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Carcinogenesis Advance Access published online on August 3, 2007
Carcinogenesis, doi:10.1093/carcin/bgm154
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© The Author 2007. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

MAP17 inhibits Myc-induced apoptosis through PI3K/AKT pathway activation

Maria Valle Guijarro, Wolfgang Link, Aránzazu Rosado, Juan F. M. Leal and Amancio Carnero*

Experimental Therapeutics Programme, Centro Nacional de Investigaciones Oncológicas (CNIO), Madrid, Spain

* Correspondence to: Amancio Carnero, Experimental Therapeutics Programme, Centro Nacional de Investigaciones Oncológicas (CNIO), Melchor Fernández Almagro, 3, 28029, Madrid, Spain, Phone: +34 91 732 8021, Fax: +34 91 732 8051, e-mail: acarnero{at}cnio.es

MAP17 is a nonglycosylated membrane-associated protein that has been shown to be overexpressed in human carcinomas, suggesting a possible role of this protein in tumorigenesis. However, very little is known about the molecular mechanism mediating the possible tumor promoting properties of MAP17. To analyze the effect of MAP17 on cell survival we used Rat1 fibroblasts model where Myc overexpression promotes apoptosis in low serum conditions. In the present work we report that overexpression of MAP17 protects Rat1a fibroblasts from Myc-induced apoptosis through ROS–mediated activation of the PI3K/AKT signaling pathway. MAP17-mediated survival was associated with absence of Bax translocation to the mitochondria and reduced caspase3 activation. We show that a fraction of PTEN undergoes oxidation in MAP17-overexpressing cells. Furthermore, activation of AKT by MAP17 as measured by Thr308 phosphorylation was independent of PI3K activity. Importantly, modulation of ROS by antioxidant treatment prevented activation of AKT, restoring the level of apoptosis in serum starved Rat1/c-Myc fibroblasts. Finally, overexpression of a dominant negative mutant of AKT in MAP17-expressing clones makes them sensitive to serum depletion. Our data indicates that MAP17 protein activates AKT through ROS and this is determinant to confer resistance to Myc-induced apoptosis in the absence of serum.

Received April 25, 2007; revised June 4, 2007; accepted June 26, 2007.


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