Ets1 Is an Effector of the Transforming Growth Factor (TGF- ) Signaling Pathway and an Antagonist of the Profibrotic Effects of TGF-

Department of Medicine, Division of Rheumatology and Immunology and the Hollings Cancer Center, Laboratory of Cancer Genomics, Medical University of South Carolina, Charleston, South Carolina 29425, USA.
Journal of Biological Chemistry (Impact Factor: 4.57). 07/2002; 277(23):20399-408. DOI: 10.1074/jbc.M200206200
Source: PubMed


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 COL1A2 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 p300/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.

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    • "Recent reports implicate p300 in the regulation of collagen gene expression by TGF-β1[48]. The expression of p300 and CBP is significantly elevated in the skin of patients with systemic sclerosis[32,36]. In addition, p300 levels in explanted normal fibroblasts were dramatically increased by TGF-β1, and histone H4 hyperacetylation was increased upon p300 accumulation at the collagen gene promoter[31]. "
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    • "There are several key positive and negative regulator proteins of collagen transcription in the setting of fibrotic disease that interact with these sites. The Sp1 family of proteins activates collagen transcription through G/C rich sites [150] [151] , while the Ets domain family of proteins both activate and repress collagen gene expression in fibroblasts [152] [153] . Fig. 2 Model of collagen repression by CIITA during IFN-γ. "
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    • "This confirms previous in vitro studies that showed competition of Ets1 and Fli1 for the Ets binding site on the COL1A2 promoter [10]. While Ets1 has been shown to be a positive mediator of fibrosis [18], [25], its direct role in collagen gene regulation has not been fully defined, and surprisingly overexpression of Ets1 in dermal fibroblasts leads to inhibition of the COL1A2 gene [26]. Interestingly, recent ChIP-chip analysis of the Smad2/3 binding sites in HaCaT cells has revealed that the binding elements for Ets are significantly enriched in the Smad2/3 binding sites and knockdown of Ets1 results in overall alteration of TGF-β-induced transcription, suggesting that Ets contributes to the induction of the TGF-β-Smad pathways [27]. "
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