Akt inhibits the orphan nuclear receptor Nur77 and T-cell apoptosis
Akt inhibits the orphan nuclear receptor Nur77 and T-cell apoptosis
复制标题
DOI：
10.1074/jbc.m105431200
复制
发表时间：
2001-08-31
影响因子：
4.8
通讯作者：
Gotoh, Y
中科院分区：
文献类型：
--
作者：
Masuyama, N;Oishi, K;Gotoh, Y
Akt是多种情况下细胞存活的常见介质。虽然已经描述了一些候选Akt靶点，但Akt的功能尚未完全理解，特别是因为细胞类型和环境依赖性凋亡调节。在这项研究中，我们证明了Akt拮抗细胞凋亡的机制之一涉及抑制Nur 77，Nur 77是一种与T细胞受体介导的细胞凋亡有关的转录因子。有研究表明Akt直接磷酸化Nur 77，但Akt是否抑制Nur 77的生物学功能尚不清楚。我们发现Akt抑制Nur 77的DNA结合活性，并以磷酸化位点依赖的方式刺激其与14-3-3的结合。此外，我们发现Akt的表达抑制Nur 77诱导的成纤维细胞凋亡和活化诱导的T细胞杂交瘤细胞死亡。Akt对Nur 77的抑制表明了一种机制，该机制解释了T细胞受体活化如何在某些情况下即使在Nur 77被诱导时也能促进存活。总的来说，这些结果可能表明Akt是Nur 77在T细胞凋亡中的负调节因子。
Akt is a common mediator of cell survival in a variety of circumstances. Although some candidate Akt targets have been described, the function of Akt is not fully understood, particularly because of the cell type- and context-dependent apoptosis regulation. In this study, we demonstrate that one of the mechanisms by which Akt antagonizes apoptosis involves the inhibition of Nur77, a transcription factor implicated in T-cell receptor-mediated apoptosis. It has been suggested that Akt phosphorylates Nur77 directly, but whether Akt suppresses biological functions of Nur77 remains unknown. We found that Akt inhibited the DNA binding activity of Nur77 and stimulated its association with 14-3-3 in a phosphorylation site-dependent manner. Moreover, we found that expression of Akt suppressed Nur77-induced apoptosis in fibroblasts and activation-induced cell death of T-cell hybridomas. The inhibition of Nur77 by Akt suggests a mechanism that explains how T-cell receptor activation can promote survival in some instances even when Nur77 is induced. Collectively, these results may suggest that Akt is a negative regulator of Nur77 in T-cell apoptosis.