Involvement of the PTEN-AKT-FOXO3a pathway in neuronal apoptosis in developing rat brain after hypoxia-ischemia.
Involvement of the PTEN-AKT-FOXO3a pathway in neuronal apoptosis in developing rat brain after hypoxia-ischemia.
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PTEN-AKT-FOXO3a 通路参与发育中大鼠大脑缺氧缺血后神经元凋亡。
DOI：
10.1038/jcbfm.2009.102
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发表时间：
2009-12
期刊：
影响因子：
--
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中科院分区：
文献类型：
--
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10号染色体上的磷酸酶和张力素同源物缺失（PTEN）磷酸酶的促凋亡功能与其拮抗磷脂酰肌醇-3-激酶- akt信号通路的能力有关。先前的研究表明叉头转录因子（FOXO3a）是pten介导的肿瘤抑制因子的关键效应因子。然而，PTEN-Akt - FOXO3a通路是否参与发育大鼠脑缺氧缺血（hypoxia ischemia， HI）后神经元凋亡尚不清楚。在这项研究中，我们用出生后10天的大鼠建立了HI模型。免疫组织化学和western blot检测总PTEN、磷酸化PTEN、Akt、FOXO3a及其靶基因Bim的表达。我们发现PTEN的去磷酸化伴随着Akt和FOXO3a的去磷酸化，从而诱导FOXO3a易位到细胞核中，上调了Bim的表达。此外，我们发现双氧钒抑制PTEN显著增加了Akt和FOXO3a的磷酸化，减少了FOXO3a的核易位，抑制了HI后Bim的表达。此外，PTEN抑制引起的Bim下调可减轻发育中的大鼠脑细胞凋亡。我们的研究结果表明，PTEN-Akt-FOXO3a通路参与了HI后新生大鼠脑神经元凋亡。靶向PTEN的药物可能为拯救HI脑损伤的神经元提供了希望。
The proapoptotic function of phosphatase and tensin homolog deleted on chromosome 10 (PTEN) phosphatase has been linked to its capacity to antagonize the phosphatidylinositol-3-kinase–Akt signaling pathway. Previous studies have shown that the Forkhead transcriptional factor (FOXO3a) is a critical effector of the PTEN-mediated tumor suppressor. However, whether the PTEN–Akt– FOXO3a pathway is involved in neuronal apoptosis in developing rat brain after hypoxia–ischemia (HI) is unclear. In this study, we generated an HI model using postnatal day 10 rats. Immunohistochemistry and western blot were used to detect the expression of total and phosphorylated PTEN, Akt, and FOXO3a, as well as its target gene Bim. We found that dephosphorylation of PTEN was accompanied by dephosphorylation of Akt and FOXO3a, which induced FOXO3a translocation into the nucleus and upregulated the expression of Bim. Furthermore, we found that PTEN inhibition by bisperoxovanadium significantly increased the phosphorylation of Akt and FOXO3a, decreased the nuclear translocation of FOXO3a, and inhibited Bim expression after HI. Moreover, the downregulation of Bim caused by PTEN inhibition attenuated cellular apoptosis in developing rat brain. Our findings suggest that the PTEN–Akt–FOXO3a pathway is involved in neuronal apoptosis in neonatal rat brain after HI. Agents targeting PTEN may offer a promise to rescue neurons from HI brain damage.
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