title: Constitutively active Akt induces ectodermal defects and impaired bone morphogenetic protein signaling.
abstract: Aberrant activation of the Akt pathway has been implicated in several human pathologies including cancer. However, current knowledge on the involvement of Akt signaling in development is limited. Previous data have suggested that Akt-mediated signaling may be an essential mediator of epidermal homeostasis through cell autonomous and noncell autonomous mechanisms. Here we report the developmental consequences of deregulated Akt activity in the basal layer of stratified epithelia, mediated by the expression of a constitutively active Akt1 (myrAkt) in transgenic mice. Contrary to mice overexpressing wild-type Akt1 (Akt(wt)), these myrAkt mice display, in a dose-dependent manner, altered development of ectodermally derived organs such as hair, teeth, nails, and epidermal glands. To identify the possible molecular mechanisms underlying these alterations, gene profiling approaches were used. We demonstrate that constitutive Akt activity disturbs the bone morphogenetic protein-dependent signaling pathway. In addition, these mice also display alterations in adult epidermal stem cells. Collectively, we show that epithelial tissue development and homeostasis is dependent on proper regulation of Akt expression and activity.
authors.affiliation: Molecular Oncology Unit, Division of Biomedicine, Centro de Investigaciones Energéticas, Medioambientales y Tecnológicas, E-28040 Madrid, Spain.
authors.forename: Carmen
authors.initials: C
authors.lastname: Segrelles
authors.forename: Marta
authors.initials: M
authors.lastname: Moral
authors.forename: Corina
authors.initials: C
authors.lastname: Lorz
authors.forename: Mirentxu
authors.initials: M
authors.lastname: Santos
authors.forename: Jerry
authors.initials: J
authors.lastname: Lu
authors.forename: José Luis
authors.initials: JL
authors.lastname: Cascallana
authors.forename: M Fernanda
authors.initials: MF
authors.lastname: Lara
authors.forename: Steve
authors.initials: S
authors.lastname: Carbajal
authors.forename: Ana Belén
authors.initials: AB
authors.lastname: Martínez-Cruz
authors.forename: Ramón
authors.initials: R
authors.lastname: García-Escudero
authors.forename: Linda
authors.initials: L
authors.lastname: Beltran
authors.forename: José C
authors.initials: JC
authors.lastname: Segovia
authors.forename: Ana
authors.initials: A
authors.lastname: Bravo
authors.forename: John
authors.initials: J
authors.lastname: DiGiovanni
authors.forename: Jesús M
authors.initials: JM
authors.lastname: Paramio
mesh_terms: D000818:Animals; D019485:Bone Morphogenetic Proteins / Q000378:metabolism*; D004475:Ectoderm / Q000002:abnormalities* / Q000201:enzymology* / Q000473:pathology; D004789:Enzyme Activation; D004817:Epidermis / Q000201:enzymology / Q000473:pathology; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000378:metabolism; D015971:Gene Expression Regulation, Enzymologic; D006197:Hair / Q000002:abnormalities / Q000648:ultrastructure; D006706:Homeostasis; D051379:Mice; D008822:Mice, Transgenic; D009264:Nails, Malformed / Q000201:enzymology; D020411:Oligonucleotide Array Sequence Analysis; D010641:Phenotype; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D013234:Stem Cells / Q000166:cytology / Q000201:enzymology; D014071:Tooth Abnormalities / Q000201:enzymology
chemical_list: D019485:Bone Morphogenetic Proteins; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors; C474033:FoxO3 protein, mouse; D051057:Proto-Oncogene Proteins c-akt