Regulation of ΔNp63α by tumor necrosis factor‐α in epithelial homeostasis

A dominant negative form of p63, ΔNp63α, is critical for maintaining the proliferative potential of epidermal stem cells and progenitor cells. The expression of ΔNp63α also confers a selective advantage for cancer cell survival, underscoring the importance of ΔNp63α in both normal and neoplastic stratified epithelia. Regulation of ΔNp63α 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‐α (TNF‐α), a multifunctional cytokine that has been implicated in epidermal homeostasis during normal and pathophysiologic conditions, also triggers the degradation of ΔNp63α in immortalized keratinocytes and cervical cancer cells. Conversely, downregulation of ΔNp63α sensitized cancer cells to TNF‐α‐induced apoptosis, suggesting a counteractive interaction between TNF‐α and ΔNp63α in the regulation of epithelial cell death. The degradation of ΔNp63α by TNF‐α was delayed when cells were treated with nuclear factor‐κB inhibitors, whereas the induction of apoptosis by TNF‐α was accompanied by the dramatic upregulation of the proapoptotic gene Puma . These observations further elucidate the relationship between TNF‐α and ΔNp63α, two well‐known mediators of epidermal homeostasis, and further suggest crosstalk between the two molecules in normal and pathophysiologic epidermis.