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Vasodilation of Isolated Vessels and the Isolation of the Extracellular Matrix of Tight-skin Mice
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TNF receptor deficiency reveals a translational control mechanism for adriamycin-induced Fas expression in cardiac

Yu-Chin Lien1, Chotiros Daosukho, Daret K St Clair

  • 1Graduate Center for Toxicology, University of Kentucky, Lexington, KY 40536, USA.

Cytokine
|April 18, 2006
PubMed

Insights

Adriamycin (ADR) causes heart cell death. Tumor necrosis factor (TNF) receptors protect against ADR toxicity by regulating Fas expression at the protein level, not the mRNA level.

Area of Science:

  • Cardiovascular research
  • Molecular biology
  • Cancer therapeutics

Background:

  • Adriamycin (ADR) induces cardiomyocyte apoptosis through the Fas/Fas ligand pathway.
  • Tumor necrosis factor-alpha (TNF-alpha) receptors may offer cardioprotection against ADR toxicity by suppressing Fas-mediated cell death.
  • The precise role of TNF-alpha receptors in modulating ADR-induced Fas expression remains unclear.

Purpose of the Study:

  • To elucidate the molecular mechanisms by which ADR induces Fas expression.
  • To investigate the role of TNF-alpha receptors in this process, particularly at transcriptional and translational levels.

Main Methods:

  • Examining ADR-induced Fas expression in the presence and absence of TNF receptors.
  • Analyzing p53 and AP-1 interactions and Fas mRNA levels.
  • Quantifying Fas protein levels in cardiac tissues of wild-type and TNF receptor-deficient mice.

Main Results:

  • ADR-mediated p53 and AP-1 interaction increased Fas mRNA levels independently of TNF receptors.
  • Fas protein levels were elevated in cardiac tissues of TNF receptor-deficient mice but not in wild-type mice.
  • TNF receptors suppress ADR-induced Fas expression at a post-transcriptional (translational) level.

Conclusions:

  • TNF receptors do not affect ADR-induced Fas mRNA transcription.
  • TNF receptors play a crucial role in suppressing ADR-induced Fas protein accumulation, likely via translational regulation.
  • Understanding this mechanism could lead to novel cardioprotective strategies against chemotherapy-induced cardiotoxicity.

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