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Expression of S100A6 in cardiac myocytes limits apoptosis induced by tumor necrosis factor-alpha

James N Tsoporis1, Shehla Izhar, Thomas G Parker

  • 1Division of Cardiology, Department of Medicine, Keenan Research Centre, Li Ka Shing Knowledge Institute, St. Michael's Hospital, University of Toronto, Toronto, Ontario M5B 1W8, Canada.

The Journal of Biological Chemistry
|August 30, 2008
PubMed

Insights

S100A6 protein is upregulated by tumor necrosis factor-alpha through NF-kappaB signaling. This protein limits myocyte apoptosis by regulating p53 phosphorylation, playing a key role in cardiac homeostasis.

Area of Science:

  • Cardiovascular Biology
  • Molecular Cell Biology
  • Biochemistry

Background:

  • S100A6 expression increases in the heart after myocardial infarction and upon stimulation with growth factors and inflammatory cytokines.
  • S100A6 overexpression in cardiomyocytes impairs cardiac-specific gene expression in response to trophic signals.
  • Understanding S100A6 regulation and function is crucial for cardiac health.

Purpose of the Study:

  • To characterize the human S100A6 promoter and identify regulatory elements.
  • To investigate the functional role of S100A6 in tumor necrosis factor-alpha (TNF-α)-induced myocyte apoptosis.
  • To elucidate the signaling pathways involved in S100A6 regulation by TNF-α.

Main Methods:

  • Promoter analysis using deletion constructs in cardiac myocytes, fibroblasts, and vascular smooth muscle cells.
  • Electrophoretic mobility shift assays (EMSA) and chromatin immunoprecipitation (ChIP) to assess transcription factor binding.
  • Small interfering RNA (siRNA) and gene transfer for S100A6 manipulation.
  • Assessment of myocyte apoptosis and p53 phosphorylation.

Main Results:

  • The functional S100A6 promoter was localized to the region -167/+134, with positive regulatory elements at -361/-167 and -588/-361, and a negative element at -1371/-1194.
  • TNF-α maximally induced S100A6 promoter activity and NF-kappaB (p65) binding to a site at -460/-451.
  • NF-kappaB inhibition and mutation of the binding site blocked TNF-α-induced S100A6 promoter activation.
  • S100A6 inhibition potentiated TNF-α-induced myocyte apoptosis, while S100A6 overexpression protected against it by interfering with p53 phosphorylation.

Conclusions:

  • S100A6 is induced by TNF-α via an NF-kappaB-dependent pathway.
  • S100A6 plays a protective role in cardiac homeostasis by limiting TNF-α-induced apoptosis.
  • S100A6 exerts its protective effect through the regulation of p53 phosphorylation.

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