulin control and a key mediator of intracellular calcium signaling. The biochemical and biological functions of Calcineurin in epithelial cells have been mostly unexplored. In recent work, we have shown that Calcineurin plays a key role in growth/differentiation control of epidermal cells and the hair cycle. We propose to explore the hypothesis that Calcineurin plays a similarly important role in the acute response of epidermal cells to Ultraviolet Light (UV) exposure, impinging on intrinsic regulation of their behavior as well as their capability to modulate other cell types in the skin. We will further test the hypothesis that Calcineurin plays an essential function in the long term response of epidermal cells to UV exposure, specifically in maintenance of stem cell populations and/or carcinogenesis.