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

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

ABSTRACT 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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    • "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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    ABSTRACT: Extracellular matrix (ECM) within the vascular network provides both a structural and regulatory role. The ECM is a dynamic composite of multiple proteins that form structures connecting cells within the network. Blood vessels are distended by blood pressure and, therefore, require ECM components with elasticity yet with enough tensile strength to resist rupture. The ECM is involved in conducting mechanical signals to cells. Most importantly, ECM regulates cellular function through chemical signaling by controlling activation and bioavailability of the growth factors. Cells respond to ECM by remodeling their microenvironment which becomes dysregulated in vascular diseases such hypertension, restenosis and atherosclerosis. This review examines the cellular and ECM components of vessels, with specific emphasis on the regulation of collagen type I and implications in vascular disease.
    01/2014; 28(1):25-39. DOI:10.7555/JBR.27.20130064
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    • "Previous studies have identified an essential role for p300 acetyltransferase and its interaction with Smads in TGF-binduced profibrotic responses (Ghosh et al., 2000, 2001, 2004, 2009; Czuwara-Ladykowska et al., 2002). Despite its critical role in modulating profibrotic responses elicited by TGF-b and other mediators, the regulation of p300 expression and activity, as well as the mechanisms underlying their derangement in fibrotic diseases, have received scant attention to date. "
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    ABSTRACT: Fibrosis, the hallmark of systemic sclerosis (SSc), is characterized by persistent fibroblast activation triggered by transforming growth factor-β (TGF-β). As the acetyltransferase p300 has a key role in fibrosis and its availability governs the intensity of fibrotic responses, we investigated p300 expression in SSc and the molecular basis of its regulation. We found that expression of p300 was markedly elevated in SSc skin biopsies and was induced by TGF-β in explanted normal skin fibroblasts. Stimulation of p300 by TGF-β was independent of Smads and involved the early-immediate transcription factor Egr-1 (early growth response 1), a key regulator of profibrotic TGF-β signaling. Indeed, Egr-1 was both sufficient and necessary for p300 regulation in vitro and in vivo. Increased p300 accumulation in TGF-β-treated fibroblasts was associated with histone hyperacetylation, whereas p300 depletion, or selective pharmacological blockade of its acetyltransferase activity, attenuated TGF-β-induced responses. Moreover, TGF-β enhanced both p300 recruitment and in vivo histone H4 acetylation at the COL1A2 (collagen, type I, α2) locus. These findings implicate p300-mediated histone acetylation as a fundamental epigenetic mechanism in fibrogenesis and place Egr-1 upstream in TGF-β-driven stimulation of p300 gene expression. The results establish a firm link between fibrosis with aberrant p300 expression and epigenetic activity that, to our knowledge, is previously unreported. Targeted disruption of p300-mediated histone acetylation might therefore represent a viable antifibrotic strategy.Journal of Investigative Dermatology advance online publication, 10 January 2013; doi:10.1038/jid.2012.479.
    Journal of Investigative Dermatology 01/2013; 133(5). DOI:10.1038/jid.2012.479 · 6.37 Impact Factor
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    • "Far less is known about Ets factor function(s) in non-neoplastic disease, but, as in neoplasia, Ets factors appear to be important disease modifiers. Ets1 exerts an anti-fibrogenic effect in fibroblasts, antagonizing the effects of TGFβ (Knittel et al., 1999; Czuwara-Ladykowska et al., 2002), and Ets1 knock-out mice exhibit features of autoimmune disease in multiple organs (Wang et al., 2005). Additionally, 3' polymorphisms of Ets1 are associated with different clinical manifestations of systemic lupus erythematosus (Sullivan et al., 2000). "
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    ABSTRACT: Ets transcription factors comprise a large family of sequence-specific regulators of gene expression with important and diverse roles in development and disease. Most Ets family members are expressed in the developing and/or mature intestine, frequently in a compartment-specific and temporally dynamic manner. However, with the exception of the highly expressed Elf3, involved in embryonic epithelial differentiation, little is known about Ets functions in intestinal development and homeostasis. Ets factors show altered expression in colon cancer, where they regulate pathways relevant to tumor progression. Ets factors also likely act as important modifiers of non-neoplastic intestinal disease by regulating pathways relevant to tissue injury and repair. Despite a large body of published work on Ets biology, much remains to be learned about the precise functions of this large and diverse gene family in intestinal morphogenesis, homeostasis, and both neoplastic and non-neoplastic pathology.
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