Ets1 is an effector of the transforming growth factor β (TGF-β) signaling pathway and an antagonist of the profibrotic effects of TGF-β
Ets1 is an effector of the transforming growth factor β (TGF-β) signaling pathway and an antagonist of the profibrotic effects of TGF-β
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DOI：
10.1074/jbc.m200206200
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发表时间：
2002-06-07
影响因子：
4.8
通讯作者：
Trojanowska, M
中科院分区：
文献类型：
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作者：
Czuwara-Ladykowska, J;Sementchenko, VI;Trojanowska, M
细胞外基质(ECM)的产生和周转在正常生理条件下受到严格控制。ETS因子通过激活几种金属蛋白酶(MMPs)的转录来调节基质的周转，在侵袭性肿瘤和关节炎中经常过表达。鉴于转化生长因子-β在细胞外基质合成中的重要作用，本研究旨在探讨Ets1与转化生长因子-β途径之间可能的相互作用。在人成纤维细胞中腺病毒递送Ets1的实验已经证实，Ets1强烈抑制转化生长因子-β对I型胶原和其他基质相关基因的诱导，并逆转转化生长因子-β依赖的对基质金属蛋白酶-1的抑制。随后利用COLIA2启动子的实验证明，在存在转化生长因子-β信号的情况下，Ets1干扰了p300的刺激作用。为了进一步了解Ets1抑制转化生长因子-β信号转导的机制，我们分析了经转化生长因子-β处理后Ets1的蛋白水平和翻译后修饰。经转化生长因子-β刺激24 h后，总Ets1蛋白水平无明显变化。此外，转化生长因子-β并不影响Ets1的丝氨酸或苏氨酸的磷酸化水平。然而，转化生长因子-β可诱导Ets1快速而持久的赖氨酸乙酰化。此外，对内源性p300-Ets1复合体的分析表明，乙酰化的Ets1优先与p300/CBP复合体结合。转化生长因子-β处理导致Ets1从CBP/p300复合体中解离。综上所述，这些发现表明，成纤维细胞中Ets1的高表达从根本上改变了它们对转化生长因子-β的反应，有利于基质降解，而不是像关节炎和癌症那样的基质沉积。
Extracellular matrix (ECM) production and turnover are tightly controlled under normal physiological conditions. Ets factors regulate matrix turnover by activating transcription of several metalloproteinases (MMPs) and are frequently overexpressed in aggressive tumors and arthritis. Because of the prominent role of transforming growth factor beta (TGF-beta) in ECM synthesis, this study was undertaken to determine the possible interactions between Ets1 and the TGF-beta pathway. Experiments using adenoviral delivery of Ets1 in human fibroblasts have established that Ets1 strongly suppresses TGF-beta induction of collagen type I and other matrix-related genes and reverses TGF-beta-dependent inhibition of MMP-1. Subsequent experiments utilizing COLIA2 promoter demonstrated that Ets1 in the presence of TGF-beta signaling interferes with the stimulatory role of p300. To gain further insight into the mechanism of Ets1 inhibition of the TGF-beta signaling, the protein levels and post-translational modifications of Ets1 after TGF-beta treatment were analyzed. The level of total Ets1 protein was not affected after 24 h of TGF-beta stimulation. Moreover, TGF-beta did not affect either serine or threonine phosphorylation levels of Ets1. However, TGF-beta induced rapid and prolonged lysine acetylation of Ets1. In addition, analyses of endogenous p300-Ets1 complexes revealed that acetylated Ets1 is preferentially associated with the p3oo/CBP complexes. TGF-beta treatment leads to dissociation of Ets1 from the CBP/p300 complexes. Together, these findings suggest that elevated expression of Ets1 in fibroblasts fundamentally alters their responses to TGF-beta in favor of matrix degradation and away from matrix deposition as exemplified by arthritis and cancer.