Negative regulation of hormone signaling by RIP140
Negative regulation of hormone signaling by RIP140
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DOI：
10.1016/j.jsbmb.2006.09.005
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发表时间：
2006-12-01
影响因子：
4.1
通讯作者：
Cavailles, Vincent
中科院分区：
文献类型：
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作者：
Augereau, Patrick;Badia, Eric;Cavailles, Vincent
受体相互作用蛋白（RIP） 140是核激素受体的负转录调节因子，是维持能量稳态和排卵所必需的。尽管它被激动剂配体受体招募，但该蛋白表现出强烈的抑制活性，这最初归因于与核受体上的辅激活物结合的竞争。然而，RIP 140也对羧基末端结合蛋白（ctbp）和历史性去乙酰化酶（HDACs）产生活性抑制。我们最近证明了分子的羧基末端区域包含两个额外的沉默域，它们需要翻译后修饰才能完全激活。在人乳腺癌细胞中，核受体的各种配体在转录水平上上调RIP140的表达。我们最近克隆了人类RIP140基因，并确定了雌激素对其调控的机制。为了更好地描述RIP 140在激素信号传导中的作用，我们研究了它与雄激素受体的相互作用，并证明了它抑制雄激素转录调节的能力。RIP140还能抑制雌激素受体相关受体（ERR α、β和γ）对含有不同类型应答元件的天然或人工报告基因的反激活。令人惊讶的是，当受体通过与Sp1转录因子的相互作用被募集到目标启动子时，RIP140正调控ERR的转激活，这种作用可能涉及组蛋白去乙酰化酶的滴定。总之，这些结果表明，通过辅助因子RIP140对激素信号的转录调节涉及依赖于多个结构域和伙伴的复杂机制。(c) 2006 Elsevier Ltd.版权所有。
Receptor interacting protein (RIP) 140 is a negative transcriptional regulator of nuclear hormone receptors which is required for the maintenance of energy homeostasis and ovulation. Despite its recruitment by agonist-liganded receptors, this protein exhibits a strong repressive activity which was initially attributed to competition with coactivator binding on nuclear receptors. However, RIP 140 also exerts active repression implicating the Carboxyl-terminal binding proteins (CtBPs) and historic deacetylases (HDACs). We recently demonstrated that the Carboxyl-terminal region of the molecule contains two additional silencing domains which require post-translational modifications to be fully active. In human breast cancer cells, RIP140 expression is up-regulated at the transcriptional level by various ligands of nuclear receptors. We have recently cloned the human RIP140 gene and defined the mechanism of its regulation by estrogens. In order to better characterize the role of RIP 140 in hormone signaling, we have studied its interaction with the androgen receptor and demonstrated its ability to repress transcriptional regulation by androgens. RIP140 also inhibits transactivation by estrogen receptor-related receptors (ERR alpha, beta and gamma) on natural or artificial reporter genes containing different types of response elements. Surprisingly, RIP140 positively regulates ERR transactivation when the receptors are recruited to target promoters through interaction with the Sp1 transcription factor and this effect could involve titration of histone deacetylases. Altogether, these results underline that transcriptional regulation of hormone signaling by the cofactor RIP140 involves complex mechanisms relying on multiple domains and partners. (c) 2006 Elsevier Ltd. All rights reserved.