Mechanisms responsible for the promoter-specific effects of myocardin

Jiliang Zhou, B. Paul Herring

Research output: Contribution to journalArticle

41 Scopus citations

Abstract

Understanding the mechanism of smooth muscle cell (SMC) differentiation will provide the foundation for elucidating SMC-related diseases such as atherosclerosis, restenosis, and asthma. Recent studies have demonstrated that the interaction of SRF with the co-activator myocardin is a critical determinant of smooth muscle development. It has been proposed that the specific transcriptional activation of smooth muscle-restricted genes (as opposed to other SRF-dependent genes) by myocardin results from the presence of multiple CArG boxes in smooth muscle genes that facilitate myocardin homodimer formation. This proposal was further tested in the current study. Our results show that the SMC-specific telokin promoter, which contains only a single CArG box, is strongly activated by myocardin. Furthermore, myocardin and a dimerization defective mutant myocardin induce expression of endogenous telokin but not c-fos in 10T1/2 fibroblast cells. Knocking down myocardin by small interfering RNA decreased telokin promoter activity and expression in A10 SMCs. A series of telokin and c-fos promoter chimeric and mutant reporter genes was generated to determine the mechanisms responsible for the promoter-specific effects of myocardin. Data from these experiments demonstrated that the ets binding site in the c-fos promoter partially blocks the activation of this promoter by myocardin. However, the binding of ets factors alone was not sufficient to explain the promoter-specific effects of myocardin. Elements 3′ of the CArG box in the c-fos promoter act in concert with the ets binding site to block the ability of myocardin to activate the promoter. Conversely, elements 5′ and 3′ of the CArG box in the telokin promoter act in concert with the CArG box to facilitate myocardin stimulation of the promoter. Together these data suggest that the promoter specificity of myocardin is dependent on complex combinatorial interactions of multiple cis elements and their trans binding factors.

Original languageEnglish (US)
Pages (from-to)10861-10869
Number of pages9
JournalJournal of Biological Chemistry
Volume280
Issue number11
DOIs
StatePublished - Mar 18 2005

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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