TA-p63-γ regulates expression of ΔN-p63 in a manner that is sensitive to p53

Abstract

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.

p63 and p73 in human cancer: defining the network

“…Both positive and negative regulation of DNp63 mRNA and protein have been shown by different groups to be mediated by both p53 and DNp63 itself (Harmes et al, 2003;Waltermann et al, 2003;Antonini et al, 2006;Romano et al, 2006). DNp63 may also be positively regulated by TAp63g in a manner that is independent of p53, suggesting yet another possible feedback mechanism (Li et al, 2006). Additional feedback mechanisms with potential relevance to human cancer have been proposed and involve distinct p63 target genes.…”

The role of P63 in cancer, stem cells and cancer stem cells

“…Moreover, ΔNp63 is recruited to and can activate its own promoter, thus providing an autoregulatory loop of self-regulation [28,83]. Importantly, loss of p53 leads to the stabilization of TAp63γ [84]. Consequently, disruption of TAp63γ expression leads to decreased expression of ΔNp63, and overexpression of TAp63γ enhances the activity of the ΔNp63 promoter.…”

TRAF4 is potently induced by TAp63 isoforms and localised according to differentiation in SCCHN

“…32,10 Though little is known about the biological functions of TRAF4, our results indicate that the localization of the TRAF4 protein is associated with histological differentiation of SCCHN and that p63 cooperating with TRAF4 might be involved in the kerati- nocyte differentiation pathway. Since TRAF4 is also transactivated by p53 and TAp73, and as p53 family members are known to interact physically and functionally, 33,34 the in vivo regulation of TRAF4 expression is highly complex and tissue specific. In addition, TRAF4 localizes to the nuclei in all normal oral epithelial cells but this localization is disturbed in poorly differentiated SCCHN cells, indicating the existence of tumor-specific factors that regulate the intracellular distribution of TRAF4 in this tumor type.…”