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

J. Biol. Chem., Vol. 281, Issue 29, 20608-20622, July 21, 2006

This Article Full Text Full Text (PDF) All Versions of this Article: 281/29/20608    most recent M600214200v1 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 Chaqour, B. Articles by Sha, Q. Search for Related Content PubMed PubMed Citation Articles by Chaqour, B. Articles by Sha, Q. Social Bookmarking                      What's this?

Mechanical Stretch Modulates the Promoter Activity of the Profibrotic Factor CCN2 through Increased Actin Polymerization and NF-B Activation^*

From the Department of Anatomy and Cell Biology, State University of New York Downstate Medical Center, Brooklyn, New York 11203

The connective tissue growth factor known as CCN2 is an inducible, profibrotic molecule that becomes aberrantly expressed in mechanical overload-bearing tissues. In this study, we found that CCN2 gene expression is rapidly induced in cyclically stretched bladder smooth muscle cells (SMCs) in vitro and in the detrusor muscle of a mechanically overloaded bladder in a rat model of experimental urethral obstruction. The activity of CCN2 promoter constructs, transiently transfected into cultured SMCs, was increased (up to 6-fold) by continuous cyclic stretching. Molecular analyses of the CCN2 promoter by serial construct deletions, cis-element mutagenesis, and electrophoretic mobility shift assays revealed that a highly conserved NF-B binding site located within the CCN2 proximal promoter region is responsible for the activation of the promoter by stretch. Chromatin immunoprecipitation assays showed that NF-B binds to the endogenous CCN2 promoter in both stretched cells and mechanically overloaded bladder tissues. Furthermore, stretch-dependent CCN2 promoter activity was significantly reduced upon inhibition of either phosphatidylinositol 3-kinase, p38 stress-activated kinase, or RhoA GTPase and was completely abolished upon inhibition of actin polymerization. Concordantly, actin polymerization was increased in either mechanically stretched cells or overloaded bladder tissues. Incubation of cultured SMCs with a cell-penetrating peptide containing the N-terminal sequence, Ac-EEED, of smooth muscle -actin, altered both actin cytoskeleton organization and stretch-mediated nuclear relocation of NF-B, and subsequently, it reduced CCN2 promoter activity. Thus, mechanical stretch-induced changes in actin dynamics mediate NF-B activation and induce CCN2 gene expression, which probably initiates the fibrotic reactions observed in mechanical overloadassociated pathologies.

Received for publication, January 9, 2006 , and in revised form, May 15, 2006.

^* This work was supported by NIDDK, National Institutes of Health, Grants R01-DK060572 and R21-DK068483 (to B. C.). 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.

¹ To whom correspondence should be addressed: Dept. of Anatomy and Cell Biology, State University of New York Downstate Medical Center, 450 Clarkson Ave., Box 5, Brooklyn, NY 11203. Tel.: 718-270-8285; Fax: 718-270-3732; E-mail: bchaqour{at}downstate.edu.

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

This article has been cited by other articles:

				R. Yang, J. Amir, H. Liu, and B. Chaqour Mechanical strain activates a program of genes functionally involved in paracrine signaling of angiogenesis Physiol Genomics, December 12, 2008; 36(1): 1 - 14. [Abstract] [Full Text] [PDF]

				M. R. Quinlan, N. G. Docherty, R. W. G. Watson, and J. M. Fitzpatrick Exploring mechanisms involved in renal tubular sensing of mechanical stretch following ureteric obstruction Am J Physiol Renal Physiol, July 1, 2008; 295(1): F1 - F11. [Abstract] [Full Text] [PDF]

				V. Haydont, B. L. Riser, J. Aigueperse, and M.-C. Vozenin-Brotons Specific signals involved in the long-term maintenance of radiation-induced fibrogenic differentiation: a role for CCN2 and low concentration of TGF-{beta}1 Am J Physiol Cell Physiol, June 1, 2008; 294(6): C1332 - C1341. [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. Liu, R. Yang, B. Tinner, A. Choudhry, N. Schutze, and B. Chaqour Cysteine-Rich Protein 61 and Connective Tissue Growth Factor Induce Deadhesion and Anoikis of Retinal Pericytes Endocrinology, April 1, 2008; 149(4): 1666 - 1677. [Abstract] [Full Text] [PDF]

				B. Hinz, S. H. Phan, V. J. Thannickal, A. Galli, M.-L. Bochaton-Piallat, and G. Gabbiani The Myofibroblast: One Function, Multiple Origins Am. J. Pathol., June 1, 2007; 170(6): 1807 - 1816. [Abstract] [Full Text] [PDF]

				S. Muehlich, I. Cicha, C. D. Garlichs, B. Krueger, G. Posern, and M. Goppelt-Struebe Actin-dependent regulation of connective tissue growth factor Am J Physiol Cell Physiol, May 1, 2007; 292(5): C1732 - C1738. [Abstract] [Full Text] [PDF]

				B. K. Ray, A. Shakya, and A. Ray Vascular Endothelial Growth Factor Expression in Arthritic Joint Is Regulated by SAF-1 Transcription Factor J. Immunol., February 1, 2007; 178(3): 1774 - 1782. [Abstract] [Full Text] [PDF]