A new function for the C-terminal zinc finger of the glucocorticoid receptor - Repression of RelA transactivation
A new function for the C-terminal zinc finger of the glucocorticoid receptor - Repression of RelA transactivation
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DOI：
10.1074/jbc.272.34.21467
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发表时间：
1997-08-22
影响因子：
4.8
通讯作者：
Okret, S
中科院分区：
文献类型：
--
作者：
Liden, J;Delaunay, F;Okret, S
糖皮质激素通过干扰NF-κ B转录因子RelA来抑制NF-κ B信号传导，先前的研究已经确定糖皮质激素受体（GR）中的DNA结合结构域（DBD）是负责这种抑制活性的主要区域，使用具有嵌合DBD的GR突变体，发现抑制功能位于C末端锌指，正如从这些结果预测的，含有与GR相同的C-末端锌指的盐皮质激素受体也能够抑制RelA依赖性转录，GR DBD第二锌指中保守精氨酸或赖氨酸的突变（Arg-488或Lys-490在大鼠GR中）取消GR抑制RelA活性的能力，相反，C-末端锌指GR突变体的二聚化盒突变或突变所需的完整的转录GR活性仍然能够抑制RelA依赖的转录。此外，我们发现已知诱导AP-1的GR反式阻遏的类固醇类似物ZK 98299对RelA活性没有抑制作用。总之，这些结果证明糖皮质激素对NF-κ B的抑制涉及GR的C末端锌指中的两个关键氨基酸。使用盐皮质激素受体和抗糖皮质激素的结果提示GR介导的NF-κ B和AP-1抑制的机制是不同的。
Glucocorticoids inhibit NF-kappa B signaling by interfering with the NF-kappa B transcription factor RelA, Previous studies have identified the DNA binding domain (DBD) in the glucocorticoid receptor (GR) as the major region responsible for this repressive activity, Using GR mutants with chimeric DBDs the repressive function was found to be located in the C-terminal zinc finger, As predicted from these results the mineralocorticoid receptor that contains a C-terminal zinc finger identical to that of the GR was also able to repress RelA-dependent transcription, Mutation of a conserved arginine or a lysine in the second zinc finger of the GR DBD (Arg-488 or Lys-490 in the rat GR) abolished the ability of GR to inhibit RelA activity, In contrast, C-terminal zinc finger GR mutants with mutations in the dimerization box or mutations necessary for full transcriptional GR activity were still able to repress RelA-dependent transcription. In addition, we found that the steroid analog ZK98299 known to induce GR transrepression of AP-1 had no inhibitory effect on RelA activity, In summary, these results demonstrate that the inhibition of NF-kappa B by glucocorticoids involves two critical amino acids in the C-terminal zinc finger of the GR. Furthermore, the results from the use of mineralocorticoid receptor and anti-glucocorticoids suggest that the mechanisms for GR-mediated repression of NF-kappa B and AP-1 are different.