Genetic analysis indicates that TP63 is required for establishment and preservation of self-renewing progenitors within the basal layer of several epithelial structures, however, the specific contributions of transactivating (TA-p63) and dominant-negative (ΔN-p63) isoforms remain largely undefined. Recent studies have suggested a model in which TA-p63 plays an important role in the establishment of progenitor populations in which expression of ΔN-p63 contributes to the preservation of self-renewing capacity. Our previous studies indicate that ΔN-p63 is a transcriptional target of p53, however, the absence of overt epithelial deficiencies in p53−/− mice and reports of increased expression of ΔN-p63 in p53−/− mice suggest p53-independent mechanisms also contribute to expression of ΔN-p63. Here, we present data indicating that, prolonged loss of p53 leads to the activation of a p53-independent mechanism for transcriptional regulation of ΔN-p63. This p53-independent mechanism is sensitive to ectopic p53 but not to a p53 mutant that lacks the transactivation domain. We further show that in cells in which p53 is expressed TA-p63-γ protein is destabilized in a manner that is p53 dependent and sensitive to pharmacologic inhibition of the 26S proteosome. Consistent with this observation, we demonstrate that loss of p53 leads to the stabilization of TA-p63-γ that is reversible by ectopic p53. Finally, we present evidence that disruption of TA-p63-γ expression leads to decreased expression of ΔN-p63 and that overexpression of TA-p63-γ was sufficient to enhance the activity of the ΔN-p63 promoter. Taken together, our studies indicate that TA-p63-γ is capable of activating expression of ΔN-p63 and that this mechanism may account for p53-independent expression of ΔN-p63.