title: YB-1 coordinates vascular smooth muscle alpha-actin gene activation by transforming growth factor beta1 and thrombin during differentiation of human pulmonary myofibroblasts.
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 beta1 (TGFbeta1) and thrombin, in directing expression of the vascular smooth muscle alpha-actin (SMalphaA) gene, an important determinant of myofibroblast differentiation and early protein marker for stromal cell response to tissue injury. TGFbeta1 is a well known transcriptional activator of the SMalphaA gene in myofibroblasts. In contrast, thrombin independently elevates SMalphaA expression in human pulmonary myofibroblasts at the posttranscriptional level. A common feature of SMalphaA up-regulation mediated by thrombin and TGFbeta1 is the involvement of the cold shock domain protein YB-1, a potent repressor of SMalphaA gene transcription in human fibroblasts that also binds mRNA and regulates translational efficiency. YB-1 dissociates from SMalphaA enhancer DNA in the presence of TGFbeta1 or its Smad 2, 3, and 4 coregulatory mediators. Thrombin does not effect SMalphaA gene transcription but rather displaces YB-1 from SMalphaA 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 SMalphaA 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.
authors.affiliation: 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, USA.
authors.forename: Aiwen
authors.initials: A
authors.lastname: Zhang
authors.forename: Xiaoying
authors.initials: X
authors.lastname: Liu
authors.forename: John G
authors.initials: JG
authors.lastname: Cogan
authors.forename: Matthew D
authors.initials: MD
authors.lastname: Fuerst
authors.forename: John A
authors.initials: JA
authors.lastname: Polikandriotis
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Kelm
authors.forename: Arthur R
authors.initials: AR
authors.lastname: Strauch
mesh_terms: D000199:Actins / Q000235:genetics / Q000502:physiology*; D000818:Animals; D002454:Cell Differentiation; D002467:Cell Nucleus / Q000378:metabolism; D002478:Cells, Cultured; D003593:Cytoplasm / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000502:physiology*; D004742:Enhancer Elements, Genetic; D005091:Exons; D005347:Fibroblasts / Q000166:cytology* / Q000378:metabolism; D005786:Gene Expression Regulation; D020868:Gene Silencing; D006801:Humans; D007231:Infant, Newborn; D008168:Lung / Q000166:cytology; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000378:metabolism*; D009687:Nuclear Proteins; D011401:Promoter Regions, Genetic; D021381:Protein Transport; D013917:Thrombin / Q000502:physiology*; D015533:Transcriptional Activation; D016212:Transforming Growth Factor beta / Q000502:physiology*; D053773:Transforming Growth Factor beta1; D051840:Y-Box-Binding Protein 1
chemical_list: D000199:Actins; D004268:DNA-Binding Proteins; D009687:Nuclear Proteins; C508960:TGFB1 protein, human; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; D051840:Y-Box-Binding Protein 1; C070856:YBX1 protein, human; D013917:Thrombin