The Purα/Purß single-strand DNA-binding proteins attenuate smooth-muscle actin gene transactivation in myofibroblasts.
J Cell Physiol
; 229(9): 1256-71, 2014 Sep.
Article
em En
| MEDLINE
| ID: mdl-24446247
ABSTRACT
Expression of smooth muscle alpha-actin (SMαA) is essential for myofibroblast-mediated wound contraction following tissue injury. The Pur α/ß and YB-1 transcriptional repressors govern the DNA-binding activity of serum response factor (SRF) and phosphorylated Smad3 (pSmad3) transcriptional activators during induction of SMαA gene expression in human pulmonary myofibroblasts. In quiescent fibroblasts, Pur α exhibited a novel function in enhancing stability of pre-existing SRF complexes with SMαA core promoter DNA, whereas Pur ß was more effective in disrupting SRF-DNA interaction. Pur proteins were less efficient competitors of pre-existing, core-promoter complexes containing both SRF and pSmad3 in nuclear extracts from TGFß1-activated myofibroblasts. TGFß1 signaling dissociated a SRF/Pur protein complex with concurrent formation of a transient pSmad3/MRTF-A/Pur ß complex during early phase myofibroblast differentiation. Pur ß was replaced by Pur α in the pSmad3/MRTF-A complex in mature myofibroblasts. Combining all three repressors potently inhibited SRF and pSmad3 binding to promoter DNA in quiescent fibroblasts and TGFß1-activated myofibroblasts, respectively. The results point to dynamic interplay between transcriptional activators and repressors in regulating SMαA gene output during myofibroblast differentiation. Therapeutic targeting of nucleoprotein complexes regulating the SMαA promoter may prevent excessive myofibroblast accumulation associated with chronic cardiopulmonary fibrosis and dysfunctional tissue remodeling.
Texto completo:
1
Coleções:
01-internacional
Temas:
Geral
Base de dados:
MEDLINE
Assunto principal:
Fibrose Pulmonar
/
Fatores de Transcrição
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Diferenciação Celular
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Ativação Transcricional
/
Actinas
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Proteínas de Ligação a DNA
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Miofibroblastos
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Pulmão
Limite:
Humans
Idioma:
En
Revista:
J Cell Physiol
Ano de publicação:
2014
Tipo de documento:
Article
País de afiliação:
Estados Unidos