Regulation of DeltaNp63alpha by tumor necrosis factor-alpha in epithelial homeostasis.

A dominant negative form of p63, DeltaNp63alpha, is critical for maintaining the proliferative potential of epidermal stem cells and progenitor cells. The expression of DeltaNp63alpha also confers a selective advantage for cancer cell survival, underscoring the importance of DeltaNp63alpha in both normal and neoplastic stratified epithelia. Regulation of DeltaNp63alpha can be achieved at the transcriptional and post-translational levels, the latter being greatly influenced by external stimuli such as UV irradiation. In this study, we have found that tumor necrosis factor-alpha (TNF-alpha), a multifunctional cytokine that has been implicated in epidermal homeostasis during normal and pathophysiologic conditions, also triggers the degradation of DeltaNp63alpha in immortalized keratinocytes and cervical cancer cells. Conversely, downregulation of DeltaNp63alpha sensitized cancer cells to TNF-alpha-induced apoptosis, suggesting a counteractive interaction between TNF-alpha and DeltaNp63alpha in the regulation of epithelial cell death. The degradation of DeltaNp63alpha by TNF-alpha was delayed when cells were treated with nuclear factor-kappaB inhibitors, whereas the induction of apoptosis by TNF-alpha was accompanied by the dramatic upregulation of the proapoptotic gene Puma. These observations further elucidate the relationship between TNF-alpha and DeltaNp63alpha, two well-known mediators of epidermal homeostasis, and further suggest crosstalk between the two molecules in normal and pathophysiologic epidermis.