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c-MYC apoptotic function is mediated by NRF-1 target genes

Fionnuala Morrish1, Christopher Giedt, David Hockenbery

  • 1Fred Hutchinson Cancer Research Center, Division of Molecular Medicine, Seattle, Washington 98109, USA.

Genes & Development
|January 21, 2003
PubMed

Insights

The c-Myc protein triggers apoptosis by disrupting mitochondrial function. This study reveals c-Myc directly targets cytochrome c, a key regulator of apoptosis, linking its action to mitochondrial gene regulation.

Area of Science:

  • Molecular Biology
  • Cell Biology
  • Biochemistry

Background:

  • The precise mechanisms by which c-Myc induces apoptosis remain unclear.
  • c-Myc's role in regulating genes involved in mitochondrial biogenesis is under investigation.
  • Nuclear Respiratory Factor-1 (NRF-1) regulates nuclear-encoded mitochondrial genes, including cytochrome c.

Purpose of the Study:

  • To investigate the link between c-Myc-induced mitochondrial gene expression and apoptosis.
  • To determine if cytochrome c is a direct target of c-Myc.
  • To explore the role of NRF-1 in c-Myc-mediated apoptosis.

Main Methods:

  • Northern analysis to assess gene expression.
  • Transactivation assays to measure gene activity.
  • In vitro and in vivo promoter binding assays to confirm protein-DNA interactions.
  • Use of dominant-negative NRF-1 to interfere with gene regulation.

Main Results:

  • Cytochrome c was identified as a direct transcriptional target of c-Myc.
  • Overexpression of NRF-1 sensitized cells to apoptosis, similar to c-Myc.
  • Interference with c-Myc's induction of NRF-1 target genes blocked c-Myc-induced apoptosis but not proliferation.
  • Serum depletion led to increased NRF-1 target gene induction and apoptosis sensitization.

Conclusions:

  • c-Myc expression contributes to mitochondrial dysfunction and apoptosis through the deregulation of mitochondrial genes.
  • NRF-1 plays a critical role in mediating c-Myc's apoptotic effects.
  • Targeting the c-Myc/NRF-1 pathway may offer therapeutic strategies for conditions involving apoptosis.

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