Smooth muscle-specific genes are differentially sensitive to inhibition by Elk-1

Jiliang Zhou, Guoqing Hu, B. Paul Herring

Research output: Contribution to journalArticle

50 Citations (Scopus)

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. In the current study, overexpression of Elk-1 in SMCs down-regulated expression of several endogenous smooth muscle-restricted proteins, including telokin, SM22α, and smooth muscle α-actin. In contrast, down-regulation of endogenous Elk-1 in smooth muscle cells increased the expression of only telekin and SM22α, suggesting that smooth muscle-specific promoters are differentially sensitive to the inhibitory effects of Elk-1. Consistent with this, overexpression of the DNA binding domain of Elk-1, which acts as a dominant-negative protein by displacing endogenous Elk-1, enhanced the expression of telokin and SM22α without affecting expression of smooth muscle α-actin. Elk-1 suppressed the activity of smooth muscle-restricted promoters, including the telokin promoter that does not contain a consensus Elk-1 binding site, through its ability to block myocardin-induced activation of the promoters. Gel mobility shift and chromatin immunoprecipitation assays revealed that Elk-1 binds to a nonconsensus binding site in the telokin promoter and Elk-1 binding is dependent on serum response factor (SRF) binding to a nearby CArG box. Although overexpression of the SRF-binding B-box domain of Elk-1 is sufficient to repress the myocardin activation of the telokin promoter, this repression is not as complete as that seen with an Elk-1 fragment that includes the DNA binding domain. In addition, reporter gene assays demonstrate that an intact Elk-1 binding site in the telekin promoter is required for Elk-1 to maximally inhibit promoter activity. Together, these data suggest that the differential sensitivity of smooth muscle-specific genes to inhibition by Elk-1 may play a role in the complex changes in smooth muscle-specific protein expression that are observed under pathological conditions.

Original languageEnglish (US)
Pages (from-to)9874-9885
Number of pages12
JournalMolecular and Cellular Biology
Volume25
Issue number22
DOIs
StatePublished - Nov 1 2005

Fingerprint

Smooth Muscle
Genes
Serum Response Factor
Smooth Muscle Myocytes
Muscle Proteins
Binding Sites
Actins
Chromatin Immunoprecipitation
DNA
Reporter Genes
Cell Differentiation
Atherosclerosis
Down-Regulation
Asthma
Gels
telokin
Proteins

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

Cite this

Smooth muscle-specific genes are differentially sensitive to inhibition by Elk-1. / Zhou, Jiliang; Hu, Guoqing; Herring, B. Paul.

In: Molecular and Cellular Biology, Vol. 25, No. 22, 01.11.2005, p. 9874-9885.

Research output: Contribution to journalArticle

Zhou, Jiliang ; Hu, Guoqing ; Herring, B. Paul. / Smooth muscle-specific genes are differentially sensitive to inhibition by Elk-1. In: Molecular and Cellular Biology. 2005 ; Vol. 25, No. 22. pp. 9874-9885.
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