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J. Biol. Chem., Vol. 278, Issue 52, 53090-53097, December 26, 2003

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Regulation of Tension-induced Mechanotranscriptional Signals by the Microtubule Network in Fibroblasts^*

Mario D'Addario, Pamela D. Arora, Richard P. Ellen, and Christopher A. G. McCulloch

From the Canadian Institutes of Health Research (CIHR) Group in Matrix Dynamics, Institute of Dental Research, Faculty of Dentistry, University of Toronto, Toronto, Ontario M5S 3E2, Canada

Mechanical loading of connective tissues induces the expression of extracellular matrix and cytoskeletal genes that are involved in matrix remodeling. These processes depend in part on force transmission through ₁ integrins and actin filaments, but the role of microtubules in regulating mechanotranscriptional responses is not well defined. We assessed the involvement of microtubules in the mechanotranscriptional regulation of filamin A, an actin-cross-linking protein that protects cells against force-induced apoptosis by stabilizing cell membranes. Collagen-coated magnetite beads and magnetic fields were used to apply tensile forces to cultured fibroblasts at focal adhesions. Force enhanced recruitment of -tubulin and the plus end microtubule-binding protein cytoplasmic linker protein-170 (CLIP-170) at focal adhesions. Immunoprecipitation studies demonstrated no direct binding of tubulin to actin or filamin A, but CLIP-170 interacted with tubulin, filamin A, and -actin. The association of CLIP-170 with -actin was enhanced by force. Force activated the p38 mitogen-activated protein kinase, increased filamin A expression, and induced the relocation of p38 and filamin A to focal adhesions. Disruption of microtubules with nocodazole, independent of force application, enhanced filamin A expression and Sp1-mediated filamin A promoter activity, while stabilization of microtubules with Taxol inhibited force induction of both filamin A mRNA and protein. We conclude that in response to tensile forces applied through ₁ integrins and actin the microtubule network modulates mechanotranscriptional coupling of filamin A.

Received for publication, August 14, 2003 , and in revised form, October 9, 2003.

^* This work was supported by CIHR group, operating, and major equipment grants (Operating Grant CIHR MOP-37783) (to R. P. E. and C. A. G. M.) and the Heart and Stroke Foundation of Ontario (to C. A. G. M.). 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 a CIHR

To whom correspondence should be addressed: University of Toronto, Rm. 244, Fitzgerald Bldg., 150 College St., Toronto, Ontario M5S 3E2, Canada. Tel.: 416-978-1258; Fax: 416-978-5956; E-mail: christopher.mcculloch{at}utoronto.ca.

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