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首页> 外文期刊>Molecular and Cellular Biology >PSF Is a Novel Corepressor That Mediates Its Effect through Sin3A and the DNA Binding Domain of Nuclear Hormone Receptors
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PSF Is a Novel Corepressor That Mediates Its Effect through Sin3A and the DNA Binding Domain of Nuclear Hormone Receptors

机译：PSF是一种新型的Corepressor，通过Sin3A和核激素受体的DNA结合域介导其作用。

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Members of the type II nuclear hormone receptor subfamily (e.g., thyroid hormone receptors [TRs], retinoic acid receptors, retinoid X receptors [RXRs], vitamin D receptor, and the peroxisome proliferator-activated receptors) bind to their response sequences with or without ligand. In the absence of ligand, these DNA-bound receptors mediate different degrees of repression or silencing of gene expression which is thought to result from the association of their ligand binding domains (LBDs) with corepressors. Two related corepressors, N-CoR and SMRT, interact to various degrees with the LBDs of these type II receptors in the absence of their cognate ligands. N-CoR and SMRT have been proposed to act by recruiting class I histone deacetylases (HDAC I) through an association with Sin3, although they have also been shown to recruit class II HDACs through a Sin3-independent mechanism. In this study, we used a biochemical approach to identify novel nuclear factors that interact with unliganded full-length TR and RXR. We found that the DNA binding domains (DBDs) of TR and RXR associate with two proteins which we identified as PSF (polypyrimidine tract-binding protein-associated splicing factor) and NonO/p54nrb. Our studies indicate that PSF is a novel repressor which interacts with Sin3A and mediates silencing through the recruitment of HDACs to the receptor DBD. In vivo studies with TR showed that although N-CoR fully dissociates in the presence of ligand, the levels of TR-bound PSF and Sin3A appear to remain unchanged, indicating that Sin3A can be recruited to the receptor independent of N-CoR or SMRT. RXR was not detected to bind N-CoR although it bound PSF and Sin3A as effectively as TR, and this association with RXR did not change with ligand. Our studies point to a novel PSF/Sin3-mediated pathway for nuclear hormone receptors, and possibly other transcription factors, which may fine-tune the transcriptional response as well as play an important role in mediating the repressive effects of those type II receptors which only weakly interact with N-CoR and SMRT.
机译：II型核激素受体亚家族的成员（例如，甲状腺激素受体[TRs]，视黄酸受体，类维生素A X受体[RXRs]，维生素D受体和过氧化物酶体增殖物激活的受体）在有或无时与它们的反应序列结合配体。在不存在配体的情况下，这些与DNA结合的受体介导基因表达的不同程度的抑制或沉默，这被认为是由于其配体结合域（LBD）与共加压因子的缔合而导致的。在没有它们的同源配体的情况下，两种相关的核心抑制剂N-CoR和SMRT与这些II型受体的LBD相互作用程度不同。 N-CoR和SMRT已被提议通过与Sin3的关联募集I类组蛋白脱乙酰基酶（HDAC I）发挥作用，尽管它们也被证明可以通过Sin3独立机制募集II类HDAC。在这项研究中，我们使用一种生物化学方法来鉴定与未配体的全长TR和RXR相互作用的新型核因子。我们发现TR和RXR的DNA结合结构域（DBDs）与我们确定为PSF（聚嘧啶束结合蛋白相关剪接因子）和NonO / p54 nrb < / sup>。我们的研究表明，PSF是与Sin3A相互作用并通过将HDAC募集到受体DBD介导沉默的新型阻遏物。用TR进行的体内研究表明，尽管在配体存在下N-CoR完全解离，但TR结合的PSF和Sin3A的水平似乎保持不变，表明Sin3A可以独立于N-CoR或SMRT募集至受体。尽管RXR与PSF和Sin3A的结合程度与TR一样，但仍未检测到RXR与N-CoR的结合，并且与RXR的这种结合不会随着配体而改变。我们的研究指向核激素受体以及可能的其他转录因子的新型PSF / Sin3介导的途径，该途径可能会微调转录反应，并且在介导那些II型受体的抑制作用中起重要作用，仅与N-CoR和SMRT的互动较弱。

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