The transcriptional cofactor nab2 is induced by tgf-Beta and suppresses fibroblast activation: physiological roles and impaired expression in scleroderma.
The transcriptional cofactor nab2 is induced by tgf-Beta and suppresses fibroblast activation: physiological roles and impaired expression in scleroderma.
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DOI：
10.1371/journal.pone.0007620
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发表时间：
2009-10-26
期刊：
影响因子：
3.7
通讯作者：
Varga J
中科院分区：
文献类型：
--
作者：
Bhattacharyya S;Wei J;Melichian DS;Milbrandt J;Takehara K;Varga J
转化生长因子-β(转化生长因子-β)通过刺激胶原合成和肌成纤维细胞分化，在组织修复和纤维化中发挥重要作用。早期生长反应-1(Egr-1)转录因子介导促纤维化转化生长因子-β反应，其在硬皮病患者的活检组织中表达升高。NGF1-A结合蛋白2(Nab2)是一种保守的转录辅助因子，可直接与Egr-1结合，对Egr-1靶基因转录起正向或负向调节作用。尽管NAb2在调节Egr-1依赖的反应强度方面具有公认的重要性，但在纤维化的转化生长因子-β信号转导中，NaB2的调节和功能尚不清楚。在此，我们发现转化生长因子-β对正常成纤维细胞的NaB2蛋白和基因表达有时间依赖性的刺激作用。在这些细胞中异位表达NaB2阻断了Egr-1依赖的转录反应，并取消了转化生长因子-β诱导的胶原合成和肌成纤维细胞分化的刺激。NaB2的这些抑制作用涉及到NuRD染色质重塑复合体对COL1A2启动子的募集，并伴随着组蛋白H4乙酰化的减少。靶向缺失NaB2的小鼠显示真皮中胶原沉积增加，基因或siRNA介导的成纤维细胞中NaB2的丢失与胶原合成的结构性增加和体外依附于Egr-1的转化生长因子-β反应的增强有关。硬皮病患者皮肤活检组织中Nab2的表达明显上调，且主要定位于表皮角质形成细胞。相反，在真皮成纤维细胞中可检测到少量的NaB2。这些结果表明，NaB2是一种新型的内源性负调控因子，参与调节纤维化反应的强度，调节Egr-1依赖的转化生长因子-β信号转导。真皮成纤维细胞中NAB2的表达或功能缺陷可能在硬皮病的持续性纤维化反应中起作用。
By stimulating collagen synthesis and myofibroblasts differentiation, transforming growth factor-β (TGF- β) plays a pivotal role in tissue repair and fibrosis. The early growth response-1 (Egr-1) transcription factor mediates profibrotic TGF-β responses, and its expression is elevated in biopsies from patients with scleroderma. NGF1-A-binding protein 2 (Nab2) is a conserved transcriptional cofactor that directly binds to Egr-1 and positively or negatively modulates Egr-1 target gene transcription. Despite the recognized importance of Nab2 in governing the intensity of Egr-1-dependent responses, the regulation and function of Nab2 in the context of fibrotic TGF-β signaling is unknown. Here we show that TGF-β caused a time-dependent stimulation of Nab2 protein and mRNA in normal fibroblasts. Ectopic expression of Nab2 in these cells blocked Egr-1-dependent transcriptional responses, and abrogated TGF-β-induced stimulation of collagen synthesis and myofibroblasts differentiation. These inhibitory effects of Nab2 involved recruitment of the NuRD chromatin remodeling complex to the COL1A2 promoter and were accompanied by reduced histone H4 acetylation. Mice with targeted deletion of Nab2 displayed increased collagen accumulation in the dermis, and genetic or siRNA-mediated loss of Nab2 in fibroblasts was associated with constitutively elevated collagen synthesis and accentuation of Egr-1-dependent TGF-β responses in vitro. Expression of Nab2 was markedly up-regulated in skin biopsies from patients with scleroderma, and was localized primarily to epidermal keratinocytes. In contrast, little Nab2 could be detected in dermal fibroblasts. These results identify Nab2 as a novel endogenous negative regulator of Egr-1-dependent TGF-β signaling responsible for setting the intensity of fibrotic responses. Defective Nab2 expression or function in dermal fibroblasts might play a role in persistent fibrotic responses in scleroderma.
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影响因子：
6
作者：
Bhattacharyya, Swati;Chen, Shu-Jen;Varga, John
通讯作者：
Varga, John
影响因子：
4.8
作者：
Ihn, H;LeRoy, EC;Trojanowska, M
通讯作者：
Trojanowska, M
DOI：
10.1016/j.bbrc.2006.12.011
发表时间：
2007-02-02
影响因子：
3.1
作者：
Fukuda, Toru;Kanomata, Kazuhiro;Katagiri, Takenobu
通讯作者：
Katagiri, Takenobu
DOI：
10.1006/bbrc.2001.4810
发表时间：
2001-05-04
影响因子：
3.1
作者：
Houston, P;Campbell, CJ;Braddock, M
通讯作者：
Braddock, M
影响因子：
--
作者：
Mori, Y;Ishida, W;Varga, J
通讯作者：
Varga, J