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Carcinogenesis Advance Access published online on March 6, 2007
Carcinogenesis, doi:10.1093/carcin/bgm052
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© The Author 2007. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

PTEN, MORE THAN THE AKT PATHWAY

Carmen Blanco-Aparicio, Oliver Renner, Juan F.M. Leal and Amancio Carnero*

Experimental Therapeutics Programme, Spanish National Cancer Centre (CNIO), C/Melchor Fernandez Almagro 3, 28029 Madrid, Spain

* Corresponding author: Amancio Carnero, Experimental Therapeutics Programme, Spanish National Cancer Centre (CNIO), C/Melchor Fernandez Almagro 3, 28029 Madrid, Spain (E-mail: acarnero{at}cnio.es)

PTEN/PI3K/AKT constitute an important pathway regulating the signalling of multiple biological process such as apoptosis, metabolism, cell proliferation and cell growth. PTEN is a dual protein/lipid phosphatase which its main substrate phosphatidyl-inositol,3,4,5 triphosphate (PIP3), is the product of PI3K. Increase in PIP3 recruits AKT to the membrane where is activated by other kinases also dependent on PIP3. Many components of this pathway have been described as causal forces in cancer. PTEN activity is lost by mutations, deletions or promoter methylation silencing at high frequency in many primary and metastatic human cancers. Germline mutations of PTEN are found in several familial cancer predisposition syndromes. Recently, many activating mutations in the PI3KCA gene (coding for the p110{alpha} catalytic subunit of PI3K) have been described in human tumors. Activation of PI3K and AKT are reported to occur in breast, ovarian, pancreatic, esophageal and other cancers. Genetically modified mice confirm these PTEN activities. Tissue specific deletions of PTEN usually provoke cancer. Moreover, an absence of PTEN cooperates with an absence of p53 to promote cancer. However, we have observed very different results with the expression of activated versions of AKT in several tissues. Activated AKT transgenic lines do not develop tumors in breast nor prostate tissues and do not cooperate with an absence of p53. This data suggests an AKT-independent mechanism contributes to PTEN tumorigenesis. Croses with transgenic mice expressing possible PTEN targets indicates that neither cyclinD1 nor p53 are these AKT-independent targets. However, AKT is more than a passive bridge towards PTEN tumorigenesis, since its expression not only allows, but also enforces and accelerates the tumorigenic process in combination with other oncogenes

Received December 29, 2006; revised February 28, 2007; accepted March 1, 2007.


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