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Carcinogenesis Advance Access originally published online on August 3, 2007
Carcinogenesis 2007 28(12):2443-2450; 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 V. Guijarro, Wolfgang Link, Aránzazu Rosado, Juan F.M. Leal and Amancio Carnero*

Experimental Therapeutics Programme, Centro Nacional de Investigaciones Oncológicas, Madrid 28029, Spain

* To whom correspondence should be addressed. Tel: +34 91 732 8021; Fax: +34 91 732 8051; Email: acarnero{at}cnio.es

MAP17 is a non-glycosylated membrane-associated protein that has been shown to be over-expressed 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 over-expression promotes apoptosis in low serum conditions. In the present work, we report that over-expression of MAP17 protects Rat1a fibroblasts from Myc-induced apoptosis through reactive oxygen species (ROS)-mediated activation of the PI3K/AKT signaling pathway. MAP17-mediated survival was associated with absence of Bax translocation to the mitochondria and reduced caspase-3 activation. We show that a fraction of PTEN undergoes oxidation in MAP17-over-expressing 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, over-expression of a dominant-negative mutant of AKT in MAP17-expressing clones makes them sensitive to serum depletion. Our data indicate that MAP17 protein activates AKT through ROS and this is determinant to confer resistance to Myc-induced apoptosis in the absence of serum.

Abbreviations: DMEM, Dulbecco's modified Eagle's medium; FBS, fetal bovine serum; FAC, flow cytometry; GSH, glutathione; NAC, N-acetylcysteine; PBS, phosphate-buffered saline; sROS, reactive oxygen species

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


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