In the epidermis, p53 plays an important role in UV-B protection that led us to examine the role, if any, that p63, a p53 homologue highly expressed in the basal layer of the epidermis, might play in the epidermal UV-B response. One p63 isoform, ΔNp63α, decreased dramatically in normal keratinocytes or newborn epidermis at both the protein and RNA levels after UV-B irradiation. In an attempt to further investigate the significance of the UV-B-induced decrease of this p63 isoform as well as further delineate the function of p63 in the epidermis, we generated transgenic mice that constitutively expressΔNp63α in the mouse epidermis using the loricrin promoter(ML.ΔNp63α). The ML.ΔNp63α mouse epidermis developed normally,with no overt phenotype and an unaltered proliferation rate. When challenged by UV-B exposure, the ML.ΔNp63α mice exhibited a 40–45% decrease in the number of apoptotic cells in the epidermis as compared with nontransgenic littermates. These results suggest that aberrant expression of ΔNp63α altered the UV-B-induced apoptotic pathway in the transgenic epidermis, proving that down-regulation ofΔNp63α in response to UV-B is important to epidermal apoptosis. The forced overexpression of ΔNp63α may act via a dominant negative effect on the endogenous p53 transcriptional activity required for UV-B-induced apoptosis.