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首页> 外文期刊>Molecular and Cellular Biology >Proteasomal Inhibition Enhances Glucocorticoid Receptor Transactivation and Alters Its Subnuclear Trafficking
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Proteasomal Inhibition Enhances Glucocorticoid Receptor Transactivation and Alters Its Subnuclear Trafficking

机译：蛋白酶体抑制增强糖皮质激素受体反式激活并改变其亚核贩运。

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The ubiquitin-proteasome pathway regulates the turnover of many transcription factors, including steroid hormone receptors such as the estrogen receptor and progesterone receptor. For these receptors, proteasome inhibition interferes with steroid-mediated transcription. We show here that proteasome inhibition with MG132 results in increased accumulation of the glucocorticoid receptor (GR), confirming that it is likewise a substrate for the ubiquitin-proteasome degradative pathway. Using the mouse mammary tumor virus (MMTV) promoter integrated into tissue culture cells, we found that proteasome inhibition synergistically increases GR-mediated transactivation. This increased activation was observed in a number of cell lines and on various MMTV templates, either as transiently transfected reporters or stably integrated into chromatin. These observations suggest that the increase in GR-mediated transcription due to proteasome inhibition may occur downstream of the initial chromatin remodeling step. In support of this concept, the increase in transcription did not correlate with an increase in chromatin remodeling, as measured by restriction enzyme hypersensitivity, or transcription factor loading, as exemplified by nuclear factor 1. To investigate the relationship between GR turnover, transcription, and subnuclear trafficking, we examined the effect of proteasome inhibition on the mobility of the GR within the nucleus and association of the GR with the nuclear matrix. Blocking GR turnover reduced the mobility of the GR within the nucleus, and this correlated with increased association of the receptor with the nuclear matrix. As a result of proteasome inhibition, GR mobility within the nucleus was reduced while its association with the nuclear matrix was increased. Thus, while altered nuclear mobility of steroid receptors may be a common feature of proteasome inhibition, GR is unique in its enhanced transactivation activity that results when proteasome function is compromised. Proteasomes may therefore impact steroid receptor action at multiple levels and exert distinct effects on individual receptor types.
机译：泛素-蛋白酶体途径调节许多转录因子的转换，包括类固醇激素受体，例如雌激素受体和孕激素受体。对于这些受体，蛋白酶体抑制会干扰类固醇介导的转录。我们在这里显示，用MG132抑制蛋白酶体会导致糖皮质激素受体（GR）的积累增加，从而证实它同样是泛素-蛋白酶体降解途径的底物。使用整合到组织培养细胞中的小鼠乳腺肿瘤病毒（MMTV）启动子，我们发现蛋白酶体抑制协同增加GR介导的反式激活。在许多细胞系中以及在各种MMTV模板上都观察到了这种增加的激活，这些模板既可以是瞬时转染的报告基因，也可以稳定整合到染色质中。这些观察结果表明，由于蛋白酶体抑制，GR介导的转录增加可能发生在初始染色质重塑步骤的下游。为支持这一概念，转录的增加与染色质重塑的增加不相关，染色质的重塑通过限制性内切酶超敏反应或转录因子负载（以核因子1为例）来衡量。研究遗传资源更新，转录和表达之间的关系在亚核贩运中，我们研究了蛋白酶体抑制对GR在核内的流动性以及GR与核基质的缔合的影响。阻止GR转换会降低GR在核内的移动性，这与受体与核基质的缔合增加有关。蛋白酶体抑制的结果是，核内的GR迁移率降低了，而与核基质的结合却增加了。因此，虽然类固醇受体的核迁移率改变可能是蛋白酶体抑制的常见特征，但GR的独特之处在于其增强的反式激活活性，这是当蛋白酶体功能受损时导致的。因此，蛋白酶体可能在多个水平上影响类固醇受体的作用，并对单个受体类型产生不同的作用。

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