Functional redundancy of the Nur77 and Nor-1 orphan steroid receptors in T-cell apoptosis
Functional redundancy of the Nur77 and Nor-1 orphan steroid receptors in T-cell apoptosis
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DOI：
10.1093/emboj/16.8.1865
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发表时间：
1997-04-15
期刊：
影响因子：
11.4
通讯作者：
Winoto, A
中科院分区：
文献类型：
--
作者：
Cheng, LEC;Chan, FKM;Winoto, A
转录因子Nur77(NGFI-B)是类固醇核受体超家族成员之一，在T细胞受体(TCR)介导的细胞凋亡过程中被诱导到高水平，转基因显性负性Nur77蛋白可以抑制胸腺细胞伴随负选择的凋亡过程，而Nur77的结构性表达导致大量细胞死亡，然而Nur77缺陷小鼠没有表型，提示可能存在一种对Nur77具有冗余功能的蛋白。为了探讨这种可能性，我们研究了两个Nur77家族成员Nurr1和NOR-1在TCR诱导的细胞凋亡中的作用。我们发现NOR-1和Nurr1可以通过与Nur77相同的DNA元件反式激活，并且它们的反式激活活性可以被NUR77显性负性蛋白阻断。在TCR刺激下，NOR-1蛋白被诱导到很高的水平，并具有与Nur77相似的动力学特征。相反，在刺激的胸腺细胞中检测不到NOR-1。此外，NOR-1在胸腺细胞中的结构性表达导致大量的细胞凋亡和CD25的上调，这表明NOR-77和NOR-1基因产物之间存在功能冗余，就像我们的Nur77-FL转基因小鼠的情况一样，在NOR-1转基因小鼠的胸腺细胞中检测不到FastNur77在GLD/GLD小鼠中的结构性表达挽救了快速突变小鼠的淋巴增殖表型，因此，NOR-1和Nur77在明显不依赖于Fas的细胞凋亡中显示出功能冗余。
The transcription factor Nur77 (NGFI-B), a member of the steroid nuclear receptor superfamily, is induced to a high level during T-cell receptor (TCR)-mediated apoptosis, A transgenic dominant-negative Nur77 protein can inhibit the apoptotic process accompanying negative selection in thymocytes, while constitutive expression of Nur77 leads to massive cell death, Nur77-deficient mice, however, have no phenotype, suggesting the possible existence of a protein with redundant function to Nur77, To explore this possibility, we have characterized the role of two Nur77 family members, Nurr1 and Nor-1, in TCR-induced apoptosis, We found that Nor-1 and Nurr1 can transactivate through the same DNA element as Nur77, and that their transactivation activities can be blocked by a Nur77 dominant-negative protein, In thymocytes, Nor-1 protein is induced to a very high level upon TCR stimulation and has similar kinetics to Nur77, In contrast, Nurr1 is undetectable in stimulated thymocytes, Furthermore, constitutive expression of Nor-1 in thymocytes leads to massive apoptosis and up-regulation of CD25, suggesting a functional redundancy between Nur77 and Nor-1 gene products, As in the case of our Nur77-FL mice, Fast is not detectable in the thymocytes of Nor-1 transgenic mice, Constitutive expression of Nur77 in gld/gld mice rescues the lymphoproliferative phenotype of the Fast mutant mice, Thus, Nor-1 and Nur77 demonstrate functional redundancy in an apparently Fas-independent apoptosis.