title: Impaired keratinocyte proliferative and clonogenic potential in transgenic mice overexpressing 14-3-3σ in the epidermis.
abstract: The 14-3-3 protein family controls diverse biochemical processes through interaction with phosphorylated consensus sequences in protein targets. Its epithelial specific member, 14-3-3σ, also known as stratifin, is highly expressed in differentiated keratinocytes, and in vitro evidence indicates that 14-3-3σ downregulation leads to keratinocyte immortalization. To define the role of 14-3-3σ in skin homeostasis in vivo, we generated transgenic mice overexpressing 14-3-3σ in proliferating keratinocytes of the epidermis and hair follicle. Transgenic animals show decreased epidermal thickness and hair follicle density associated with reduced number of proliferating keratinocytes and decreased levels of keratins 14, 5, and 15. Primary keratinocytes isolated from transgenic mice manifest reduced proliferation and migration. Moreover, clonogenicity assessment and label-retaining analysis reveal a reduction in keratinocyte progenitor cell number in transgenic mice. Response to IGF-1 is strongly impaired in cultured transgenic keratinocytes compared with wild-type cells. Consistently, activation of phosphoinositol 3-kinase (PI3K), AKT, and Rac1, all IGF-1 downstream mediators, is reduced. Our results demonstrate that 14-3-3σ controls the in vivo epidermal proliferation-differentiation switch by reducing proliferative potential and forcing keratinocytes to exit the cell cycle, and that this effect associates with inhibition of the IGF-1 pathway.
authors.affiliation: Laboratory of Molecular and Cell Biology, IDI-IRCCS, Rome, Italy.
authors.forename: Francesca
authors.initials: F
authors.lastname: Cianfarani
authors.forename: Silvia
authors.initials: S
authors.lastname: Bernardini
authors.forename: Naomi
authors.initials: N
authors.lastname: De Luca
authors.forename: Elena
authors.initials: E
authors.lastname: Dellambra
authors.forename: Laura
authors.initials: L
authors.lastname: Tatangelo
authors.forename: Cecilia
authors.initials: C
authors.lastname: Tiveron
authors.forename: Carien M
authors.initials: CM
authors.lastname: Niessen
authors.forename: Giovanna
authors.initials: G
authors.lastname: Zambruno
authors.forename: Daniele
authors.initials: D
authors.lastname: Castiglia
authors.forename: Teresa
authors.initials: T
authors.lastname: Odorisio
mesh_terms: D048948:14-3-3 Proteins / Q000235:genetics* / Q000378:metabolism*; D000818:Animals; D014408:Biomarkers, Tumor / Q000235:genetics* / Q000378:metabolism*; D002455:Cell Division / Q000502:physiology; D002478:Cells, Cultured; D002999:Clone Cells / Q000166:cytology / Q000502:physiology; D000078404:Epidermal Cells; D004817:Epidermis / Q000502:physiology*; D005092:Exonucleases / Q000235:genetics* / Q000378:metabolism*; D005095:Exoribonucleases; D018859:Hair Follicle / Q000166:cytology / Q000502:physiology*; D007334:Insulin-Like Growth Factor I / Q000378:metabolism; D015603:Keratinocytes / Q000166:cytology / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D008822:Mice, Transgenic; D010641:Phenotype; D011401:Promoter Regions, Genetic / Q000502:physiology; D015398:Signal Transduction / Q000502:physiology; D013234:Stem Cells / Q000166:cytology / Q000502:physiology
chemical_list: D048948:14-3-3 Proteins; D014408:Biomarkers, Tumor; D007334:Insulin-Like Growth Factor I; D005092:Exonucleases; D005095:Exoribonucleases; C413442:SFN protein, human