Mitochondrial H2O2 regulates the angiogenic phenotype via PTEN oxidation
Mitochondrial H2O2 regulates the angiogenic phenotype via PTEN oxidation
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DOI：
10.1074/jbc.m410690200
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发表时间：
2005-04-29
影响因子：
4.8
通讯作者：
Melendez, JA
中科院分区：
文献类型：
--
作者：
Connor, KM;Subbaram, S;Melendez, JA
最近的研究表明，肿瘤抑制基因PTEN(10号染色体缺失的磷酸酶和张力蛋白同源物)是磷酸肌醇-3-激酶(PI3K)信号级联的拮抗剂，对依赖H_2O_2的氧化失活非常敏感。这项研究描述了使用氧化还原工程细胞系来鉴定PTEN对线粒体过氧化氢氧化失活敏感。由于锰超氧化物歧化酶(Sod2)的过度表达，线粒体来源的过氧化氢的稳态产量增加，导致PTEN氧化，而这种氧化被过氧化氢解毒酶过氧化氢酶的共表达逆转。PTEN氧化失活部分的积累有利于质膜上磷脂酰肌醇3，4，5-三磷酸的形成，从而增加Akt的活性并调节其下游靶点。线粒体过氧化氢氧化PTEN增强了PI3K信号，导致血管生成的关键调节因子血管内皮生长因子的表达增加。PTEN的过表达可阻止依赖H_2O_2的血管内皮生长因子启动子活性和免疫反应蛋白的增加，而缺乏磷酸酶活性的突变体PTEN(G129R)则不能。此外，在三维体外血管生成实验中，Sod2产生的线粒体过氧化氢促进了内皮细胞的萌发，而过氧化氢酶共表达或PI3K抑制剂LY2949002抑制了这一实验。此外，根据鸡绒毛膜尿囊膜实验的评估，Sod2过表达导致体内血管形成增加，这是过氧化氢依赖的。我们的发现为线粒体过氧化氢参与调节PTEN功能和血管生成开关提供了第一个证据，表明Sod2可以作为强大的信号分子过氧化氢的替代生理来源。
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.