A nuclear receptor corepressor modulates transcriptional activity of antagonist-occupied steroid hormone receptor.
A nuclear receptor corepressor modulates transcriptional activity of antagonist-occupied steroid hormone receptor.
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DOI：
10.1210/mend.12.4.0089
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发表时间：
1998-04
影响因子：
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通讯作者：
Xun Zhang;M. Jeyakumar;S. Petukhov;M. Bagchi
中科院分区：
文献类型：
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作者：
Xun Zhang;M. Jeyakumar;S. Petukhov;M. Bagchi
合成类固醇激素拮抗剂是临床上重要的化合物，可调节对类固醇激素的生理反应。拮抗剂与激素受体（配体诱导转录因子）结合，并调节其基因调节活性。在大多数情况下，类固醇受体，例如孕酮受体（PR）或雌激素受体（ER），当与拮抗剂复合时转录失活，并通过同源激素占据受体竞争性抑制靶类固醇反应基因的反式激活。然而，在某些细胞和启动子环境中，拮抗剂占据的 PR 或 ER 获得了矛盾的激动剂样活性。决定拮抗剂结合类固醇受体转录调节从负向模式转变为正向模式的细胞机制尚不清楚。我们现在提供了强有力的证据支持细胞抑制辅助因子的存在，该因子与与抗孕激素 RU486 复合的人类 PR B 型（PR-B）相互作用，以维持其转录失活状态。在未配体的甲状腺激素受体 (TR) 或 ER 与抗雌激素 4-羟基三苯氧胺复合的情况下，RU486-PR-B 可能会隔离有限的抑制性辅助因子，即使在没有激素激动剂的情况下，RU486-PR-B 也可以充当孕酮反应基因的转录激活剂。相反，激素占据的 TR 或 ER 无法诱导 RU486-PR-B 的反式激活。最近的研究表明，转录辅阻遏物 NCoR（核受体辅阻遏物）与未配体的 TR 相互作用，但不与配体的 TR 相互作用。有趣的是，NCoR 的共表达有效地抑制了拮抗剂占据的 PR-B 的部分激动活性，但不影响激动剂结合的 PR-B 的反式激活。我们进一步证明 RU486-PR-B 在体外与 NCoR 发生物理相互作用。这些新的观察结果表明，与 RU486-PR-B 相关并抑制其转录活性的抑制辅助因子与辅阻遏物 NCoR 相同或结构相关。我们提出，决定 RU486-PR-B 从拮抗活性转变为激动活性的细胞机制涉及从拮抗剂结合受体中去除辅阻遏物，以便它可以影响部分但显着的基因激活。
Synthetic steroid hormone antagonists are clinically important compounds that regulate physiological responses to steroid hormones. The antagonists bind to the hormone receptors, which are ligand-inducible transcription factors, and modulate their gene-regulatory activities. In most instances, a steroid receptor, such as progesterone receptor (PR) or estrogen receptor (ER), is transcriptionally inactive when complexed with an antagonist and competitively inhibits transactivation of a target steroid-responsive gene by the cognate hormone-occupied receptor. In certain cellular and promoter contexts, however, antagonist-occupied PR or ER acquires paradoxical agonist-like activity. The cellular mechanisms that determine the switch from the negative to the positive mode of transcriptional regulation by an antagonist-bound steroid receptor are unknown. We now provide strong evidence supporting the existence of a cellular inhibitory cofactor that interacts with the B form of human PR (PR-B) complexed with the antiprogestin RU486 to maintain it in a transcriptionally inactive state. In the presence of unliganded thyroid hormone receptor (TR) or ER complexed with the antiestrogen 4-hydroxytamoxifen, which presumably sequesters a limiting pool of the inhibitory cofactor, RU486-PR-B functions as a transcriptional activator of a progesterone-responsive gene even in the absence of hormone agonist. In contrast, hormone-occupied TR or ER fails to induce transactivation by RU486-PR-B. Recent studies revealed that a transcriptional corepressor, NCoR (nuclear receptor corepressor), interacts with unliganded TR but not with liganded TR. Interestingly, coexpression of NCoR efficiently suppresses the partial agonistic activity of antagonist-occupied PR-B but fails to affect transactivation by agonist-bound PR-B. We further demonstrate that RU486-PR-B interacts physically with NCoR in vitro. These novel observations suggest that the inhibitory cofactor that associates with RU486-PR-B and represses its transcriptional activity is either identical or structurally related to the corepressor NCoR. We propose that cellular mechanisms that determine the switch from the antagonistic to the agonistic activity of RU486-PR-B involve removal of the corepressor from the antagonist-bound receptor so that it can effect partial but significant gene activation.