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

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.

14-3-3σFunctions as an Intestinal Tumor Suppressor

“…The exclusive homodimerization critically contributes to the ability of 14-3-3s to inhibit cell proliferation in the presence of other 14-3-3 family members, which are often highly expressed (6). More recently, we demonstrated that 14-3-3s-deficiency in mice leads to an increased frequency and size of DMBA/12-O-tetradecanoylphorbol-13-acetate (TPA)-induced papilloma (7).…”

Expression profile and prognostic value of SFN in human ovarian cancer

“…To response the DNA damage, SFN often plays a role in inhibiting DNA errors during mitosis [4,5]. Generally, SFN is expressed at low levels on the nervous and reproductive systems, including in the cortex, retina, placenta, and ovary [6]. Nevertheless, SFN has been reported to be a novel biomarker in various cancers.…”

Molecular and cytoskeletal regulations in epidermal development

“…Based on the Er model, it has been shown that stratifin regulates proliferation and differentiation by changing transcription factor YAP1 localization by binding to YAP1 and facilitating nuclear transcriptional function [40]. Intriguingly, a recently generated mouse model with Cre-mediated stratifin depletion did not show significant epidermis defects, suggesting that the Er model may not entirely recapitulate the effects of stratifin ablation [41]. Further experiments will be needed to resolve the contradiction between the two models and clarify the role of stratifin in skin development.…”