title: 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.
authors.affiliation: Experimental and Molecular Pathology, Institute of Pathology, Ludwig-Maximilians-Universität München, Munich, Germany.
authors.forename: Markus
authors.initials: M
authors.lastname: Winter
authors.affiliation: Institute of Neuroimmunology and Institute for Multiple Sclerosis Research, University Medical Center Göttingen, Göttingen, Germany.
authors.forename: Dmitri
authors.initials: D
authors.lastname: Lodygin
authors.affiliation: Institute of Pathology, Ruhr-University Bochum, Bochum, Germany.
authors.forename: Berlinda
authors.initials: B
authors.lastname: Verdoodt
authors.affiliation: Experimental and Molecular Pathology, Institute of Pathology, Ludwig-Maximilians-Universität München, Munich, Germany.|German Cancer Consortium (DKTK), Heidelberg, Germany.|German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: Heiko
authors.initials: H
authors.lastname: Hermeking
mesh_terms: D048948:14-3-3 Proteins / Q000235:genetics* / Q000378:metabolism; D015127:9,10-Dimethyl-1,2-benzanthracene / Q000633:toxicity; D000818:Animals; D063646:Carcinogenesis / Q000139:chemically induced / Q000235:genetics*; D002454:Cell Differentiation; D049109:Cell Proliferation; D018389:Codon, Nonsense; D004195:Disease Models, Animal; D015536:Down-Regulation; D000078404:Epidermal Cells; D004817:Epidermis / Q000473:pathology*; D005091:Exons / Q000235:genetics; D005260:Female; D000073659:Gain of Function Mutation; D017353:Gene Deletion; D018859:Hair Follicle / Q000473:pathology*; D006579:Heterozygote; D007150:Immunohistochemistry; D019426:Integrases / Q000235:genetics; D015603:Keratinocytes / Q000473:pathology; D008297:Male; D051379:Mice; D010212:Papilloma / Q000139:chemically induced / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D012878:Skin Neoplasms / Q000139:chemically induced / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D013755:Tetradecanoylphorbol Acetate / Q000633:toxicity
chemical_list: D048948:14-3-3 Proteins; D018389:Codon, Nonsense; C499130:Sfn protein, mouse; D015127:9,10-Dimethyl-1,2-benzanthracene; C045073:Cre recombinase; D019426:Integrases; D013755:Tetradecanoylphorbol Acetate
keywords: 14-3-3sigma knock-out mouse; repeated epilation/ER; skin carcinogenesis