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J. Biol. Chem., Vol. 282, Issue 48, 34672-34683, November 30, 2007

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Transforming Growth Factor-β Regulates DNA Binding Activity of Transcription Factor Fli1 by p300/CREB-binding Protein-associated Factor-dependent Acetylation^*

From the Division of Rheumatology and Immunology, Medical University of South Carolina, Charleston, South Carolina 29425

Fli1, a member of Ets transcriptional factors, has been shown to be a negative regulator of collagen gene expression in dermal fibroblasts. Although Fli1 down-regulation is implicated in pathological matrix remodeling such as cutaneous fibrosis in scleroderma, very little is known about the post-translational mechanisms regulating Fli1 function. The aim of this study was to investigate the role of acetylation, one of the main post-translational regulatory mechanisms, in regulating Fli1 activity. We initially demonstrated that Fli1 is acetylated by transforming growth factor (TGF)-β1 in dermal fibroblasts. An in vivo acetylation assay using 293T cells revealed that Fli1 is mainly acetylated by the histone acetyltransferase activity of p300/CBP-associated factor (PCAF) at lysine 380. Acetylation of Fli1 resulted in a decreased stability of Fli1 protein. More importantly, reduced binding of acetylated Fli1 to the human 2(I) collagen (COL1A2) promoter was observed in DNA affinity precipitation and chromatin immunoprecipitation. Conversely, a Fli1 K380R mutant that is resistant to acetylation by PCAF showed increased DNA binding ability. Furthermore, PCAF overexpression reversed the inhibitory effect of Fli1 on TGF-β1-mediated COL1A2 promoter activity. In contrast, the Fli1 K380R mutant had a greater inhibitory effect on TGF-β1-induced COL1A2 promoter activity than wild-type Fli1, and PCAF failed to reverse this effect. These results indicate that PCAF-dependent acetylation of lysine 380 abrogates repressor function of Fli1 with respect to collagen gene expression. Furthermore, these data strongly suggest that the TGF-β-dependent acetylation of Fli1 may represent the principal mechanism responsible for the TGF-β-induced dissociation of Fli1 from the collagen promoter.

Received for publication, May 11, 2007 , and in revised form, September 13, 2007.

^* This work was supported by National Institutes of Health Grants AR42334 and PO1 CA78582. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ Present address: Dept. of Dermatology, Central Clinical Hospital MSWiA, Woloska 137, Warsaw 02-507, Poland.

² To whom correspondence should be addressed: Division of Rheumatology and Immunology, Medical University of South Carolina, CSB 912, 96 Jonathan Lucas St., Charleston, SC 29425. Tel.: 843-792-7921; Fax: 843-792-7121; E-mail: trojanme{at}musc.edu.

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