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Submitted on September 12, 2003
Accepted on November 3, 2003
1 Instituto de Biomedicina de Valencia (IBV-CSIC) Jaime Roig 11, E-46010 Valencia (Spain); Project on Cell and Molecular Biology and Gene Therapy, CIEMAT. Av. Complutense 22, E-28040 Madrid (Spain); Department of Animal Pathology. Faculty of Veterinary Science, University of Santiago de Compostela, E-27002 Lugo (Spain); These two authors contributed equally to this work
* To whom correspondence should be addressed. E-mail: paloma.perez{at}ibv.csic.es.
The skin-targeted overexpression of the glucocorticoid receptor (GR) in transgenic mice dramatically impairs the inflammatory responses to tumor promoter agents and suppresses skin tumor development. The anti-inflammatory, rapid effects of corticosteroids are partially exerted through interference of GR with the phosphatidylinositol 3-kinase (PI3K)/Akt signaling pathway in several tissues, a highly relevant pathway in the mouse skin tumor progression process. In this work, we aimed to elucidate whether a cross-talk mechanism between GR and PI3K/Akt occurred in intact skin as well as the biological relevance of this interaction during skin tumorigenesis. We report that, in transgenic mice overexpressing the receptor, GR physically associated with p85
/PI3K in skin, resulting in decreased Akt and I
B kinase (IKK) activity. GR activation by dexamethasone (Dex) in normal mouse skin also decreased Akt activity within minutes, whereas cotreatment with the GR antagonist RU486 abolished Dex action. Indeed, GR exerted a non-genomic action since keratinocyte transfection with a transcriptionally defective receptor mutant still decreased PI3K and Akt activity. Moreover, GR coexpression greatly reduced the accelerated growth of malignant tumors and increased Akt activity induced by Akt-transfected keratinocytes, as shown by in vivo tumorigenic assays. Overall, our data strongly indicate that GR/PI3K-Akt cross-talk constitutes a major mechanism underlying the anti-tumor effect of glucocorticoids in skin.
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