Selective activation of the glucocorticoid receptor by steroid antagonists in human breast cancer and osteosarcoma cells
Selective activation of the glucocorticoid receptor by steroid antagonists in human breast cancer and osteosarcoma cells
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DOI：
10.1074/jbc.m908729199
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发表时间：
2000-06-09
影响因子：
4.8
通讯作者：
Archer, TK
中科院分区：
文献类型：
--
作者：
Fryer, CJ;Kinyamu, HK;Archer, TK
类固醇激素通过高亲和力受体调节许多基因的转录，这些受体与染色质重塑复合物、辅激活因子和辅抑制因子一起起作用。我们比较了各种糖皮质激素受体（GR）拮抗剂在乳腺癌和骨肉瘤细胞系中的活性，这些细胞系被工程化以稳定地维持小鼠乳腺肿瘤病毒启动子。在这两种细胞类型中，地塞米松通过破坏小鼠乳腺肿瘤病毒染色质结构和募集受体辅激活蛋白来激活GR。然而，当用多种拮抗剂攻击时，GR显示出在两种细胞类型内激活转录的差异能力。对于乳腺癌细胞，拮抗剂不能激活启动子，也不能促进GR与重塑蛋白或共激活蛋白的结合。相反，在骨肉瘤细胞中，抗糖皮质激素RU486和RU43044表现出部分激动剂活性。这些拮抗剂在骨肉瘤细胞中刺激转录的能力反映在RU 486结合受体重塑染色质和与染色质重塑蛋白相关的能力中。类似地，RU 486结合受体不能完全激活转录的观察结果与其不能募集受体辅激活蛋白一致。
Steroid hormones regulate the transcription of numerous genes via high affinity receptors that act in concert with chromatin remodeling complexes, coactivators and corepressors, We have compared the activities of a variety of glucocorticoid receptor (GR) antagonists in breast cancer and osteosarcoma cell lines engineered to stably maintain the mouse mammary tumor virus promoter. In both cell types, GR activation by dexamethasone occurs via the disruption of mouse mammary tumor virus chromatin structure and the recruitment of receptor coactivator proteins. However, when challenged with a variety of antagonists the GR displays differential ability to activate transcription within the two cell types. For the breast cancer cells, the antagonists fail to activate the promoter and do not promote the association of the GR with either remodeling or coactivator proteins. In contrast, in osteosarcoma cells, the antiglucocorticoids, RU486 and RU43044, exhibit partial agonist activity. The capacity of these antagonists to stimulate transcription in the osteosarcoma cells is reflected in the ability of the RU486-bound receptor to remodel chromatin and associate with chromatin-remodeling proteins. Similarly, the observation that the RU486-bound receptor does not fully activate transcription is consistent with its inability to recruit receptor coactivator proteins.