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Molecular & Cellular Proteomics 3:466-477, 2004.
© 2004 by The American Society for Biochemistry and Molecular Biology, Inc.

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Research

Transforming Growth Factor-ß₁ Specifically Induce Proteins Involved in the Myofibroblast Contractile Apparatus^*

Johan Malmström, Henrik Lindberg, Claes Lindberg, Charlotte Bratt^,, Elisabet Wieslander^¶, Eva-Lena Delander^¶, Bengt Särnstrand^||, Jorge S. Burns^**, Peter Mose-Larsen^**, Stephen Fey^** and György Marko-Varga^,

From the Department of Molecular Sciences, AstraZeneca R&D Lund, SE-221 87 Lund, Sweden; ^¶ Department of Bioscience, AstraZeneca R&D Lund, SE-221 87 Lund, Sweden; ^|| Department of Clinical Development, AstraZeneca R&D Lund, SE-221 87 Lund, Sweden; and ^** The Center for Proteome Analysis in Life Science, University of Southern Denmark, Forskerparken 10/B, Odense, Denmark

Transforming growth factor-ß₁ (TGF-ß₁) induces -smooth muscle actin (-SMA) and collagen synthesis in fibroblast both in vivo and in vitro and plays a significant role in tissue repair and the development of fibrosis. During these processes the fibroblasts differentiate into activated fibroblasts (so called myofibroblasts), characterized by increased -SMA expression. Because TGF-ß₁ is considered the main inducer of the myofibroblast phenotype and cytoskeletal changes accompany this differentiation, the main objective of this investigation was to study how TGF-ß₁ alters protein expression of cytoskeletal-associated proteins. Metabolic labeling of cell cultures by [³⁵S]methionine, followed by protein separation on two-dimensional gel electrophoresis, displayed 2500 proteins in the pIinterval of 3–10. Treatment of TGF-ß₁ led to specific spot pattern changes that were identified by mass spectrometry and represent specific induction of several members of the contractile apparatus such as calgizzarin, cofilin, and profilin. These proteins have not previously been shown to be regulated by TGF-ß₁, and the functional role of these proteins is to participate in the depolymerization and stabilization of the microfilaments. These results show that TGF-ß₁ induces not only -SMA but a whole set of actin-associated proteins that may contribute to the increased contractile properties of the myofibroblast. These proteins accompany the induced expression of -SMA and may participate in the formation of stress fibers, cell contractility, and cell spreading characterizing the myofibroblasts phenotype.

To whom correspondence should be addressed: AstraZeneca R&D Lund, Scheelevägen 8, SE-221 87 Lund, Sweden. Tel.: 46-46-336887; Fax: 46-46-337164; E-mail: gyorgy.marko-varga.{at}astrazeneca.com

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