Protein kinase C regulates mitochondrial targeting of Nur77 and its family member Nor-1 in thymocytes undergoing apoptosis.
Protein kinase C regulates mitochondrial targeting of Nur77 and its family member Nor-1 in thymocytes undergoing apoptosis.
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DOI：
10.1002/eji.200940231
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发表时间：
2010-07
影响因子：
5.4
通讯作者：
Winoto, Astar
中科院分区：
文献类型：
--
作者：
Thompson, Jennifer;Burger, Megan L.;Whang, Hannah;Winoto, Astar
Nur77孤儿类固醇受体及其家族成员NOR-1是发育中的T细胞凋亡所必需的。在胸腺细胞中，来自TCR复合体的信号诱导Nur77和NOR-1的表达，随后从细胞核转位到线粒体。Nur77和NOR-1与线粒体中的Bcl2结合，导致构象改变，暴露了BH3结构域，BH3结构域是Bcl2的促凋亡分子。由于Nur77和NOR-1是高度磷酸化的，我们研究了线粒体易位和BH3暴露对Nur77和NOR-1磷酸化的要求。我们发现，PKC激动剂HK434与钙离子载体结合，可以诱导Nur77和NOR-1的磷酸化、易位、Bcl2、BH3暴露和胸腺细胞的凋亡。经典形式和新形式的PKC的抑制剂都能够阻断这一过程。相比之下，只有普通的而不是经典的PKC特异性抑制剂能够阻断由PMA启动的相同过程，PMA是一种常用的PKC激动剂。这些结果说明了PMA和HK434对胸腺细胞中PKC亚型的不同激活，并表明PKC在TCR诱导胸腺细胞凋亡过程中线粒体易位的Nur77/NOR-1和Bcl2构象变化中的重要作用。
Nur77 orphan steroid receptor and its family member Nor-1 are required for apoptosis of developing T cells. In thymocytes, signals from the TCR complex induce Nur77 and Nor-1 expression followed by translocation from the nucleus to mitochondria. Nur77 and Nor-1 associate with Bcl-2 in the mitochondria, resulting in a conformation change that exposes the Bcl-2 BH3 domain, a presumed pro-apoptotic molecule of Bcl-2. As Nur77 and Nor-1 are heavily phosphorylated, we examined the requirement of Nur77 and Nor-1 phosphorylation in mitochondria translocation and Bcl-2 BH3 exposure. We found that HK434, a PKC agonist, in combination with calcium ionophore, can induce Nur77 and Nor-1 phosphorylation, translocation, Bcl-2 BH3 exposure and thymocyte apoptosis. Inhibitors of both classical and novel forms of PKC were able to block this process. In contrast, only the general but not classical PKC-specific inhibitors were able to block the same process initiated by PMA, a commonly used PKC agonist. These data demonstrate a differential activation of PKC isoforms by PMA and HK434 in thymocytes, and show the importance of PKC in mitochondria translocation of Nur77/Nor-1 and Bcl-2 conformation change during TCR-induced thymocyte apoptosis.
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影响因子：
4.8
作者：
Garcia-Bermejo, ML;Leskow, FC;Kazanietz, MG
通讯作者：
Kazanietz, MG
影响因子：
2.1
作者：
Fujii, Yasushi;Matsuda, Satoshi;Koyasu, Shigeo
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Koyasu, Shigeo
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2.7
作者：
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Marquez, VE
影响因子：
32.4
作者：
LINETTE, GP;GRUSBY, MJ;KORSMEYER, SJ
通讯作者：
KORSMEYER, SJ
影响因子：
12.8
作者：
Kim, H;Lee, JE;Youn, HD
通讯作者：
Youn, HD