Role of mitochondrial glucocorticoid receptor in glucocorticoid-induced apoptosis.
Role of mitochondrial glucocorticoid receptor in glucocorticoid-induced apoptosis.
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DOI：
10.1084/jem.20050433
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发表时间：
2006-01-23
影响因子：
15.3
通讯作者：
Yefenof, Eitan
中科院分区：
文献类型：
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作者：
Sionov, Ronit Vogt;Cohen, Orly;Kfir, Shlomit;Zilberman, Yael;Yefenof, Eitan
糖皮质激素受体（GR）介导糖皮质激素（GC）诱导的细胞凋亡的机制尚不清楚。我们研究了线粒体 GR 在此过程中的作用。地塞米松在 GC 敏感的 T 细胞系中诱导 GR 易位至线粒体，但在 GC 抗性的 T 细胞系中则不然。相反，核 GR 易位发生在所有细胞类型中。胸腺上皮细胞以 GR 依赖性方式引起 PD1.6 T 细胞系凋亡，诱导 GR 易位至线粒体，但不易位至细胞核，表明线粒体 GR 在引发细胞凋亡中发挥作用。这一假设得到了以下发现的证实：仅在线粒体中表达的 GR 变体会引发多种癌细胞系的凋亡。假定的线粒体定位信号被定义为人 GR 的氨基酸 558-580，位于配体结合域的 NH2 末端部分。总而言之，我们的数据表明，GR 的线粒体和核易位受到差异性调节，并且线粒体 GR 易位与 GC 诱导的细胞凋亡的易感性相关。
The mechanisms by which glucocorticoid receptor (GR) mediates glucocorticoid (GC)-induced apoptosis are unknown. We studied the role of mitochondrial GR in this process. Dexamethasone induces GR translocation to the mitochondria in GC-sensitive, but not in GC-resistant, T cell lines. In contrast, nuclear GR translocation occurs in all cell types. Thymic epithelial cells, which cause apoptosis of the PD1.6 T cell line in a GR-dependent manner, induce GR translocation to the mitochondria, but not to the nucleus, suggesting a role for mitochondrial GR in eliciting apoptosis. This hypothesis is corroborated by the finding that a GR variant exclusively expressed in the mitochondria elicits apoptosis of several cancer cell lines. A putative mitochondrial localization signal was defined to amino acids 558–580 of human GR, which lies within the NH2-terminal part of the ligand-binding domain. Altogether, our data show that mitochondrial and nuclear translocations of GR are differentially regulated, and that mitochondrial GR translocation correlates with susceptibility to GC-induced apoptosis.