Direct association with thioredoxin allows redox regulation of glucocorticoid receptor function
Direct association with thioredoxin allows redox regulation of glucocorticoid receptor function
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DOI：
10.1074/jbc.274.5.3182
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发表时间：
1999-01-29
影响因子：
4.8
通讯作者：
Tanaka, H
中科院分区：
文献类型：
--
作者：
Makino, Y;Yoshikawa, N;Tanaka, H
糖皮质激素受体(GR)被认为是一类转录因子，其功能受氧化还原调节。我们最近证实，硫氧还蛋白(Trx)是一种细胞还原催化剂，在体内氧化条件下GR功能的恢复中发挥着重要作用。尽管GR的配体结合域和其他结构域都被认为受到TRX的调控，但这种相互作用的分子机制在很大程度上还不清楚。在本研究中，我们假设在核受体中高度保守的GRDNA结合域(DBD)在体内也负责与Trx的通讯，哺乳动物双杂交实验和谷胱甘肽S转移酶下拉实验揭示了Trx与GRDBD的直接联系。此外，Trx和含有单纯疱疹病毒蛋白16反式激活结构域的嵌合蛋白以及GR DBD的亚细胞定位分析表明，在氧化条件下，这种相互作用可能发生在细胞核内。综上所述，这些观察表明，TRX通过与保守的DBD基序直接关联，可能是细胞氧化还原信号和核受体介导的信号转导之间相互作用的关键中介。
The glucocorticoid receptor (GR) is considered to belong to a class of transcription factors, the functions of which are exposed to redox regulation. We have recently demonstrated that thioredoxin (TRX), a cellular reducing catalyst, plays an important role in restoration of GR function in vivo under oxidative conditions. Although both the ligand binding domain and other domains of the GR have been suggested to be modulated by TRX, the molecular mechanism of the interaction is largely unknown. In the present study, we hypothesized that the DNA binding domain (DBD) of the GR, which is highly conserved among the nuclear receptors, is also responsible for communication with TRX in vivo, Mammalian two-hybrid assay and glutathione S-transferase pull-down assay revealed the direct association between TRX and the GR DBD. Moreover, analysis of subcellular localization of TRX and the chimeric protein harboring herpes simplex viral protein 16 transactivation domain and the GR DBD indicated that the interaction might take place in the nucleus under oxidative conditions. Together these observations indicate that TRX, via a direct association with the conserved DBD motif, may represent a key mediator operating in interplay between cellular redox signaling and nuclear receptor-mediated signal transduction.