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Vol. 16, Issue 10, 4931-4940, October 2005

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YB-1 Coordinates Vascular Smooth Muscle -Actin Gene Activation by Transforming Growth Factor 1 and Thrombin during Differentiation of Human Pulmonary Myofibroblasts

Aiwen Zhang ^*, Xiaoying Liu ^*, John G. Cogan ^*, Matthew D. Fuerst ^*, John A. Polikandriotis ^* , Robert J. Kelm, Jr. , and Arthur R. Strauch ^*

^* Department of Physiology and Cell Biology, The Dorothy M. Davis Heart and Lung Research Institute, The Ohio State University College of Medicine and Public Health, Columbus, OH 43210; Department of Medicine, College of Medicine, University of Vermont, Colchester, VT 05446

Submitted March 16, 2005; Revised July 7, 2005; Accepted August 2, 2005
Monitoring Editor: Carl-Henrik Heldin

Profibrotic regulatory mechanisms for tissue repair after traumatic injury have developed under strong evolutionary pressure to rapidly stanch blood loss and close open wounds. We have examined the roles played by two profibrotic mediators, transforming growth factor 1 (TGF1) and thrombin, in directing expression of the vascular smooth muscle -actin (SMA) gene, an important determinant of myofibroblast differentiation and early protein marker for stromal cell response to tissue injury. TGF1 is a well known transcriptional activator of the SMA gene in myofibroblasts. In contrast, thrombin independently elevates SMA expression in human pulmonary myofibroblasts at the posttranscriptional level. A common feature of SMA up-regulation mediated by thrombin and TGF1 is the involvement of the cold shock domain protein YB-1, a potent repressor of SMA gene transcription in human fibroblasts that also binds mRNA and regulates translational efficiency. YB-1 dissociates from SMA enhancer DNA in the presence of TGF1 or its Smad 2, 3, and 4 coregulatory mediators. Thrombin does not effect SMA gene transcription but rather displaces YB-1 from SMA exon 3 coding sequences previously shown to be required for mRNA translational silencing. The release of YB-1 from promoter DNA coupled with its ability to bind RNA and shuttle between the nucleus and cytoplasm is suggestive of a regulatory loop for coordinating SMA gene output in human pulmonary myofibroblasts at both the transcriptional and translational levels. This loop may help restrict organ-destructive remodeling due to excessive myofibroblast differentiation.

Present address: Department of Medicine, Division of Pulmonary, Allergy, and Critical Care Medicine, Emory University, Atlanta, GA 30322.

Address correspondence to: Arthur R. Strauch (strauch.1{at}osu.edu).

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