Cell cycle phase regulates glucocorticoid receptor function.
Cell cycle phase regulates glucocorticoid receptor function.
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DOI：
10.1371/journal.pone.0022289
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发表时间：
2011
期刊：
影响因子：
3.7
通讯作者：
Ray D
中科院分区：
文献类型：
--
作者：
Matthews L;Johnson J;Berry A;Trebble P;Cookson A;Spiller D;Rivers C;Norman M;White M;Ray D
糖皮质激素受体（GR）是配体激活转录因子核激素受体超家族的成员。与许多其他核受体相反，GR被认为在静止细胞中仅存在于细胞质中，并且仅在配体结合时移位到细胞核。现在，我们证明了显着的核GR的配体，这需要核定位信号1（NLS 1）的情况下。活细胞成像显示，在有丝分裂开始时，GR通过间期进入细胞核，并迅速从细胞核中排除，这持续到G1早期。这表明GR分布的异质性反映了细胞周期阶段。分析了细胞周期驱动的GR运输对一组糖皮质激素作用的影响。在G2/M-富集的细胞中，糖皮质激素诱导的ERK激活显著延长。这是伴随着DNA模板特异性，配体非依赖性GR反式激活。使用嵌合和结构域缺失的受体，我们证明，这种反式激活作用是由AF 1反式激活结构域介导的。AF-1含有多个磷酸化位点，这些位点是包括CDK在内的激酶的共有序列，其活性在细胞周期中发生变化。在G2/M中，在残基203和211上有明显的配体非依赖性GR磷酸化诱导，这两个残基在配体活化后都被磷酸化。配体非依赖性的反式激活需要诱导磷酸化S211 GR，而不是S203 GR，从而直接连接细胞周期驱动的GR修饰与改变GR功能。因此，细胞周期阶段调节GR定位和翻译后修饰，其选择性地影响GR活性。这表明，细胞周期阶段是一个重要的决定因素，在细胞反应Gc，有丝分裂指数有助于组织Gc的敏感性。
The glucocorticoid receptor (GR) is a member of the nuclear hormone receptor superfamily of ligand-activated transcription factors. In contrast to many other nuclear receptors, GR is thought to be exclusively cytoplasmic in quiescent cells, and only translocate to the nucleus on ligand binding. We now demonstrate significant nuclear GR in the absence of ligand, which requires nuclear localisation signal 1 (NLS1). Live cell imaging reveals dramatic GR import into the nucleus through interphase and rapid exclusion of the GR from the nucleus at the onset of mitosis, which persists into early G1. This suggests that the heterogeneity in GR distribution is reflective of cell cycle phase. The impact of cell cycle–driven GR trafficking on a panel of glucocorticoid actions was profiled. In G2/M-enriched cells there was marked prolongation of glucocorticoid-induced ERK activation. This was accompanied by DNA template-specific, ligand-independent GR transactivation. Using chimeric and domain-deleted receptors we demonstrate that this transactivation effect is mediated by the AF1 transactivation domain. AF-1 harbours multiple phosphorylation sites, which are consensus sequences for kinases including CDKs, whose activity changes during the cell cycle. In G2/M there was clear ligand independent induction of GR phosphorylation on residues 203 and 211, both of which are phosphorylated after ligand activation. Ligand-independent transactivation required induction of phospho-S211GR but not S203GR, thereby directly linking cell cycle driven GR modification with altered GR function. Cell cycle phase therefore regulates GR localisation and post-translational modification which selectively impacts GR activity. This suggests that cell cycle phase is an important determinant in the cellular response to Gc, and that mitotic index contributes to tissue Gc sensitivity.
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