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

J. Biol. Chem., Vol. 278, Issue 13, 11661-11669, March 28, 2003

This Article Full Text Full Text (PDF) All Versions of this Article: 278/13/11661    most recent M211337200v1 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 King, K. E. Articles by Shanahan, C. M. Search for Related Content PubMed PubMed Citation Articles by King, K. E. Articles by Shanahan, C. M. Social Bookmarking                      What's this?

Krüppel-like Factor 4 (KLF4/GKLF) Is a Target of Bone Morphogenetic Proteins and Transforming Growth Factor 1 in the Regulation of Vascular Smooth Muscle Cell Phenotype^*

Kathryn E. King, Valentine P. Iyemere, Peter L. Weissberg, and Catherine M. Shanahan

From the University of Cambridge, Department of Medicine, Addenbrooke's Centre for Clinical Investigation Level 6, Box 110 Addenbrooke's Hospital, Hills Rd., Cambridge CB2 2QQ, United Kingdom

Vascular smooth muscle cell (VSMC) differentiation and phenotypic modulation is characterized by changes in mRNA expression for smooth muscle (SM) marker contractile proteins such as -SM actin and SM22. Transforming growth factor 1 (TGF-1) is a potent VSMC differentiation factor; however, it is not known if other TGF--superfamily members, in particular the bone morphogenetic proteins (BMPs), modulate VSMC phenotype. Here we demonstrate that a large subset of TGF--superfamily members and their type I receptors are differentially co-expressed as VSMC phenotype changes during fetal/neonatal development and that BMP2, -4, and -6 reciprocally regulate SM-marker mRNA and protein expression in vitro. BMP2 and BMP6 decrease expression of the SM markers -SM actin, SM22, and calponin in rat VSMCs, whereas BMP4 increases their expression. The effects of BMP-2, -4, and -6 on SM marker gene transcription are mediated through a consensus TGF--controlling element, the TCE, which is common to regulatory regions of SM-marker genes. Moreover, co-treatment experiments revealed that BMP-2, -4, and -6 each inhibit TGF-1-modulated increases in SM22 reporter gene activity. Regardless of whether they positively or negatively regulate SM marker expression, TGF-1 and BMP-2, -4, and -6 all induced binding of the Krüppel-like transcription factor, GKLF/KLF4, to the TGF- control element. Induction of KLF4 was confirmed by immunocytochemistry and Western blotting, which revealed that a lower molecular weight KLF4 protein is induced after treatment with TGF--superfamily members. Taken together, our results demonstrate that multiple members of the TGF- superfamily act in concert to modulate VSMC phenotype.

CiteULike

Complore

Connotea

Del.icio.us

Digg

Reddit

Technorati

This article has been cited by other articles:

				K. Kawai-Kowase, T. Ohshima, H. Matsui, T. Tanaka, T. Shimizu, T. Iso, M. Arai, G. K. Owens, and M. Kurabayashi PIAS1 Mediates TGF{beta}-Induced SM {alpha}-Actin Gene Expression Through Inhibition of KLF4 Function-Expression by Protein Sumoylation Arterioscler. Thromb. Vasc. Biol., January 1, 2009; 29(1): 99 - 106. [Abstract] [Full Text] [PDF]

				P. B. Yu, D. Y. Deng, H. Beppu, C. C. Hong, C. Lai, S. A. Hoyng, N. Kawai, and K. D. Bloch Bone Morphogenetic Protein (BMP) Type II Receptor Is Required for BMP-mediated Growth Arrest and Differentiation in Pulmonary Artery Smooth Muscle Cells J. Biol. Chem., February 15, 2008; 283(7): 3877 - 3888. [Abstract] [Full Text] [PDF]

				G. Lagna, M. M. Ku, P. H. Nguyen, N. A. Neuman, B. N. Davis, and A. Hata Control of Phenotypic Plasticity of Smooth Muscle Cells by Bone Morphogenetic Protein Signaling through the Myocardin-related Transcription Factors J. Biol. Chem., December 21, 2007; 282(51): 37244 - 37255. [Abstract] [Full Text] [PDF]

				R. J. LeClair, T. Durmus, Q. Wang, P. Pyagay, A. Terzic, and V. Lindner Cthrc1 Is a Novel Inhibitor of Transforming Growth Factor-{beta} Signaling and Neointimal Lesion Formation Circ. Res., March 30, 2007; 100(6): 826 - 833. [Abstract] [Full Text] [PDF]

				K. Hayashi, S. Nakamura, W. Nishida, and K. Sobue Bone Morphogenetic Protein-Induced Msx1 and Msx2 Inhibit Myocardin-Dependent Smooth Muscle Gene Transcription Mol. Cell. Biol., December 15, 2006; 26(24): 9456 - 9470. [Abstract] [Full Text] [PDF]

				G. Lagna, P. H. Nguyen, W. Ni, and A. Hata BMP-dependent activation of caspase-9 and caspase-8 mediates apoptosis in pulmonary artery smooth muscle cells. Am J Physiol Lung Cell Mol Physiol, November 1, 2006; 291(5): L1059 - L1067. [Abstract] [Full Text] [PDF]

				A. Bobik Transforming Growth Factor-{beta}s and Vascular Disorders Arterioscler. Thromb. Vasc. Biol., August 1, 2006; 26(8): 1712 - 1720. [Abstract] [Full Text] [PDF]

				Y. Zeng, S. Zhuang, J. Gloddek, C.-C. Tseng, G. R. Boss, and R. B. Pilz Regulation of cGMP-dependent Protein Kinase Expression by Rho and Kruppel-like Transcription Factor-4 J. Biol. Chem., June 23, 2006; 281(25): 16951 - 16961. [Abstract] [Full Text] [PDF]

				K. A. Hruska, S. Mathew, and G. Saab Bone Morphogenetic Proteins in Vascular Calcification Circ. Res., July 22, 2005; 97(2): 105 - 114. [Abstract] [Full Text] [PDF]

				P. B. Yu, H. Beppu, N. Kawai, E. Li, and K. D. Bloch Bone Morphogenetic Protein (BMP) Type II Receptor Deletion Reveals BMP Ligand-specific Gain of Signaling in Pulmonary Artery Smooth Muscle Cells J. Biol. Chem., July 1, 2005; 280(26): 24443 - 24450. [Abstract] [Full Text] [PDF]

				X. Yang, L. Long, M. Southwood, N. Rudarakanchana, P. D. Upton, T. K. Jeffery, C. Atkinson, H. Chen, R. C. Trembath, and N. W. Morrell Dysfunctional Smad Signaling Contributes to Abnormal Smooth Muscle Cell Proliferation in Familial Pulmonary Arterial Hypertension Circ. Res., May 27, 2005; 96(10): 1053 - 1063. [Abstract] [Full Text] [PDF]

				K. Bostrom, A. F. Zebboudj, Y. Yao, T. S. Lin, and A. Torres Matrix GLA Protein Stimulates VEGF Expression through Increased Transforming Growth Factor-{beta}1 Activity in Endothelial Cells J. Biol. Chem., December 17, 2004; 279(51): 52904 - 52913. [Abstract] [Full Text] [PDF]

				H. Wang, L. Yang, Md. S. Jamaluddin, and D. D. Boyd The Kruppel-like KLF4 Transcription Factor, a Novel Regulator of Urokinase Receptor Expression, Drives Synthesis of This Binding Site in Colonic Crypt Luminal Surface Epithelial Cells J. Biol. Chem., May 21, 2004; 279(21): 22674 - 22683. [Abstract] [Full Text] [PDF]

				A. Y. Pandya, L. I. Talley, A. R. Frost, T. J. Fitzgerald, V. Trivedi, M. Chakravarthy, D. C. Chhieng, W. E. Grizzle, J. A. Engler, H. Krontiras, et al. Nuclear Localization of KLF4 Is Associated with an Aggressive Phenotype in Early-Stage Breast Cancer Clin. Cancer Res., April 15, 2004; 10(8): 2709 - 2719. [Abstract] [Full Text] [PDF]