Published online before print February 7, 2008, doi: 10.1161/CIRCRESAHA.107.167395
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Submitted on November 5, 2007
Revised on December 11, 2007
Accepted on January 15, 2008
Angiotensin II–Inducible Platelet-Derived Growth Factor-D Transcription Requires Specific Ser/Thr Residues in the Second Zinc Finger Region of Sp1
Nicole Y. Tan ;
From the Centre for Vascular Research (N.Y.T., V.C.M., M.M.K., F.S.S., X.L., R.P., R.G.F., L.M.K.), School of Medical Sciences, University of New South Wales, Sydney; Department of Immunology (M.C.B.), Monash University, Clayton; and Australian Proteome Analysis Facility (M.P.M.), Macquarie University, Sydney, Australia.
* To whom correspondence should be addressed. E-mail: L.Khachigian{at}unsw.edu.au.
Sp1, the first identified and cloned transcription factor, regulates gene expression via multiple mechanisms including direct protein–DNA interactions, protein–protein interactions, chromatin remodeling, and maintenance of methylation-free CpG islands. Sp1 is itself regulated at different levels, for example, by glycosylation, acetylation, and phosphorylation by kinases such as the atypical protein kinase C-æ. Although Sp1 controls the basal and inducible regulation of many genes, the posttranslational processes regulating its function and their relevance to pathology are not well understood. Here we have used a variety of approaches to identify 3 amino acids (Thr668, Ser670, and Thr681) in the zinc finger domain of Sp1 that are modified by PKC-æ and have generated novel anti-peptide antibodies recognizing the PKC-æ–phosphorylated form of Sp1. Angiotensin II, which activates PKC-æ phosphorylation (at Thr410) via the angiotensin II type 1 receptor, stimulates Sp1 phosphorylation and increases Sp1 binding to the platelet-derived growth factor-D promoter. All 3 residues in Sp1 (Thr668, Ser670, and Thr681) are required for Sp1-dependent platelet-derived growth factor-D activation in response to angiotensin II. Immunohistochemical analysis revealed that phosphorylated Sp1 is expressed in smooth muscle cells of human atherosclerotic plaques and is dynamically expressed together with platelet-derived growth factor-D in smooth muscle cells of the injured rat carotid artery wall. This study provides new insights into the regulatory mechanisms controlling the PKC-æ–phospho-Sp1 axis and angiotensin II–inducible gene expression.
Key words: Sp1 phosphorylation • PKC-æ • PDGF-D • transcription
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