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

The p53-inducible cell cycle regulator 14-3-3 sigma exhibits tumor suppressive functions and is highly expressed in differentiating layers of the epidermis and hair follicles. 14-3-3 sigma/SFN/stratifin is frequently silenced in human epithelial cancers, and experimental down-regulation of 14-3-3 sigma expression immortalizes primary human keratinocytes. In the repeated-epilation (ER) mouse model, a heterozygous nonsense mutation of 14-3-3 sigma causes repeated hair-loss, hyper-proliferative epidermis, and spontaneous development of papillomas and squamous cell carcinomas in aging mice. Therefore, loss of 14-3-3 sigma function might contribute to epithelial tumor development. Here, we generated mice with loxP sites surrounding the single 14-3-3 sigma exon which allowed Cre-mediated deletion of the gene. 14-3-3 sigma-deficient mice are viable, but demonstrate a permanently disheveled fur. However, histological analyses of the skin did not reveal obvious defects in the hair follicles or the epidermis. Deletion of 14-3-3 sigma did not enhance spontaneous epidermal tumor development, whereas it increased the frequency and size of DMBA/TPA-induced papillomas. In conclusion, 14-3-3 sigma is dispensable for normal epidermal homeostasis but critical for suppression of chemically-induced skin carcinogenesis. In addition, these results suggest that the ER mutation of 14-3-3 sigma is not equivalent to loss of 14-3-3 sigma, but may represent a gain-of-function variant, which does not reflect the organismal function of wild-type 14-3-3 sigma.