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Oncogene-dependent apoptosis is mediated by caspase-9
H O Fearnhead1, J Rodriguez, E E Govek
1Cold Spring Harbor Laboratory, 1 Bungtown Road, Cold Spring Harbor, NY 11724, USA.
Summary
Oncogenic transformation sensitizes cells to apoptosis by facilitating caspase-9 activation. This process, involving cytochrome c release, offers a potential strategy for selectively killing tumor cells.
Area of Science:
- Cellular biology
- Molecular oncology
- Biochemistry
Background:
- Oncogenic transformation can alter cellular apoptosis pathways.
- Understanding these alterations may lead to targeted cancer therapies.
- A cell-free system was previously established to study oncogene-dependent apoptosis.
Purpose of the Study:
- To investigate the molecular mechanisms by which oncogenes sensitize cells to apoptosis.
- To validate the role of the caspase-9, Apaf-1, and cytochrome c complex in oncogene-induced apoptosis.
Main Methods:
- Utilized a cell-free system to study apoptosis.
- Examined the role of the caspase-9 activation complex.
- Investigated the effect of E1A, an adenoviral oncogene, on apoptosis and caspase-9 activation.
- Assessed cytochrome c release from mitochondria.
Main Results:
- Oncogene-dependent apoptosis requires the caspase-9, Apaf-1, and cytochrome c complex.
- Inhibition of caspase-9 activation blocked drug-induced apoptosis in E1A-sensitized cells.
- Oncogenes like E1A facilitate caspase-9 activation, partly through controlling cytochrome c release.
Conclusions:
- The caspase-9 activation complex is crucial for oncogene-sensitized apoptosis.
- Targeting caspase-9 activation presents a potential therapeutic strategy for cancers driven by oncogenes.
- Oncogenes modulate mitochondrial pathways to promote apoptosis.