title: 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.
authors.affiliation: James Graham Brown Cancer Center, University of Louisville School of Medicine, 301 East Muhammad Ali Boulevard, Louisville, KY 40202, USA. q.li@louisville.edu
authors.forename: Qiutang
authors.initials: Q
authors.lastname: Li
authors.forename: Sumitha A T
authors.initials: SA
authors.lastname: Sambandam
authors.forename: Helen J
authors.initials: HJ
authors.lastname: Lu
authors.forename: Alexander
authors.initials: A
authors.lastname: Thomson
authors.forename: Sung-hye
authors.initials: SH
authors.lastname: Kim
authors.forename: Huayi
authors.initials: H
authors.lastname: Lu
authors.forename: Ying
authors.initials: Y
authors.lastname: Xin
authors.forename: Qingxian
authors.initials: Q
authors.lastname: Lu
mesh_terms: D048948:14-3-3 Proteins / Q000502:physiology*; D015127:9,10-Dimethyl-1,2-benzanthracene / Q000633:toxicity; D000818:Animals; D015153:Blotting, Western; D002273:Carcinogens / Q000633:toxicity; D002454:Cell Differentiation; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic; D020868:Gene Silencing; D006706:Homeostasis; D015603:Keratinocytes / Q000166:cytology; D051379:Mice; D008817:Mice, Mutant Strains; D010750:Phosphoproteins / Q000235:genetics / Q000502:physiology*; D016133:Polymerase Chain Reaction; D012878:Skin Neoplasms / Q000139:chemically induced / Q000473:pathology / Q000503:physiopathology*; D013755:Tetradecanoylphorbol Acetate / Q000633:toxicity; D015534:Trans-Activators / Q000235:genetics / Q000502:physiology*
chemical_list: D048948:14-3-3 Proteins; D002273:Carcinogens; D010750:Phosphoproteins; C499130:Sfn protein, mouse; D015534:Trans-Activators; C486419:Trp63 protein, mouse; D015127:9,10-Dimethyl-1,2-benzanthracene; D013755:Tetradecanoylphorbol Acetate