Peroxisome Proliferator-activated Receptor Mediates Cross-talk with Thyroid Hormone Receptor by Competition for Retinoid X Receptor
Peroxisome Proliferator-activated Receptor Mediates Cross-talk with Thyroid Hormone Receptor by Competition for Retinoid X Receptor
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过氧化物酶体增殖物激活受体通过竞争视黄醇 X 受体介导与甲状腺激素受体的串扰
DOI：
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发表时间：
1995
影响因子：
4.8
通讯作者：
C. Meier
中科院分区：
文献类型：
--
作者：
C. Juge;A. Gorla;Agns Pernin;T. Lemberger;W. Wahli;A. Burger;C. Meier
过氧化物酶体增殖物激活受体（peroxisome proliferator-activated receptor，PPAR）和甲状腺激素受体（thyroid hormone receptor，TR）是核受体超家族的成员，它们调节脂质代谢和组织分化。为了与DNA结合并激活转录，PPAR需要与维甲酸X受体（RXR）形成异二聚体。除了通过其自身的反应元件激活转录外，PPAR还能够选择性地下调TR的转录活性，而不是维生素D受体。这种功能相互作用的分子基础尚未完全阐明。通过hPPARα的定点突变，我们将其对TR的抑制作用定位于PPAR配体结合结构域中的亮氨酸拉链样基序，该基序在该受体的所有亚型中高度保守，并介导与RXR的异源二聚化。在hPPARα的433位用精氨酸取代单个亮氨酸（L433 R），消除了PPAR与RXR的异源二聚化，从而消除了其反式激活能力。然而，在位置422处的亮氨酸残基至精氨酸的类似突变未显示异源二聚化、DNA结合或转录激活的改变。二聚化缺陷突变体L433 R不再能够抑制TR作用，表明PPAR的选择性抑制作用来自于对RXR以及可能对其他TR辅助蛋白的竞争。相反，通过PPAR的P-box（C122 S）中的突变消除DNA结合并没有消除TR反式激活的抑制，表明不涉及对DNA结合的竞争。此外，在免疫共沉淀实验中没有发现PPAR：TR异二聚体形成的证据。总之，我们已经证明，过氧化物酶体增殖物激活受体选择性地抑制转录活性的TRs的竞争RXR和可能的非RXR TR辅助蛋白。相反，这种功能相互作用是独立的形成的PPAR：TR异二聚体或竞争DNA结合。
The peroxisome proliferator-activated receptors (PPAR) and thyroid hormone receptors (TR) are members of the nuclear receptor superfamily, which regulate lipid metabolism and tissue differentiation. In order to bind to DNA and activate transcription, PPAR requires the formation of heterodimers with the retinoid X receptor (RXR). In addition to activating transcription through its own response elements, PPAR is able to selectively down-regulate the transcriptional activity of TR, but not vitamin D receptor. The molecular basis of this functional interaction has not been fully elucidated. By means of site-directed mutagenesis of hPPARα we mapped its inhibitory action on TR to a leucine zipper-like motif in the ligand binding domain of PPAR, which is highly conserved among all subtypes of this receptor and mediates heterodimerization with RXR. Replacement of a single leucine by arginine at position 433 of hPPARα (L433R) abolished heterodimerization of PPAR with RXR and consequently its trans-activating capacity. However, a similar mutation of a leucine residue to arginine at position 422 showed no alteration of heterodimerization, DNA binding, or transcriptional activation. The dimerization deficient mutant L433R was no longer able to inhibit TR action, demonstrating that the selective inhibitory effect of PPAR results from the competition for RXR as well as possibly for other TR-auxiliary proteins. In contrast, abolition of DNA binding by a mutation in the P-box of PPAR (C122S) did not eliminate the inhibition of TR trans-activation, indicating that competition for DNA binding is not involved. Additionally, no evidence for the formation of PPAR:TR heterodimers was found in co-immunoprecipitation experiments. In summary, we have demonstrated that PPAR selectively inhibits the transcriptional activity of TRs by competition for RXR and possibly non-RXR TR-auxiliary proteins. In contrast, this functional interaction is independent of the formation of PPAR:TR heterodimers or competition for DNA binding.
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DOI：
--
发表时间：
1993
期刊：
The Journal of biological chemistry
影响因子：
--
作者：
Nagaya,T;Jameson,JL
通讯作者：
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DOI：
--
发表时间：
1993
期刊：
The Journal of biological chemistry
影响因子：
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作者：
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DOI：
--
发表时间：
1987
期刊：
The Journal of biological chemistry
影响因子：
--
作者：
Flug,F;Copp,RP;Casanova,J;Horowitz,ZD;Janocko,L;Plotnick,M;Samuels,HH
通讯作者：
Samuels,HH