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Papers In Press, published online ahead of print January 9, 2002
Medicine, Duke University Medical Center, Durham, NC 27710
Corresponding Author: cdkontos{at}duke.edu
Phosphatidylinositol 3-kinase (PI3K) is activated by vascular endothelial growth factor (VEGF), and many of the angiogenic cellular responses of VEGF are regulated by the lipid products of PI3K. The tumor suppressor PTEN has been shown to down-regulate PI3K signaling, yet the effects of PTEN on VEGF-mediated signaling and angiogenesis are unknown. Inhibition of endogenous PTEN in cultured endothelial cells by adenovirus-mediated overexpression of a dominant negative PTEN mutant (PTEN-C/S) enhanced VEGF-mediated Akt phosphorylation, and this effect correlated with decreases in caspase-3 cleavage, caspase-3 activity, and DNA degradation following induction of apoptosis with TNFa. Overexpression of PTEN-C/S also enhanced VEGF-mediated endothelial cell proliferation and migration. In contrast, overexpression of wild-type (WT) PTEN inhibited the anti-apoptotic, proliferative, and chemotactic effects of VEGF. Moreover, PTEN-C/S increased the length of vascular sprouts in the rat aortic ring assay and modulated VEGF-mediated tube formation in an in vitro angiogenesis assay, whereas PTEN-WT inhibited these effects. Taken together, these findings demonstrate that PTEN potently modulates VEGF-mediated signaling and function and that PTEN is a viable target in therapeutic approaches to promote or inhibit angiogenesis.
J. Biol. Chem, 10.1074/jbc.M110219200
Submitted on October 24, 2001
Revised on December 18, 2001
Accepted on January 9, 2002
PTEN modulates vascular endothelial growth factor-mediated signaling and angiogenic effects
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