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c-Myc-induced sensitization to apoptosis is mediated through cytochrome c release
P Juin1, A O Hueber, T Littlewood
1Imperial Cancer Research Fund, London WC2A 3PX, UK.
Genes & Development
|June 11, 1999
Summary
The oncogene c-Myc promotes apoptosis by triggering the release of cytochrome c from mitochondria. This release is essential for sensitizing cells to death signals, though downstream caspase activation requires additional cellular cues.
Area of Science:
- Cell Biology
- Molecular Biology
- Oncology
Background:
- The transcription factor c-Myc is known to sensitize cells towards apoptosis.
- The precise molecular mechanisms underlying c-Myc-induced apoptosis are complex and involve multiple signaling pathways.
Purpose of the Study:
- To elucidate the role of mitochondrial cytochrome c release in c-Myc-mediated apoptosis.
- To investigate the signaling pathways involved in and regulating c-Myc's pro-apoptotic function.
Main Methods:
- Investigating cytochrome c release from mitochondria upon c-Myc activation.
- Utilizing microinjection of anti-cytochrome c antibodies and holocytochrome c.
- Examining the involvement of p53 and CD95/Fas signaling pathways.
Main Results:
- c-Myc activation induces caspase-independent release of mitochondrial holocytochrome c into the cytosol.
- This release is inhibited by the survival factor IGF-1 and blocked by anti-cytochrome c antibodies.
- Microinjection of holocytochrome c mimics c-Myc's pro-apoptotic effect, sensitizing cells to DNA damage and CD95 signaling.
- While p53 and CD95/Fas are not required for cytochrome c release, CD95 inhibition prevents apoptosis by blocking caspase activation downstream of cytochrome c.
Conclusions:
- c-Myc directly promotes apoptosis through the release of mitochondrial cytochrome c.
- The pro-apoptotic function of released cytochrome c is dependent on additional cellular signals, including CD95/Fas pathway engagement for caspase activation.