14-3-3σ and p63 play opposing roles in epidermal tumorigenesis.

14-3-3 Sigma plays a regulatory role in epidermal epithelial differentiation and loss of 14-3-3 Sigma leads to increased proliferation and impaired differentiation. A tumor suppressor function for 14-3-3 Sigma has been proposed based on the fact that some epithelial-derived tumors lose 14-3-3 Sigma expression. p63, a p53 family member, is a master regulator of epidermal epithelial proliferation and differentiation and is necessary for the epidermal development. The function of p63 in tumorigenesis is still controversial and poorly defined as multiple isoforms have been found to play either collaborative or opposing roles. By using 'repeated epilation' heterozygous (Er/+) mice containing a dominant-negative 14-3-3 Sigma mutation, the functional relationship of p63 with 14-3-3 Sigma in epidermal proliferation, differentiation and tumorigenesis was investigated. It was found that p63, particularly the delta Np63 alpha isoform, was strongly expressed in 14-3-3 Sigma-deficient keratinocytes and knockdown of p63 remarkably inhibited proliferation in these cells. To study the functional roles of 14-3-3 Sigma and p63 in epidermal tumorigenesis, we adopted a 7,12-dimethylbenzanthracene/12-O-tetradecanoyl-phorbol-13-acetate (DMBA/TPA) two-stage tumorigenesis procedure to induce formation of skin papillomas and squamous cell carcinomas in Er/+ mice and identified strong p63 expression in resultant tumors. The loss of one allele of p63 caused by the generation of Er/+/p63(+/-) double compound mice decreased the sensitivity to DMBA-/TPA-induced tumorigenesis as compared with Er/+ mice. This study shows that p63 and 14-3-3 Sigma play opposing roles in the development of skin tumors and that the accumulation of p63 is essential for Ras/14-3-3 Sigma mutation-induced papilloma formation and squamous cell carcinoma carcinogenesis.