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PMID: 17959825 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

Constitutively active Akt induces ectodermal defects and impaired bone morphogenetic protein signaling.

Molecular biology of the cell ·Vol. 19 ·No. 1 ·2008-01-00 ·Pages 137-49

Segrelles C, Moral M, Lorz C, Santos M, Lu J, Cascallana JL, Lara MF, Carbajal S, Martínez-Cruz AB, García-Escudero R, Beltran L, Segovia JC, Bravo A, DiGiovanni J, Paramio JM

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.

MeSH Terms
Animals Bone Morphogenetic Proteins/metabolism Ectoderm/abnormalities,enzymology,pathology Enzyme Activation Epidermis/enzymology,pathology Forkhead Box Protein O3 Forkhead Transcription Factors/genetics,metabolism Gene Expression Regulation, Enzymologic Hair/abnormalities,ultrastructure Homeostasis Mice Mice, Transgenic Nails, Malformed/enzymology Oligonucleotide Array Sequence Analysis Phenotype Proto-Oncogene Proteins c-akt/genetics,metabolism Signal Transduction Stem Cells/cytology,enzymology Tooth Abnormalities/enzymology
Chemicals
Bone Morphogenetic Proteins Forkhead Box Protein O3 Forkhead Transcription Factors FoxO3 protein, mouse Proto-Oncogene Proteins c-akt
Authors & Affiliations
15 authors, click to expand affiliations / ORCID
Segrelles Carmen
Molecular Oncology Unit, Division of Biomedicine, Centro de Investigaciones Energéticas, Medioambientales y Tecnológicas, E-28040 Madrid, Spain.
Moral Marta
Lorz Corina
Santos Mirentxu
Lu Jerry
Cascallana José Luis
Lara M Fernanda
Carbajal Steve
Martínez-Cruz Ana Belén
García-Escudero Ramón
Beltran Linda
Segovia José C
Bravo Ana
DiGiovanni John
Paramio Jesús M
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Article Info
Journal
Molecular biology of the cell
Abbr.
Mol Biol Cell
ISSN
1939-4586
DOI
10.1091/mbc.e07-08-0764
Published
2008-01-00
Epub
2007-00-24
Pages
137-49
Language
English
Region
United States
NLM ID
9201390
PMCID
PMC2174171
Subset
IM
Grants
NCI NIH HHS · P30 CA016672 · United States
NCI NIH HHS · R01 CA037111 · United States
NCI NIH HHS · CA16672 · United States
NCI NIH HHS · CA37111 · United States
NIEHS NIH HHS · ES00784 · United States
External Links
PubMed source DOI: 10.1091/mbc.e07-08-0764 PMC Full Text View journal details
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