Thyroid-hormone-dependent activation of the phosphoinositide 3-kinase/Akt cascade requires Src and enhances neuronal survival
Thyroid-hormone-dependent activation of the phosphoinositide 3-kinase/Akt cascade requires Src and enhances neuronal survival
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DOI：
10.1042/bj20090643
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发表时间：
2009-12-01
影响因子：
4.1
通讯作者：
Seo, Hisao
中科院分区：
文献类型：
--
作者：
Cao, Xia;Kambe, Fukushi;Seo, Hisao
我们先前已经报道了T-3（3，3 '，5-三碘甲腺原氨酸）的非基因组作用，其通过人皮肤成纤维细胞中PI 3 K的调节亚基p85 α刺激PI 3 K（磷酸肌醇3-激酶）/Akt通路。本研究的目的是阐明T-3激活PI 3 K的机制，并研究T-3在神经细胞中的生理作用。我们发现T-3通过Src激活PI 3 K/Akt。首先，T-3在表达TR α 1（甲状腺激素受体α 1; N2 aTR α）的N2 a细胞中快速诱导Src和Akt的活化，并且两者都通过添加Src抑制剂或Src siRNA而减弱。相反，PI 3 K抑制剂只能阻断Akt的激活。其次，T-3增强TR α（1）-p85 α-Src复合物的形成，这也被Src抑制剂所消除。Src和PI 3 K/Akt的激活有助于T-3在N2 aTR α细胞中的抗凋亡作用。此外，还观察到在原代大脑皮质神经元中，T-3诱导PI 3 K/Akt的激活，并抑制血清剥夺诱导的细胞凋亡。总之，本研究的发现证明了T-3对神经元细胞存活的一种新的非基因组作用，并为这种作用的机制提供了新的见解，该机制涉及Src激活和TR α 1-p85 α-Src复合物的形成。
We have reported previously a non-genomic action of T-3 (3,3',5-tri-iodothyronine), which stimulates the PI3K (phosphoinositide 3-kinase)/Akt pathway via p85 alpha, the regulatory subunit of PI3K, in human skin fibroblasts. The aim of the present study was to elucidate the mechanism by which T-3 activates PI3K, and to investigate the physiological role of this T-3 action in neuronal cells. We found that T-3 activates PI3K/Akt through Src. First, T-3 rapidly induced the activation of Src and Akt in N2a cells expressing TR alpha 1 (thyroid hormone receptor alpha 1; N2aTR alpha), and both were attenuated by either the addition of a Src inhibitor or Src siRNA. In contrast, a PI3K inhibitor could only block the activation of Akt. Secondly, T-3 enhanced TR alpha(1)-p85 alpha-Src complex formation, which was also abrogated by a Src inhibitor. The activation of Src and PI3K/Akt contributes to the anti-apoptotic effect of T-3 in N2aTR alpha cells. Moreover, it was also observed in primary cerebral cortical neurons that T-3 induced the activation of PI3K/Akt and suppressed serum-deprivation-induced apoptosis. Together, the findings of the present study demonstrate a novel non-genomic action of T-3 on neuronal cell survival, and provide new insights into the mechanism underlying this action, which involves Src activation and TR alpha 1-p85 alpha-Src complex formation.