YB-1 coordinates vascular smooth muscle α-actin gene activation by transforming growth factor β1 and thrombin during differentiation of human pulmonary myofibroblasts

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

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

43 Scopus citations

Abstract

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 β1 (TGFβ1) and thrombin, in directing expression of the vascular smooth muscle α-actin (SMαA) gene, an important determinant of myofibroblast differentiation and early protein marker for stromal cell response to tissue injury. TGFβ1 is a well known transcriptional activator of the SMαA gene in myofibroblasts. In contrast, thrombin independently elevates SMαA expression in human pulmonary myofibroblasts at the posttranscriptional level. A common feature of SMαA up-regulation mediated by thrombin and TGFβ1 is the involvement of the cold shock domain protein YB-1, a potent repressor of SMαA gene transcription in human fibroblasts that also binds mRNA and regulates translational efficiency. YB-1 dissociates from SMαA enhancer DNA in the presence of TGFβ1 or its Smad 2, 3, and 4 coregulatory mediators. Thrombin does not effect SMαA gene transcription but rather displaces YB-1 from SMαA 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 SMαA 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.

Original languageEnglish (US)
Pages (from-to)4931-4940
Number of pages10
JournalMolecular biology of the cell
Volume16
Issue number10
DOIs
StatePublished - Oct 2005

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

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