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Molecular and Cellular Biology, April 2009, p. 1882-1894, Vol. 29, No. 7
0270-7306/09/$08.00+0     doi:10.1128/MCB.01320-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

Phosphorylation of Fli1 at Threonine 312 by Protein Kinase C {delta} Promotes Its Interaction with p300/CREB-Binding Protein-Associated Factor and Subsequent Acetylation in Response to Transforming Growth Factor β {triangledown}

Yoshihide Asano and Maria Trojanowska*

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

Received 19 August 2008/ Returned for modification 29 October 2008/ Accepted 5 January 2009

Previous studies have shown that transforming growth factor β (TGF-β)-induced collagen gene expression involves acetylation-dependent dissociation from the human {alpha}2(I) collagen (COL1A2) promoter of the transcriptional repressor Fli1. The goal of this study was to elucidate the regulatory steps preceding the acetylation of Fli1. We first showed that TGF-β induces Fli1 phosphorylation on a threonine residue(s). The major phosphorylation site was localized to threonine 312 located in the DNA binding domain of Fli1. Using several independent approaches, we demonstrated that Fli1 is directly phosphorylated by protein kinase C {delta} (PKC {delta}). Additional experiments showed that in response to TGF-β, PKC {delta} is recruited to the collagen promoter to phosphorylate Fli1 and that this step is a prerequisite for the subsequent interaction of Fli1 with p300/CREB-binding protein-associated factor (PCAF) and an acetylation event. The phosphorylation of endogenous Fli1 preceded its acetylation in response to TGF-β stimulation, and the blockade of PKC {delta} abrogated both the phosphorylation and acetylation of Fli1 in dermal fibroblasts. Promoter studies showed that a phosphorylation-deficient mutant of Fli1 exhibited an increased inhibitory effect on the COL1A2 gene, which could not be reversed by the forced expression of PCAF or PKC {delta}. These data strongly suggest that the phosphorylation-acetylation cascade triggered by PKC {delta} represents the primary mechanism whereby TGF-β regulates the transcriptional activity of Fli1 in the context of the collagen promoter.

* Corresponding author. Mailing address: Division of Rheumatology and Immunology, Medical University of South Carolina, Charleston, SC 29425. Phone: (843) 792-7921. Fax: (843) 792-7121. E-mail: trojanme{at}musc.edu

{triangledown} Published ahead of print on 21 January 2009.

Molecular and Cellular Biology, April 2009, p. 1882-1894, Vol. 29, No. 7
0270-7306/09/$08.00+0     doi:10.1128/MCB.01320-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.





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