Constitutively active calcineurin mediates delayed neuronal death through Fas‐ligand expression via activation of NFAT and FKHR transcriptional activities in mouse brain ischemia
Constitutively active calcineurin mediates delayed neuronal death through Fas‐ligand expression via activation of NFAT and FKHR transcriptional activities in mouse brain ischemia
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DOI：
10.1111/j.1471-4159.2007.04600.x
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发表时间：
2007-09
影响因子：
4.7
通讯作者：
N. Shioda;F. Han;S. Moriguchi;K. Fukunaga
中科院分区：
文献类型：
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作者：
N. Shioda;F. Han;S. Moriguchi;K. Fukunaga
我们最近证明，脑缺血后，钙蛋白酶介导的有限蛋白水解产生了钙调神经磷酸酶（CaN）的组成活性形式。脑缺血后，calpain诱导的CaN激活通过活化T细胞核因子（NFAT）向核的易位介导延迟神经元死亡。我们之前也证明了叉头转录因子和蛋白激酶B （Akt）底物叉头在沙鼠海马中的激活，通过Fas配体的表达介导了缺血诱导的神经元死亡。FKHR的激活是通过Akt活性降低和伴随的未定义磷酸酶介导的去磷酸化发生的。在这项研究中，我们发现磷酸化的FKHR的Ser - 256被组成性活性CaN去磷酸化，进而FKHR与CaN形成复合物，在脑缺血后转运到核中。在NFAT和FKHR的核易位后，NFAT和FKHR都通过结合其启动子区域刺激Fas -配体的表达。与FKHR去磷酸化激活Fas -配体启动子一致，缺血/再灌注后2天Fas -配体表达增加，并且用CaN抑制剂FK506抑制其表达。这些结果表明，FKHR是CaN的下游靶点，组成型活性CaN在脑缺血中通过上调NFAT和FKHR转录活性，通过Fas配体表达介导延迟神经元死亡。
We recently demonstrated that a constitutively active form of calcineurin (CaN) is generated by calpain‐mediated limited proteolysis following brain ischemia. The calpain‐induced CaN activation mediated delayed neuronal death through translocation of nuclear factor of activated T‐cells (NFAT) into nuclei after brain ischemia. We also previously demonstrated that activation of forkhead in rhabdomyosarcoma (FKHR), a forkhead transcription factor and substrate of protein kinase‐B (Akt), mediated ischemia‐induced neuronal death through Fas‐ligand expression in gerbil hippocampus. FKHR activation occurred through decreased Akt activity and concomitant dephosphorylation mediated by undefined phosphatases. In this study, we show that phosphorylated Ser‐256 of FKHR is dephosphorylated by constitutively active CaN and that in turn FKHR forms a complex with CaN that is translocated into nuclei after brain ischemia. After nuclear translocation of NFAT and FKHR, both NFAT and FKHR stimulated expression of Fas‐ligand by binding to its promoter region. Consistent with activation of the Fas‐ligand promoter by FKHR dephosphorylation, Fas‐ligand expression increased 2 days after ischemia/reperfusion, and treatment with the CaN inhibitor FK506 inhibited that expression. These results suggest that FKHR is a downstream target of CaN and that constitutively active CaN mediates delayed neuronal death through Fas‐ligand expression via up‐regulation of both NFAT and FKHR transcriptional activity in brain ischemia.