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 (TAp63) and dominant-negative (DN-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 DNp63 contributes to the preservation of self-renewing capacity. Our previous studies indicate that DN-p63 is a transcriptional target of p53, however, the absence of overt epithelial deficiencies in p53À/À mice and reports of increased expression of DN-p63 in p53À/À mice suggest p53-independent mechanisms also contribute to expression of DN-p63. Here, we present data indicating that, prolonged loss of p53 leads to the activation of a p53-independent mechanism for transcriptional regulation of DN-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-c 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-c that is reversible by ectopic p53. Finally, we present evidence that disruption of TA-p63-c expression leads to decreased expression of DN-p63 and that overexpression of TA-p63-c was sufficient to enhance the activity of the DN-p63 promoter. Taken together, our studies indicate that TAp63-c is capable of activating expression of DN-p63 and that this mechanism may account for p53-independent expression of DN-p63.
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