HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

J. Biol. Chem., Vol. 279, Issue 4, 2377-2382, January 23, 2004

This Article Full Text Full Text (PDF) An addition or correction has been published All Versions of this Article: 279/4/2377    most recent M308254200v1 Submit a Letter to Editor Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Bonello, M. R. Articles by Khachigian, L. M. Search for Related Content PubMed PubMed Citation Articles by Bonello, M. R. Articles by Khachigian, L. M. Social Bookmarking                      What's this?

Fibroblast Growth Factor-2 Represses Platelet-derived Growth Factor Receptor- (PDGFR-) Transcription via ERK1/2-dependent Sp1 Phosphorylation and an Atypical cis-Acting Element in the Proximal PDGFR- Promoter^*

Michelle R. Bonello and Levon M. Khachigian

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

Platelet-derived growth factor (PDGF) is a potent mitogen and chemoattractant for vascular smooth muscle cells (SMCs) whose biological activity is mediated via its high affinity interaction with specific cell surface receptors. The molecular mechanisms governing the expression of PDGF receptor- (PDGFR-) are poorly understood. Here we demonstrate that PDGFR- protein and transcriptional regulation in SMCs is under the positive regulatory influence of the zinc finger nuclear protein, Sp1. Electrophoretic mobility shift, competition, and supershift analysis revealed the existence of an atypical G-rich Sp1-binding element located in the PDGFR- promoter –61 to –52 bp upstream of the transcriptional start site. Mutation of this sequence ablated endogenous Sp1 binding and activation of the PDGFR- promoter. PDGFR- transcription, mRNA, and protein expression were repressed in SMCs exposed to fibroblast growth factor-2 (FGF-2). This inhibition was rescued by the blockade of extracellular signal-regulated kinase-1/2 (ERK1/2). FGF-2 repression of PDGFR- transcription was abrogated upon mutation of this Sp1-response element. FGF-2 stimulated Sp1 phosphorylation in an ERK1/2- but not p38-dependent manner, the growth factor enhancing Sp1 interaction with the PDGFR- promoter. Mutation of residues Thr⁴⁵³ and Thr⁷³⁹ in Sp1 (amino acids phosphorylated by ERK) blocked FGF-2 repression of PDGFR- transcription. These findings, taken together, demonstrate that FGF-2 stimulates ERK1/2-dependent Sp1 phosphorylation, thereby repressing PDGFR- transcription via the –61/–52 element in the PDGFR- promoter. Phosphorylation triggered by FGF-2 switches Sp1 from an activator to a repressor of PDGFR- transcription, a finding previously unreported in any Sp1-dependent gene.

Received for publication, July 29, 2003 , and in revised form, October 23, 2003.

^* 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. This work was supported by grants from the National Health and Medical Research Council (NHMRC), National Heart Foundation, Australian Research Council, and an Infrastructure Grant from New South Wales Department of Health. 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.

Supported by an Australian Postgraduate Research Award.

A Principal Research Fellow of the NHMRC. To whom correspondence should be addressed: Centre for Vascular Research, Dept. of Pathology, The University of New South Wales, Sydney NSW 2052 Australia. Tel.: 61-2-9385-2537; Fax: 61-2-9385-1389; E-mail: L.Khachigian{at}unsw.edu.Au.

CiteULike    Complore    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

This article has been cited by other articles:

				S. Wei, H.-C. Chuang, W.-C. Tsai, H.-C. Yang, S.-R. Ho, A. J. Paterson, S. K. Kulp, and C.-S. Chen Thiazolidinediones Mimic Glucose Starvation in Facilitating Sp1 Degradation through the Up-Regulation of {beta}-Transducin Repeat-Containing Protein Mol. Pharmacol., July 1, 2009; 76(1): 47 - 57. [Abstract] [Full Text] [PDF]

				H. S. Kim and I. K. Lim Phosphorylated Extracellular Signal-regulated Protein Kinases 1 and 2 Phosphorylate Sp1 on Serine 59 and Regulate Cellular Senescence via Transcription of p21Sdi1/Cip1/Waf1 J. Biol. Chem., June 5, 2009; 284(23): 15475 - 15486. [Abstract] [Full Text] [PDF]

				N. Y. Tan and L. M. Khachigian Sp1 Phosphorylation and Its Regulation of Gene Transcription Mol. Cell. Biol., May 15, 2009; 29(10): 2483 - 2488. [Full Text] [PDF]

				R. Jochmann, M. Thurau, S. Jung, C. Hofmann, E. Naschberger, E. Kremmer, T. Harrer, M. Miller, N. Schaft, and M. Sturzl O-Linked N-Acetylglucosaminylation of Sp1 Inhibits the Human Immunodeficiency Virus Type 1 Promoter J. Virol., April 15, 2009; 83(8): 3704 - 3718. [Abstract] [Full Text] [PDF]

				R. A. Deaton, Q. Gan, and G. K. Owens Sp1-dependent activation of KLF4 is required for PDGF-BB-induced phenotypic modulation of smooth muscle Am J Physiol Heart Circ Physiol, April 1, 2009; 296(4): H1027 - H1037. [Abstract] [Full Text] [PDF]

				K. Qin, L. Zhao, R. D. Ash, W. F. McDonough, and R. Y. Zhao ATM-mediated Transcriptional Elevation of Prion in Response to Copper-induced Oxidative Stress J. Biol. Chem., February 13, 2009; 284(7): 4582 - 4593. [Abstract] [Full Text] [PDF]

				C.-C. Wu, J.-C. Lin, S.-C. Yang, C.-W. Lin, J. J.W. Chen, J.-Y. Shih, T.-M. Hong, and P.-C. Yang Modulation of the expression of the invasion-suppressor CRMP-1 by cyclooxygenase-2 inhibition via reciprocal regulation of Sp1 and C/EBP{alpha} Mol. Cancer Ther., June 1, 2008; 7(6): 1365 - 1375. [Abstract] [Full Text] [PDF]

				J.-Y. Chuang, Y.-T. Wang, S.-H. Yeh, Y.-W. Liu, W.-C. Chang, and J.-J. Hung Phosphorylation by c-Jun NH2-terminal Kinase 1 Regulates the Stability of Transcription Factor Sp1 during Mitosis Mol. Biol. Cell, March 1, 2008; 19(3): 1139 - 1151. [Abstract] [Full Text] [PDF]

				N. Y. Tan, V. C. Midgley, M. M. Kavurma, F. S. Santiago, X. Luo, R. Peden, R. G. Fahmy, M. C. Berndt, M. P. Molloy, and L. M. Khachigian Angiotensin II-Inducible Platelet-Derived Growth Factor-D Transcription Requires Specific Ser/Thr Residues in the Second Zinc Finger Region of Sp1 Circ. Res., February 29, 2008; 102(4): e38 - e51. [Abstract] [Full Text] [PDF]

				Y. Zhang, M. Liao, and M. L. Dufau Phosphatidylinositol 3-Kinase/Protein Kinase C{zeta}-Induced Phosphorylation of Sp1 and p107 Repressor Release Have a Critical Role in Histone Deacetylase Inhibitor-Mediated Depression of Transcription of the Luteinizing Hormone Receptor Gene. Mol. Cell. Biol., September 1, 2006; 26(18): 6748 - 6761. [Abstract] [Full Text] [PDF]

				J. Jiang, X. Chen, J. Shen, Y. Wei, T. Wu, Y. Yang, H. Wang, H. Zong, J. Yang, S. Zhang, et al. beta1,4-Galactosyltransferase V Functions as a Positive Growth Regulator in Glioma J. Biol. Chem., April 7, 2006; 281(14): 9482 - 9489. [Abstract] [Full Text] [PDF]

				C. Fischer, H. Sanchez-Ruderisch, M. Welzel, B. Wiedenmann, T. Sakai, S. Andre, H.-J. Gabius, L. Khachigian, K. M. Detjen, and S. Rosewicz Galectin-1 Interacts with the {alpha}5{beta}1 Fibronectin Receptor to Restrict Carcinoma Cell Growth via Induction of p21 and p27 J. Biol. Chem., November 4, 2005; 280(44): 37266 - 37277. [Abstract] [Full Text] [PDF]

				M. R. Bonello, Y. V. Bobryshev, and L. M. Khachigian Peroxide-Inducible Ets-1 Mediates Platelet-Derived Growth Factor Receptor-{alpha} Gene Transcription in Vascular Smooth Muscle Cells Am. J. Pathol., October 1, 2005; 167(4): 1149 - 1159. [Abstract] [Full Text] [PDF]

				R. Sancho, N. Marquez, M. Gomez-Gonzalo, M. A. Calzado, G. Bettoni, M. T. Coiras, J. Alcami, M. Lopez-Cabrera, G. Appendino, and E. Munoz Imperatorin Inhibits HIV-1 Replication through an Sp1-dependent Pathway J. Biol. Chem., September 3, 2004; 279(36): 37349 - 37359. [Abstract] [Full Text] [PDF]

				K. L. Abrams, J. Xu, C. Nativelle-Serpentini, S. Dabirshahsahebi, and M. B. Rogers An Evolutionary and Molecular Analysis of Bmp2 Expression J. Biol. Chem., April 16, 2004; 279(16): 15916 - 15928. [Abstract] [Full Text] [PDF]