MAP17 inhibits Myc-induced apoptosis through PI3K/AKT pathway activation.
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.
Experimental Therapeutics Programme, Centro Nacional de Investigaciones Oncológicas, Madrid 28029, Spain.
Maria V
MV
Guijarro
Wolfgang
W
Link
Aránzazu
A
Rosado
Juan F M
JF
Leal
Amancio
A
Carnero
D017209:Apoptosis / Q000502:physiology*; D053148:Caspase 3 / Q000378:metabolism; D002460:Cell Line; D002470:Cell Survival; D016895:Culture Media, Serum-Free; D004789:Enzyme Activation; D005347:Fibroblasts / Q000378:metabolism; D006801:Humans; D008565:Membrane Proteins / Q000502:physiology*; D008928:Mitochondria / Q000378:metabolism; D051059:PTEN Phosphohydrolase / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000502:physiology*; D010766:Phosphorylation; D021381:Protein Transport; D051057:Proto-Oncogene Proteins c-akt / Q000502:physiology*; D016271:Proto-Oncogene Proteins c-myc / Q000502:physiology*; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology; D051028:bcl-2-Associated X Protein / Q000378:metabolism
D016895:Culture Media, Serum-Free; C489427:MYC protein, human; D008565:Membrane Proteins; C509768:PDZK1IP1 protein, human; D016271:Proto-Oncogene Proteins c-myc; D017382:Reactive Oxygen Species; D051028:bcl-2-Associated X Protein; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human; D053148:Caspase 3