UbcH7 interacts with the glucocorticoid receptor and mediates receptor autoregulation
UbcH7 interacts with the glucocorticoid receptor and mediates receptor autoregulation
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DOI：
10.1677/joe.1.06799
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发表时间：
2006-09-01
影响因子：
4
通讯作者：
Ray, David
中科院分区：
文献类型：
--
作者：
Garside, Helen;Waters, Charlotte;Ray, David
与其他核受体不同，糖皮质激素受体（GR）的反活化通过抑制泛素/蛋白酶体途径而增加。在这里，我们证明了泛素偶联酶（E2） UbcH7与GR发生物理相互作用，当过表达时，会降低受体上调基因表达的能力。化学抑制26S蛋白酶体可消除UbcH7过表达的下调作用，提示26S蛋白酶体和GR蛋白稳定性在介导UbcH7作用中起作用。此外，UbcH7显性负突变体（C89S）无法传递泛素，无法抑制GR转激活。事实上，过表达UbcH7突变体足以将GR和反激活提高到蛋白酶体抑制剂MG132达到的水平，但当MG132和UbcH7突变体一起使用时，没有进一步的诱导作用。显性负UbcH7的表达消除了GR蛋白的配体依赖性下调，表明UbcH7的作用是通过调节GR蛋白浓度介导的。综上所述，这些数据表明UbcH7是GR转换和糖皮质激素敏感性的关键调节因子。
Unlike other nuclear receptors, transactivation by the glucocorticoid receptor (GR) is increased by the inhibition of the ubiquitin/proteasome pathway. Here, we demonstrate that the ubiquitin-conjugating enzyme (E2), UbcH7, physically interacts with the GR and, when overexpressed, reduces the ability of the receptor to upregulate gene expression. Chemical inhibition of the 26S proteasome abolished the downregulation effect of overexpressed UbcH7, suggesting a role for the 26S proteasome, and GR protein stability in mediating the UbcH7 effect. Furthermore, a UbcH7 dominant negative mutant (C89S), unable to transfer ubiquitin, failed to repress GR transactivation. Indeed, overexpression of the mutant UbcH7 was sufficient to augment GR, transactivation to levels achieved using the proteasome inhibitor MG132, but there was no further induction when MG132 and the UbcH7 mutant were used together. Expression of the dominant negative UbcH7 abolished ligand-dependent downregulation of GR protein, suggesting that the UbcH7 effect was mediated by regulation of GR protein concentration. Taken together, these data show that UbcH7 is a key regulator of GR turnover and glucocorticoid sensitivity.