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

Abstract

14-3-3σ plays a regulatory role in epidermal epithelial differentiation and loss of 14-3-3σ leads to increased proliferation and impaired differentiation. A tumor suppressor function for 14-3-3σ has been proposed based on the fact that some epithelial-derived tumors lose 14-3-3σ 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 14-3-3σ mutation, the functional relationship of p63 with 14-3-3σ in epidermal proliferation, differentiation and tumorigenesis was investigated. It was found that p63, particularly the ΔNp63α isoform, was strongly expressed in 14-3-3σ-deficient keratinocytes and knockdown of p63 remarkably inhibited proliferation in these cells. To study the functional roles of 14-3-3σ 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 14-3-3σ play opposing roles in the development of skin tumors and that the accumulation of p63 is essential for Ras/14-3-3σ mutation-induced papilloma formation and squamous cell carcinoma carcinogenesis.

Forward genetics identifies Kdf1/1810019J16Rik as an essential regulator of the proliferation–differentiation decision in epidermal progenitor cells

“…Sfn has also been shown to inhibit p63 in keratinocytes (Li et al, 2011). We then tested whether Sfn and shd might cooperate to regulate p63.…”

Delineating Molecular Mechanisms of Squamous Tissue Homeostasis and Neoplasia: Focus on p63

“…14-3-3 σ , a protein associated with keratinocyte differentiation, is a direct target for ΔNp63 α repression in undifferentiated human epidermal keratinocytes [52]. Treatment of Er/+ mice on a p63 ( +/+ ) background with a two-stage carcinogenesis protocol resulted in the formation of tumors in which ΔNp63 α was strongly expressed, while loss of function of an endogenous allele of p63 in this context, which generated ( Er/+/p63 +/−) mice, resulted in reduced sensitivity to this protocol, suggestive of cooperation of ΔNp63 α in Ras/14-3-3 σ -induced tumorigenesis [125]. …”

Deletion of 14-3-3σ sensitizes mice to DMBA/TPA-induced papillomatosis

“…This suggested that the epidermal hyper-proliferation observed in 14-3-3σ +/ER mice is caused by the expression of the truncated 14-3-3σ protein, which acquired additional functions and presumably an altered ligand specificity, and not by the mere loss of 14-3-3σ function. Notably, p63 and YAP1 have been shown to functionally interact with the ER mutant of 14-3-3σ in murine epidermis [28, 30]. However, we could not detect an effect of 14-3-3σ loss on the localization and expression level of p63 (Supplemental Figure 2B).…”

“…In addition, heterozygous ER -mice show an extensive hyper-proliferation of the epidermis followed by the development of multiple papillomas and squamous cell carcinoma at the age of 6 month [27]. ER -mice display increased levels of p63 in the epidermal suprabasal layers, suggesting that truncated 14-3-3σ fails to block the transcription of TP63 which may contribute to hyper-proliferation of the epidermis [28]. In addition, Yap1, an essential factor of the Hippo pathway controlling organ size and tissue homeostasis [29], is expressed in the epidermal suprabasal layers of ER -mice [30].…”