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Genetic determinants that influence hypoxia-induced apoptosis
R M Alarcon1, N C Denko, A J Giaccia
1Stanford University School of Medicine, Department of Radiation Oncology, Division of Radiation & Cancer Biology, CA 94305-5152, USA.
Novartis Foundation Symposium
|December 1, 2001
Summary
The p53 tumor suppressor gene influences apoptosis magnitude under low oxygen, but cytochrome c release is key for initiating cell death, independent of p53 or Bax. This clarifies the mitochondrial apoptosis pathway in hypoxic conditions.
Area of Science:
- Cell Biology
- Molecular Biology
- Cancer Research
Background:
- The p53 tumor suppressor gene activates apoptosis via death receptor and mitochondrial pathways.
- Hypoxia-induced apoptosis resistance is linked to the mitochondrial Apaf/caspase 9 pathway, not the Fas pathway.
- The precise signaling mechanism of p53 in activating the mitochondrial pathway under hypoxia remains unclear, with potential roles for effector genes like BAX or novel factors like BNIP-3/BNIP-3L.
Purpose of the Study:
- To elucidate the role of p53 and its effector genes in signaling mitochondrial apoptosis under hypoxic conditions.
- To determine the involvement of specific apoptotic pathway components (Bax, cytochrome c, Apaf, caspase 9, caspase 3) in hypoxia-induced cell death.
- To investigate whether p53 is required for the activation of the caspase cascade during hypoxia.
Main Methods:
- Utilized genetically matched cell lines differing at key apoptotic loci (bax, cytochrome c, Apaf, caspase 9, caspase 3).
- Assessed the necessity of these genes for hypoxia-induced apoptosis in both cell culture and transplanted tumor models.
- Compared the signaling roles of p53, Bax, and cytochrome c in the activation of the apoptotic cascade under low oxygen.
Main Results:
- Except for Bax, all examined genes (cytochrome c, Apaf, caspase 9, caspase 3) were essential for hypoxia-induced apoptosis.
- Cytochrome c release plays a pivotal role in signaling apoptosis under hypoxic conditions.
- Cytochrome c release was found to be independent of both Bax and p53.
- p53 modulates the magnitude of apoptosis under hypoxia but is not required for caspase cascade activation.
Conclusions:
- Cytochrome c release is a critical, p53/Bax-independent event in initiating apoptosis during hypoxia.
- While p53 influences the extent of cell death, it is not essential for the core caspase cascade activation in response to low oxygen.
- The findings highlight the central role of the mitochondrial pathway and cytochrome c in cellular response to hypoxic stress.