Constitutive Smad signaling and Smad-dependent collagen gene expression in mouse embryonic fibroblasts lacking peroxisome proliferator-activated receptor-gamma.
Constitutive Smad signaling and Smad-dependent collagen gene expression in mouse embryonic fibroblasts lacking peroxisome proliferator-activated receptor-gamma.
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DOI：
10.1016/j.bbrc.2008.07.014
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发表时间：
2008-09-19
影响因子：
3.1
通讯作者：
Varga, John
中科院分区：
文献类型：
--
作者：
Ghosh, Asish K.;Wei, Jun;Wu, Minghua;Varga, John
转化生长因子-β(转化生长因子-β)是一种强有力的胶原合成诱导剂，与纤维化密切相关。过氧化物酶体增殖物激活受体-γ(PPAR-γ)是一种调节脂肪生成的核激素受体，是公认的多效性转录因子。我们先前已经证明，天然和药物配体激活PPAR-γ可以消除转化生长因子-β对皮肤成纤维细胞胶原基因表达的刺激作用。本研究的目的是研究内源性PPAR-γ在调节转化生长因子-β信号转导和胶原基因表达中的生理作用。我们发现，在缺乏PPAR-γ的小鼠胚胎成纤维细胞(MEF)中，基础胶原基因的表达显著增加，而PPAR-γ配体15d-PGJ2不能降低这种升高的胶原水平。PPAR-γ缺失的MEF与异位的PPAR-γ重组导致COL1A2启动子活性下调。与对照MEF相比，PPAR-γ缺失的MEF表达I型转化生长因子-β受体TβRI，并产生更多的转化生长因子-β1。此外，即使在没有外源性转化生长因子-γ刺激的情况下，PPAR-β缺失的MEF也表现出Smad2和Smad3的磷酸化。在PPAR-γ缺失的MEF中，Smad2/3的结构性磷酸化与Smad3与其同源识别位点以及与p300的配体无关的相互作用有关，p300是先前参与介导转化生长因子-β反应的辅活化子。这些结果表明，MEF中PPAR-γ的缺失与胶原基因表达的结构性上调和Smad的激活有关，至少部分是由于自分泌转化生长因子-β的刺激。重要的是，在硬皮病皮肤成纤维细胞中，PPAR-γ的水平明显低于健康对照组。因此，内源性PPAR-γ可能在调控成纤维细胞SmAD依赖的I型胶原基因表达和组织内稳态中发挥生理学作用。
Transforming growth factor-β (TGF-β), a potent inducer of collagen synthesis, is implicated in fibrosis. Peroxisome proliferator-activated receptor-γ (PPAR-γ) is a nuclear hormone receptor that regulates adipogenesis and is recognized as a pleiotropic transcription factor. We demonstrated previously that activation of PPAR-γ by natural and pharmacologic ligands abrogated the stimulation of collagen gene expression induced by TGF-β in skin fibroblasts. The goal of this study was to characterize the physiologic role of endogenous PPAR-γ in regulation of TGF-β signaling and collagen gene expression. We found that basal collagen gene expression was markedly elevated in mouse embryonic fibroblasts (MEFs) lacking PPAR-γ and PPAR-γ ligand 15d-PGJ2 failed to reduce the elevated levels of collagen. Reconstitution of PPAR-γ null MEFs with ectopic PPAR-γ resulted in down-regulation of COL1A2 promoter activity. In contrast to control MEFs, PPAR-γ null MEFs displayed elevated expression of Type I TGF-β receptor TβRI, and produced more TGF-β1. Furthermore, PPAR-γ null MEFs showed Smad2 and Smad3 phosphorylation even in the absence of stimulation by exogenous TGF-β. Constitutive Smad2/3 phosphorylation in PPAR-γ null MEFs was associated with ligand-independent interaction of Smad3 with its cognate DNA recognition site and with p300, a coactivator previously implicated in mediating TGF-β responses. These results indicate that absence of PPAR-γ in MEFs is associated with constitutive up-regulation of collagen gene expression and Smad activation, at least in part, due to autocrine TGF-β stimulation. Importantly, in scleroderma skin fibroblasts, the levels of PPAR-γ were significantly less compared to healthy controls. Therefore, endogenous PPAR-γ may have a physiologic role in controlling Smad-dependent Type I collagen gene expression in fibroblasts and in tissue homeostasis.
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影响因子：
3.7
作者：
Mori, Y;Chen, SJ;Varga, J
通讯作者：
Varga, J
影响因子：
--
作者：
Ghosh, AK;Bhattacharyya, S;Varga, J
通讯作者：
Varga, J
影响因子：
10.5
作者：
Rosen, ED;Hsu, CH;Spiegelman, BM
通讯作者：
Spiegelman, BM
影响因子：
--
作者：
Mori, Y;Chen, SJ;Varga, J
通讯作者：
Varga, J
影响因子：
4.8
作者：
Ihn, H;Ohnishi, K;Trojanowska, M
通讯作者：
Trojanowska, M