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Irradiation of mitochondria initiates apoptosis in a cell free system.
- Source :
-
Oncogene [Oncogene] 2001 Jan 11; Vol. 20 (2), pp. 167-77. - Publication Year :
- 2001
-
Abstract
- The ability to modulate the sensitivity of mammalian cells to ionizing radiation (IR) (e.g. using chemotherapeutics) is dependent on our understanding of the primary target and biochemical pathway that leads to IR-induced apoptosis. We demonstrate using a cell free assay that irradiation of mitochondria is a primary event that initiates IR-induced apoptosis. IR results in loss of mitochondrial membrane potential, opening of the permeability transition pore (PTP) and the release of cytochrome c (cyto c). Apaf-1 and ATP were required to initiate apoptosis upon release of cyto c from mitochondria. The importance of mitochondrial events in the initiation of IR-induced apoptosis was also supported by the observation that inhibition of caspase-9 by the over-expression of dominant negative mutants resulted in the inhibition of IR-induced apoptosis. In contrast, inhibition of caspase-8 had only a minor impact on IR-induced apoptosis. Over-expression of Bcl-X(L) inhibited the initiation of IR-induced apoptosis due to its ability to prevent the loss of mitochondrial membrane potential, PTP opening and cytochrome c release. In a cell free assay for apoptosis, mitochondria as well as cytosol derived from Bcl-X(L) over-expressing cells were less efficient at supporting apoptosis in response to IR suggesting multiple roles for Bcl-X(L) in the regulation of apoptosis.
- Subjects :
- Adenosine Triphosphate metabolism
Amino Acid Chloromethyl Ketones pharmacology
Apoptosis drug effects
Apoptotic Protease-Activating Factor 1
Biological Transport
Caspase 8
Caspase 9
Caspase Inhibitors
Caspases genetics
Cell Extracts pharmacology
Cell Membrane radiation effects
Cell Nucleus drug effects
Cell Nucleus radiation effects
Cell-Free System
Cyclosporine pharmacology
Cysteine Proteinase Inhibitors pharmacology
Cytochrome c Group metabolism
Cytosol radiation effects
Electrons
Humans
Jurkat Cells drug effects
Proteins metabolism
Proto-Oncogene Proteins c-bcl-2 genetics
Proto-Oncogene Proteins c-bcl-2 metabolism
Proto-Oncogene Proteins c-bcl-2 radiation effects
Reactive Oxygen Species metabolism
bcl-X Protein
Apoptosis physiology
Apoptosis radiation effects
Caspases metabolism
Mitochondria radiation effects
Subjects
Details
- Language :
- English
- ISSN :
- 0950-9232
- Volume :
- 20
- Issue :
- 2
- Database :
- MEDLINE
- Journal :
- Oncogene
- Publication Type :
- Academic Journal
- Accession number :
- 11313941
- Full Text :
- https://doi.org/10.1038/sj.onc.1204054