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J. Biol. Chem., Vol. 275, Issue 22, 16709-16716, June 2, 2000
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Induction of Platelet-derived Growth Factor B-chain Expression by Transforming Growth Factor-beta Involves Transactivation by Smads*

Lisa M. Taylor and Levon M. KhachigianDagger

From the Centre for Thrombosis and Vascular Research, The University of New South Wales and Prince of Wales Hospital, Sydney, New South Wales 2052, Australia

Transforming growth factor-beta (TGF-beta ) regulates a diverse array of biological processes, such as proliferation, differentiation, extracellular matrix production, and apoptosis. In cultured vascular endothelial cells, TGF-beta induces the expression of platelet-derived growth factor (PDGF) B-chain, a mitogen and chemoattractant, at the level of transcription. The molecular mechanism(s) underlying this process are not presently understood. In this study, we performed serial 5' deletion and transient transfection analysis to define a region in the PDGF-B promoter mediating inducible responsiveness to TGF-beta . This region contains an atypical nucleotide recognition element for the Smad family of transcriptional regulators. Electrophoretic mobility shift analysis revealed that nuclear proteins bound to this site in a transient and specific manner. Supershift studies demonstrated the physical association of Smad4 with the promoter. Overexpression of Smad4 activated the PDGF-B promoter and superinduced PDGF-B promoter-dependent expression in cells exposed to TGF-beta . Moreover, simultaneous cotransfection of Smad3 and Smad4 activated the PDGF-B promoter. This effect was attenuated when Smad4 was substituted with its dominant negative counterpart. Mutation of the -81CAGA-78 motif in the PDGF-B promoter abrogated Smad-inducible promoter-dependent expression. Overexpression of Smad2 and Smad3 transactivated the PDGF-B promoter in a synergistic manner. These findings demonstrate the existence of a novel, functional binding element in the proximal region of the PDGF-B promoter mediating responsiveness to TGF-beta .

* This work was supported in part by grants from the National Heart Foundation of Australia and National Health and Medical Research Council of Australia and by a New South Wales Health Department Infrastructure grant.The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Dagger Supported by a research fellowship from the National Health and Medical Research Council of Australia. To whom correspondence should be addressed: Centre for Thrombosis and Vascular Research, School of Pathology, The University of New South Wales, Sydney, NSW 2052, Australia. Tel.: 61-2-9385-2537; Fax: 61-2-9385-1389; Email: L. Khachigian@unsw.edu.au.

Copyright © 2000 by The American Society for Biochemistry and Molecular Biology, Inc.
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