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Regulation of serum response factor activity and smooth muscle cell apoptosis by chromodomain helicase DNA-binding

Jennifer M Rodenberg1, April M Hoggatt, Meng Chen

  • 1Department of Cellular and Integrative Physiology, Indiana University School of Medicine, Indianapolis, Indiana 46202-5120, USA.

American Journal of Physiology. Cell Physiology
|August 27, 2010
PubMed

Insights

Chromodomain helicase DNA binding protein 8 (CHD8) interacts with Serum response factor (SRF) to regulate smooth muscle cell differentiation and survival. CHD8 and SRF modulate apoptosis by controlling specific gene expressions.

Area of Science:

  • Molecular Biology
  • Cell Biology
  • Biochemistry

Background:

  • Serum response factor (SRF) is crucial for smooth muscle cell functions, including differentiation, proliferation, migration, and apoptosis.
  • SRF's diverse functions are regulated by pathway-specific cofactor interactions.
  • Chromodomain helicase DNA binding protein 8 (CHD8) is a novel SRF cofactor highly expressed in adult smooth muscle tissues.

Purpose of the Study:

  • To investigate the role of CHD8 as an SRF cofactor in smooth muscle cells.
  • To elucidate the mechanism by which CHD8 influences SRF-dependent gene expression and cell survival.

Main Methods:

  • Yeast two-hybrid screening to identify SRF interacting proteins.
  • Coimmunoprecipitation and GST-pulldown assays to confirm SRF-CHD8 interaction.
  • Adenoviral-mediated knockdown of CHD8, SRF, and CTCF in smooth muscle cells.
  • Quantitative analysis of gene expression related to differentiation and apoptosis.

Main Results:

  • CHD8 directly interacts with the MADS domain of SRF.
  • Knockdown of CHD8 attenuates the expression of SRF-dependent, smooth muscle-specific genes.
  • Knockdown of CHD8, SRF, or CTCF induces apoptosis.
  • CHD8 knockdown leads to decreased expression of anti-apoptotic proteins Birc5 and CARD10.
  • SRF knockdown affects CARD10 and Mcl-1 expression, while CTCF knockdown affects Birc5 expression.

Conclusions:

  • CHD8 plays a dual role in smooth muscle cells: modulating SRF activity for differentiation and promoting cell survival.
  • CHD8 interacts with both SRF and CTCF to regulate the expression of Birc5 and CARD10, thereby influencing cell survival.
  • These findings highlight CHD8 as a key regulator in smooth muscle biology and provide insights into mechanisms of smooth muscle cell apoptosis.

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