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

J. Biol. Chem., Vol. 280, Issue 35, 31172-31181, September 2, 2005

This Article Full Text Full Text (PDF) All Versions of this Article: 280/35/31172    most recent M504774200v1 Alert me when this article is cited 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 Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Deaton, R. A. Articles by Grant, S. R. Search for Related Content PubMed PubMed Citation Articles by Deaton, R. A. Articles by Grant, S. R. Social Bookmarking                      What's this?

Transforming Growth Factor-1-induced Expression of Smooth Muscle Marker Genes Involves Activation of PKN and p38 MAPK^*

Rebecca A. Deaton, Chang Su, Thomas G. Valencia, and Stephen R. Grant

From the Cardiovascular Research Institute, Department of Integrative Physiology and Department of Biomedical Science, University of North Texas Health Science Center, Fort Worth, Texas 76107

Differentiated vascular smooth muscle cells (SMCs) exhibit a work phenotype characterized by expression of several well documented contractile apparatus-associated proteins. However, SMCs retain the ability to de-differentiate into a proliferative phenotype, which is involved in the progression of vascular diseases such as atherosclerosis and restenosis. Understanding the mechanisms involved in maintaining SMC differentiation is critical for preventing proliferation associated with vascular disease. In this study, the molecular mechanisms through which transforming growth factor-1 (TGF-1) induces differentiation of SMCs were examined. TGF-1 stimulated actin re-organization, inhibited cell proliferation, and up-regulated SMC marker gene expression in PAC-1 SMCs. These effects were blocked by pretreatment of cells with either HA1077 or Y-27632, which inhibit the kinases downstream of RhoA. Moreover, TGF-1 activated RhoA and its downstream target PKN. Overexpression of active PKN alone was sufficient to increase the transcriptional activity of the promoters that control expression of smooth muscle (SM) -actin, SM-myosin heavy chain, and SM22. In addition, PKN increased the activities of serum-response factor (SRF), GATA, and MEF2-dependent enhancer-reporters. RNA interference-mediated inhibition of PKN abolished TGF-1-induced activation of SMC marker gene promoters. Finally, examination of MAPK signaling demonstrated that TGF-1 increased the activity of p38 MAPK, which was required for activation of the SMC marker gene promoters. Co-expression of dominant negative p38 MAPK was sufficient to block PKN-mediated activation of the SMC marker gene promoters as well as the serum-response factor, GATA, and MEF2 enhancers. Taken together, these results identify components of an important intracellular signaling pathway through which TGF-1 activates PKN to promote differentiation of SMCs.

Received for publication, May 2, 2005 , and in revised form, June 15, 2005.

^* This work was supported in part by NHLB Grant RO-1 HL67152 from the National Institutes of Health (to S. R. G.) and American Heart Association Texas Affiliate Grant 0150766 (to S. R. G). 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.

To whom correspondence should be addressed: University of North Texas Health Science Center, Dept. of Integrative Physiology, 3500 Camp Bowie Blvd., Fort Worth, TX 76107-2699. Tel.: 817-735-2134; Fax: 817-735-0341; E-mail: sgrant{at}hsc.unt.edu.

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

This article has been cited by other articles:

				T. A. Townsend, J. L. Wrana, G. E. Davis, and J. V. Barnett Transforming Growth Factor-{beta}-stimulated Endocardial Cell Transformation Is Dependent on Par6c Regulation of RhoA J. Biol. Chem., May 16, 2008; 283(20): 13834 - 13841. [Abstract] [Full Text] [PDF]

				S. H. Phan Biology of Fibroblasts and Myofibroblasts Proceedings of the ATS, April 15, 2008; 5(3): 334 - 337. [Abstract] [Full Text] [PDF]

				H. Dadlani, M. L. Ballinger, N. Osman, R. Getachew, and P. J. Little Smad and p38 MAP Kinase-mediated Signaling of Proteoglycan Synthesis in Vascular Smooth Muscle J. Biol. Chem., March 21, 2008; 283(12): 7844 - 7852. [Abstract] [Full Text] [PDF]

				S. Kennard, H. Liu, and B. Lilly Transforming Growth Factor- (TGF- 1) Down-regulates Notch3 in Fibroblasts to Promote Smooth Muscle Gene Expression J. Biol. Chem., January 18, 2008; 283(3): 1324 - 1333. [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]

				M. Betson and J. Settleman A Rho-Binding Protein Kinase C-Like Activity Is Required for the Function of Protein Kinase N in Drosophila Development Genetics, August 1, 2007; 176(4): 2201 - 2212. [Abstract] [Full Text] [PDF]

				A. Simionescu, D. T. Simionescu, and N. R. Vyavahare Osteogenic Responses in Fibroblasts Activated by Elastin Degradation Products and Transforming Growth Factor-{beta}1: Role of Myofibroblasts in Vascular Calcification Am. J. Pathol., July 1, 2007; 171(1): 116 - 123. [Abstract] [Full Text] [PDF]

				M. Ruiz-Ortega, J. Rodriguez-Vita, E. Sanchez-Lopez, G. Carvajal, and J. Egido TGF-{beta} signaling in vascular fibrosis Cardiovasc Res, May 1, 2007; 74(2): 196 - 206. [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]

				E. Larsson, X. Zhou, and L. M. Akyurek RhoA-Dependent Vascular Smooth Muscle Cell-Specific Transcription: Adding Diaphanous Formins to the Puzzle Arterioscler. Thromb. Vasc. Biol., March 1, 2007; 27(3): 448 - 449. [Full Text] [PDF]

				D. P. Staus, A. L. Blaker, J. M. Taylor, and C. P. Mack Diaphanous 1 and 2 Regulate Smooth Muscle Cell Differentiation by Activating the Myocardin-Related Transcription Factors Arterioscler. Thromb. Vasc. Biol., March 1, 2007; 27(3): 478 - 486. [Abstract] [Full Text] [PDF]

				H. Deliri and C. A. McNamara Nox 4 Regulation of Vascular Smooth Muscle Cell Differentiation Marker Gene Expression Arterioscler. Thromb. Vasc. Biol., January 1, 2007; 27(1): 12 - 14. [Full Text] [PDF]

				F. A. Lovett, I. Gonzalez, D. A. M. Salih, L. J. Cobb, G. Tripathi, R. A. Cosgrove, A. Murrell, P. J. Kilshaw, and J. M. Pell Convergence of Igf2 expression and adhesion signalling via RhoA and p38 MAPK enhances myogenic differentiation J. Cell Sci., December 1, 2006; 119(23): 4828 - 4840. [Abstract] [Full Text] [PDF]

				Q. Xu, A. Bernardo, D. Walker, T. Kanegawa, R. W. Mahley, and Y. Huang Profile and Regulation of Apolipoprotein E (ApoE) Expression in the CNS in Mice with Targeting of Green Fluorescent Protein Gene to the ApoE Locus. J. Neurosci., May 10, 2006; 26(19): 4985 - 4994. [Abstract] [Full Text] [PDF]

				S. Chen, M. Crawford, R. M. Day, V. R. Briones, J. E. Leader, P. A. Jose, and R. J. Lechleider RhoA Modulates Smad Signaling during Transforming Growth Factor-beta-induced Smooth Muscle Differentiation J. Biol. Chem., January 20, 2006; 281(3): 1765 - 1770. [Abstract] [Full Text] [PDF]