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J. Biol. Chem., Vol. 280, Issue 17, 16916-16924, April 29, 2005

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Mitochondrial H₂O₂ Regulates the Angiogenic Phenotype via PTEN Oxidation^*

Kip M. Connor, Sita Subbaram, Kevin J. Regan, Kristin K. Nelson, Joseph E. Mazurkiewicz, Peter J. Bartholomew¶, Andrew E. Aplin¶, Yu-Tzu Tai||, Julio Aguirre-Ghiso**, Sonia C. Flores, and J. Andres Melendez

From the Centers for Immunology and Microbial Disease, Neuropharmacology and Neuroscience, and ^¶Cell Biology and Cancer Research, Albany Medical College, Albany, New York 12208, ^||Harvard Medical School, Dana-Farber Cancer Institute, Boston, Massachusetts 02115, ^**Structural and Cell Biology, Department of Biomedical Sciences, School of Public Health, State University of New York, Albany, Rensselaer, New York 12144, and Webb-Waring Institute for Cancer, Aging and Antioxidant Research, University of Colorado Health Sciences Center, Denver, Colorado 80262

Recent studies have demonstrated that the tumor suppressor PTEN (phosphatase and tensin homolog deleted from chromosome 10), the antagonist of the phosphosphoinositol-3-kinase (PI3K) signaling cascade, is susceptible to H₂O₂-dependent oxidative inactivation. This study describes the use of redox-engineered cell lines to identify PTEN as sensitive to oxidative inactivation by mitochondrial H₂O₂. Increases in the steady state production of mitochondrial derived H₂O₂, as a result of manganese superoxide dismutase (Sod2) overexpression, led to PTEN oxidation that was reversed by the coexpression of the H₂O₂-detoxifying enzyme catalase. The accumulation of an oxidized inactive fraction of PTEN favored the formation of phosphatidylinositol 3,4,5-triphosphate at the plasma membrane, resulting in increased activation of Akt and modulation of its downstream targets. PTEN oxidation in response to mitochondrial H₂O₂ enhanced PI3K signaling, leading to increased expression of the key regulator of angiogenesis, vascular endothelial growth factor. Overexpression of PTEN prevented the H₂O₂-dependent increase in vascular endothelial growth factor promoter activity and immunoreactive protein, whereas a mutant PTEN (G129R), lacking phosphatase activity, did not. Furthermore, mitochondrial generation of H₂O₂ by Sod2 promoted endothelial cell sprouting in a three-dimensional in vitro angiogenesis assay that was attenuated by catalase coexpression or the PI3K inhibitor LY2949002. Moreover, Sod2 overexpression resulted in increased in vivo blood vessel formation that was H₂O₂-dependent as assessed by the chicken chorioallantoic membrane assay. Our findings provide the first evidence for the involvement of mitochondrial H₂O₂ in regulating PTEN function and the angiogenic switch, indicating that Sod2 can serve as an alternative physiological source of the potent signaling molecule, H₂O₂.

Received for publication, September 16, 2004 , and in revised form, December 23, 2004.

^* This work was supported by United States Public Health Service Grants CA77068 and CA095011 (to J. A. M.) and National Institutes of Health Predoctoral Fellowship AI49822 (to K. M. C.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

To whom correspondence should be addressed: Center for Immunology and Microbial Disease, Albany Medical College, MC 151, 47 New Scotland Ave., Albany, NY 12208. Tel.: 518-262-8791; Fax: 518-262-6161; E-mail: melenda{at}mail.amc.edu.

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