Induction of Vascular Smooth Muscle α-Actin Gene Transcription in TGFβ1-Activated Myofibroblasts Mediated by Dynamic Interplay Between the Pur Repressor Proteins and Sp1/Smad Co-activators

نویسندگان

  • Sukanya V. Subramanian
  • John A. Polikandriotis
  • Robert J. Kelm
  • Jason J. David
  • Charles G. Orosz
  • Arthur R. Strauch
چکیده

The mouse vascular smooth muscle α-actin (SMA) gene enhancer is activated in fibroblasts by TGFβ1, a potent mediator of myofibroblast differentiation and wound healing. The SMA enhancer contains tandem sites for the Sp1 transcriptional activator protein and Purα and β repressor proteins. We have examined dynamic interplay between these divergent proteins to identify checkpoints for possible control of myofibroblast differentiation during chronic inflammatory disease. A novel element in the SMA enhancer named SPUR was responsible for both basal and TGFβ1-dependent transcriptional activation in fibroblasts and capable of binding Sp1 and Pur proteins. A novel Sp1:Pur:SPUR complex was dissociated when SMA enhancer activity was increased by TGFβ1 or Smad protein over-expression. Physical association of Pur proteins with Smad2/3 was observed as was binding of Smads to an upstream enhancer region that undergoes DNA duplex unwinding in TGFβ1-activated myofibroblasts. Purβ repression of the SMA enhancer could not be relieved by TGFβ1 whereas repression mediated by Purα was partially rescued by TGFβ1 or over-expression of Smad proteins. Interplay between Pur repressor isoforms and Sp1 and Smad co-activators may regulate SMA enhancer output in TGFβ1-activated myofibroblasts during episodes of wound repair and tissue remodeling.

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تاریخ انتشار 2004