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Requirement of transforming growth factor β–activated kinase 1 for transforming growth factor β–induced -smooth muscle actin expression and extracellular matrix contraction in fibroblasts

Shi-Wen , Xu and Parapuram, Sunil K. and Pala , Daphne and Chen, Yunliang and Carter , David E. and Eastwood, Mark and Denton, Christopher P. and Abraham, David J. and Leask, Andrew (2009) Requirement of transforming growth factor β–activated kinase 1 for transforming growth factor β–induced -smooth muscle actin expression and extracellular matrix contraction in fibroblasts. Arthritis & Rheumatism, 60 (1). pp. 234-241. ISSN 0004-3591

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Official URL: http://dx.doi.org/10.1002/art.24223

Abstract

Objective - Fibrosis is believed to occur through normal tissue remodeling failing to terminate. Tissue repair intimately involves the ability of fibroblasts to contract extracellular matrix (ECM), and enhanced ECM contraction is a hallmark of fibrotic cells in various conditions, including scleroderma. Some fibrogenic transcriptional responses to transforming growth factor β (TGFβ), including -smooth muscle actin (-SMA) expression and ECM contraction, require focal adhesion kinase/Src (FAK/Src). The present study was undertaken to assess whether TGFβ-activated kinase 1 (TAK1) acts downstream of FAK/Src to mediate fibrogenic responses in fibroblasts. Methods - We used microarray, real-time polymerase chain reaction, Western blot, and collagen gel contraction assays to assess the ability of wild-type and TAK1-knockout fibroblasts to respond to TGFβ1. Results - The ability of TGF to induce TAK1 was blocked by the FAK/Src inhibitor PP2. JNK phosphorylation in response to TGFβ1 was impaired in the absence of TAK1. TGFβ could not induce matrix contraction or expression of a group of fibrotic genes, including -SMA, in the absence of TAK1. Conclusion - These results suggest that TAK1 operates downstream of FAK/Src in mediating fibrogenic responses and that targeting of TAK1 may be a viable antifibrotic strategy in the treatment of certain disorders, including scleroderma.

Item Type:Article
Research Community:University of Westminster > Life Sciences, School of
ID Code:9311
Deposited On:14 Apr 2011 11:53
Last Modified:14 Apr 2011 11:53

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