1. ¹Department of Cell and Molecular Biology, CIEMAT, Madrid, Spain
2. ²Department of Pathology, Hospital '12 de Octubre', Madrid, Spain

Correspondence: Dr JM Paramio, Department of Cell and Molecular Biology, CIEMAT (ed. 7), Ave. Complutense 22, Madrid E-28040, Spain. E-mail: jesusm.paramio@ciemat.es

⁵These two authors contributed equally to this work.

³Current address: Cancer Research Center and Institute of Cell and Molecular Biology of Cancer, CSIC-University of Salamanca, P Universidad de Coimbra s/n, Salamanca, Spain.

⁴Current address: Genomics and Pharmacoproteomics Program, FVIB-CIPF, Camino de las Moreras, Valencia, Spain.

Received 20 January 2005; Revised 5 July 2005; Accepted 23 August 2005; Published online 17 October 2005.

Abstract

The PI3K/PTEN/Akt signaling pathway has emerged in recent years as a main player in human cancers, increasing proliferation and decreasing apoptosis of transformed cells, and thus becoming a potential target for therapeutic intervention. Our previous data have demonstrated that Akt-mediated signaling is of a key relevance in the mouse skin carcinogenesis system, one of the best-known models of experimental carcinogenesis. Here, we investigated the involvement of several pathways as mediators of Akt-induced increased proliferation and tumorigenesis in keratinocytes. Tumors produced by subcutaneous injection of Akt-transformed keratinocytes showed increased Foxo3a phosphorylation, but no major alterations in p21^Cip1/WAF1, p27^Kip1 or mdm2 expression and/or localization. In contrast, we found increased expression and nuclear localization of Np63, -catenin and Lef1. Concomitantly, we also found increased expression of c-myc and CycD1, targets of the -catenin/Tcf pathway. Such increase is associated with increased phosphorylation and stabilization of c-myc protein as well as increased translation of c-myc and CycD1 due to mTOR activation. Using immunohistochemistry approaches in samples of oral dysplasias and human head and neck squamous cell carcinomas, we confirmed that increased Akt activation significantly correlates with increased Np63 and CycD expression, c-myc phosphorylation and nuclear accumulation of -catenin. Collectively, these results demonstrate that Akt is able to transform keratinocytes by specific mechanisms involving transcriptional and post-transcriptional processes.