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Characterization of the transforming growth factor-beta 1-induced apoptotic transcriptome in FaO hepatoma cells

Beth Coyle1, Caroline Freathy, Timothy W Gant

  • 1Medical Research Council Toxicology Unit, University of Leicester, Leicester LE1 9HN, United Kingdom.

The Journal of Biological Chemistry
|December 19, 2002
PubMed

Insights

Transforming growth factor-beta(1) (TGF-β1) triggers apoptosis in liver cells by altering gene expression. This study identifies key genes involved in TGF-β1-induced cell death and reactive oxygen species production.

Area of Science:

  • Cell Biology
  • Molecular Biology
  • Oncology

Background:

  • Transforming growth factor-beta(1) (TGF-β1) signaling is crucial in cellular processes, including apoptosis.
  • The downstream gene targets of TGF-β1 in apoptosis regulation remain largely unknown.
  • TGF-β1-induced apoptosis involves cytochrome c release, apoptosome formation, and caspase activation.

Purpose of the Study:

  • To identify novel downstream gene targets regulated by TGF-β1 during apoptosis in FaO hepatoma cells.
  • To elucidate the molecular mechanisms underlying TGF-β1-induced apoptosis and reactive oxygen species generation.

Main Methods:

  • Utilized in-house microarrays (approx. 5500 genes) to analyze gene expression profiles in TGF-β1-treated FaO hepatoma cells.
  • Employed a polycaspase inhibitor (benzyloxycarbonyl-VAD-fluoromethyl ketone) to differentiate caspase-dependent and -independent gene responses.
  • Performed cluster analysis to identify time-dependent changes in gene expression patterns.

Main Results:

  • Identified 142 genes with time-dependent expression changes during TGF-β1-induced apoptosis.
  • Discovered that blocking caspase activation altered the expression of 261 genes, including 185 down-regulated genes.
  • Observed up-regulation of early response genes (extracellular matrix, cytoskeleton, CTGF) and delayed response genes (pro-apoptotic genes, stress-related proteins).
  • Found nine down-regulated genes involved in antioxidant defense, potentially linked to reactive oxygen species elevation.

Conclusions:

  • TGF-β1 regulates a distinct set of genes during apoptosis, including those involved in extracellular matrix, cytoskeleton, and stress responses.
  • The down-regulation of antioxidant defense genes may contribute to TGF-β1-induced reactive oxygen species production and initiate apoptosis.
  • Identified stress-related protein genes upregulated in a caspase-independent manner, possibly due to secondary necrosis.

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