Nucleic Acids Research, 2001, Vol. 29, No. 5 1027-1033
© 2001 Oxford University Press
Sp1 phosphorylation regulates inducible expression of platelet-derived growth factor B-chain gene via atypical protein kinase C-
Department of Haematology, The Prince of Wales Hospital and Centre for Thrombosis and Vascular Research, School of Pathology, The University of New South Wales, Sydney, NSW 2052, Australia
Platelet-derived growth factor (PDGF) is a broadly expressed mitogenic and chemotactic factor with diverse roles in a number of physiologic and pathologic settings. The zinc finger transcription factors Sp1, Sp3 and Egr-1 bind to overlapping elements in the proximal PDGF B-chain promoter and activate transcription of this gene. The anthracycline nogalamycin has previously been reported to inhibit the capacity of Egr-1 to bind DNA in vitro. Here we used electrophoretic mobility shift assays to show that nogalamycin added to cells in culture did not alter the interaction of Egr-1 with the PDGF-B promoter. Instead, it enhanced the capacity of Sp1 to bind DNA. Nogalamycin increased PDGF-B mRNA expression at the level of transcription, which was abrogated by mutation of the Sp1 binding site in the PDGF-B promoter or overexpression of mutant Sp1. Rather than increasing total levels of Sp1, nogalamycin altered the phosphorylation state of the transcription factor. Overexpression of dominant-negative PKC-
blocked nogalamycin-inducible Sp1 phosphorylation and PDGF-B promoter-dependent expression. Nogalamycin stimulated the phosphorylation of PKC- (on residue Thr410). These findings demonstrate for the first time that PKC- and Sp1 phosphorylation mediate the inducible expression of this growth factor.
* To whom correspondence should be addressed. Tel: +61 2 9385 2537; Fax: +61 2 9385 1389; Email: l.khachigian{at}unsw.edu.au
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