title: 14-3-3σ regulates keratinocyte proliferation and differentiation by modulating Yap1 cellular localization.
abstract: The homozygous repeated epilation (Er/Er) mouse mutant of the gene encoding 14-3-3σ displays an epidermal phenotype characterized by hyperproliferative keratinocytes and undifferentiated epidermis. Heterozygous Er/+ mice develop spontaneous skin tumors and are highly sensitive to tumor-promoting 7,12-dimethylbenzanthracene/12-O-tetradecanoyl-phorbol-13-acetate induction. The molecular mechanisms underlying 14-3-3σ regulation of epidermal proliferation, differentiation, and tumor formation have not been well elucidated. In this study, we found that Er/Er keratinocytes failed to sequester Yap1 in the cytoplasm, leading to its nuclear localization during epidermal development in vivo and under differentiation-inducing culture conditions in vitro. In addition, enhanced Yap1 nuclear localization was also evident in 7,12-dimethylbenzanthracene/12-O-tetradecanoyl-phorbol-13-acetate-induced tumors from Er/+ skin. Furthermore, short hairpin RNA (shRNA) knockdown of Yap1 expression in Er/Er keratinocytes inhibited their proliferation, suggesting that YAP1 functions as a downstream effector of 14-3-3σ controlling epidermal proliferation. We then demonstrated that keratinocytes express all seven 14-3-3 protein isoforms, some of which form heterodimers with 14-3-3σ, either full-length wild type (WT) or the mutant form found in Er/Er mice. However, Er 14-3-3σ does not interact with Yap1, as demonstrated by coimmunoprecipitation. We conclude that Er 14-3-3σ disrupts the interaction between 14-3-3 and Yap1, and thus fails to block Yap1 nuclear transcriptional function, causing continued progenitor expansion and inhibition of differentiation in the Er/Er epidermis.
authors: Departments of Ophthalmology and Visual Sciences, James Graham Brown Cancer Center, University of Louisville School of Medicine, Louisville, Kentucky, USA.
authors: Sumitha A T
authors: SAT
authors: Sambandam
authors: Departments of Ophthalmology and Visual Sciences, James Graham Brown Cancer Center, University of Louisville School of Medicine, Louisville, Kentucky, USA.
authors: Ramesh B
authors: RB
authors: Kasetti
authors: Department of Interventional Radiology, Shanghai 10th People's Hospital, Shanghai Key Laboratory of Signaling and Disease Research, School of Life Science and Technology, Tongji University, Shanghai, China.
authors: Lei
authors: L
authors: Xue
authors: Departments of Ophthalmology and Visual Sciences, James Graham Brown Cancer Center, University of Louisville School of Medicine, Louisville, Kentucky, USA.
authors: Douglas C
authors: DC
authors: Dean
authors: Departments of Ophthalmology and Visual Sciences, James Graham Brown Cancer Center, University of Louisville School of Medicine, Louisville, Kentucky, USA.
authors: Qingxian
authors: Q
authors: Lu
authors: Departments of Ophthalmology and Visual Sciences, James Graham Brown Cancer Center, University of Louisville School of Medicine, Louisville, Kentucky, USA. Electronic address: q.li@louisville.edu.
authors: Qiutang
authors: Q
authors: Li
mesh_terms: D048948:14-3-3 Proteins / Q000378:metabolism*; D015127:9,10-Dimethyl-1,2-benzanthracene; D021581:Active Transport, Cell Nucleus; D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism*; D000818:Animals; D018797:Cell Cycle Proteins; D002454:Cell Differentiation; D002467:Cell Nucleus / Q000378:metabolism; D049109:Cell Proliferation; D003593:Cytoplasm / Q000378:metabolism; D004817:Epidermis / Q000378:metabolism; D005786:Gene Expression Regulation; D006579:Heterozygote; D006720:Homozygote; D015603:Keratinocytes / Q000166:cytology / Q000378:metabolism*; D016086:Lentivirus / Q000235:genetics; D051379:Mice; D010641:Phenotype; D010750:Phosphoproteins / Q000378:metabolism*; D020033:Protein Isoforms / Q000378:metabolism; D034741:RNA, Small Interfering / Q000378:metabolism; D012867:Skin / Q000378:metabolism; D013755:Tetradecanoylphorbol Acetate; D000091102:YAP-Signaling Proteins
chemical_list: D048948:14-3-3 Proteins; D048868:Adaptor Proteins, Signal Transducing; D018797:Cell Cycle Proteins; D010750:Phosphoproteins; D020033:Protein Isoforms; D034741:RNA, Small Interfering; C499130:Sfn protein, mouse; D000091102:YAP-Signaling Proteins; C486223:Yap1 protein, mouse; D015127:9,10-Dimethyl-1,2-benzanthracene; D013755:Tetradecanoylphorbol Acetate