Phosphatidylinositol 3-Akt-kinase-dependent phosphorylation of p21Waf1/Cip1 as a novel mechanism of neuroprotection by glucocorticoids
Phosphatidylinositol 3-Akt-kinase-dependent phosphorylation of p21Waf1/Cip1 as a novel mechanism of neuroprotection by glucocorticoids
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DOI：
10.1523/jneurosci.5110-06.2007
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发表时间：
2007-04-25
影响因子：
5.3
通讯作者：
Hoertnagl, Heide
中科院分区：
文献类型：
--
作者：
Harms, Christoph;Albrecht, Katharina;Hoertnagl, Heide
糖皮质激素在细胞凋亡调节中的作用仍然不一致。在这里，我们证明，皮质酮保护神经元凋亡的机制涉及细胞周期蛋白依赖性激酶抑制剂p21（Waf 1/Cip 1）。在初级皮质神经元中，皮质酮导致剂量和Akt激酶依赖性上调，并在Thr 145处增强磷酸化和细胞质外观p21（Waf 1/Cip 1）。神经元暴露于神经毒素乙基胆碱aziridinium（AF 64 A）导致caspase-3活化和p21（Waf 1/Cip 1）的急剧丧失，从而导致神经元凋亡。AF 64 A的这些作用可通过用皮质酮预处理来逆转。皮质酮介导的p21（Waf 1/Cip 1）上调和神经保护作用完全被糖皮质激素和盐皮质激素受体拮抗剂以及PI 3-和Akt-激酶抑制剂消除。生殖细胞和体细胞诱导的p21（Waf 1/Cip 1）缺陷消除皮质酮的神经保护作用，而p21（Waf 1/Cip 1）的过度表达足以保护神经元免于凋亡。我们确定p21（Waf 1/Cip 1）作为一种新的有丝分裂后神经元的抗凋亡因子，并暗示p21（Waf 1/Cip 1）作为高剂量糖皮质激素神经保护的分子靶点。
The role of glucocorticoids in the regulation of apoptosis remains incongruous. Here, we demonstrate that corticosterone protects neurons from apoptosis by a mechanism involving the cyclin-dependent kinase inhibitor p21(Waf1/Cip1). In primary cortical neurons, corticosterone leads to a dose- and Akt-kinase-dependent upregulation with enhanced phosphorylation and cytoplasmic appearance of p21(Waf1/Cip1) at Thr 145. Exposure of neurons to the neurotoxin ethylcholine aziridinium (AF64A) results in activation of caspase-3 and a dramatic loss of p21(Waf1/Cip1) preceding apoptosis in neurons. These effects of AF64A are reversed by pretreatment with corticosterone. Corticosterone-mediated upregulation of p21(Waf1/Cip1) and neuroprotection are completely abolished by glucocorticoid and mineralocorticoid receptor antagonists as well as inhibitors of PI3- and Akt-kinase. Both germline and somatically induced p21(Waf1/Cip1) deficiency abrogate the neuroprotection by corticosterone, whereas overexpression of p21(Waf1/Cip1) suffices to protect neurons from apoptosis. We identify p21(Waf1/Cip1) as a novel antiapoptotic factor for postmitotic neurons and implicate p21(Waf1/Cip1) as the molecular target of neuroprotection by high-dose glucocorticoids.