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

Markus Winter,Heiko Hermeking,Berlinda Verdoodt,Dmitri Lodygin

doi:10.18632/oncotarget.10478

Abstract

The p53-inducible cell cycle regulator 14-3-3σ exhibits tumor suppressive functions and is highly expressed in differentiating layers of the epidermis and hair follicles. 14-3-3σ/SFN/stratifin is frequently silenced in human epithelial cancers, and experimental down-regulation of 14-3-3σ expression immortalizes primary human keratinocytes. In the repeated-epilation (ER) mouse model, a heterozygous nonsense mutation of 14-3-3σ causes repeated hair-loss, hyper-proliferative epidermis, and spontaneous development of papillomas and squamous cell carcinomas in aging mice. Therefore, loss of 14-3-3σ function might contribute to epithelial tumor development. Here, we generated mice with loxP sites surrounding the single 14-3-3σ exon which allowed Cre-mediated deletion of the gene. 14-3-3σ-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 14-3-3σ did not enhance spontaneous epidermal tumor development, whereas it increased the frequency and size of DMBA/TPA-induced papillomas. In conclusion, 14-3-3σ 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 14-3-3σ is not equivalent to loss of 14-3-3σ, but may represent a gain-of-function variant, which does not reflect the organismal function of wild-type 14-3-3σ.

Highlights

The mammalian epidermis undergoes continuous self-renewal to repair damaged tissue and replace aged cells
Other phenotypes characteristic for 14-3-3σ+/ER mice were not observed in 14-3-3σ-deficient mice: the frequency of Ki67-positive hair follicle matrix cells (Figure 2A) or basal epidermal cells (Figure 2B) was unchanged
The number of hair follicles and the epidermal thickness showed no differences in 14-3-3σ-/- tissues (Figure 2)

Summary

Introduction

The mammalian epidermis undergoes continuous self-renewal to repair damaged tissue and replace aged cells. 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]. In keratinocytes derived from ER mice truncated 143-3σ fails to bind and sequester Yap1 in the cytoplasm, suggesting that 14-3-3σ inhibits Yap1-dependent gene expression to control epidermal proliferation and differentiation.

Results

Conclusion