Blood cells with reduced mitochondrial membrane potential and cytosolic cytochrome C can survive and maintain clonogenicity given appropriate signals to suppress apoptosis.
Reduction of mitochondrial membrane potential (Psim) and release of cytochrome c from mitochondria appear to be key events during apoptosis. Apoptosis was induced in IC.DP premast cells by the withdrawal of interleukin-3 (IL-3). Psim decreased by 12 hours and cytochrome c was detected in the cytosol at 18 hours. Despite these changes in the mitochondria after 18 hours of IL-3 deprivation, clonogenicity was unaffected when IL-3 was replenished at 18 hours. Activation of v-Abl tyrosine kinase (v-Abl TK) in IC.DP cells before IL-3 depletion led to increased levels of Bcl-XL, prevented reduction of Psim and the release of mitochondrial cytochrome c, and suppressed apoptosis. Activation of v-Abl TK 18 hours after withdrawal of IL-3 when </=10% of the cells had died restored Psim in the remaining cells. More than 40% of cells thus rescued by v-Abl TK between 18 and 42 hours could subsequently form colonies in the presence of IL-3. These data suggest that reduction in Psim precedes loss of mitochondrial cytochrome c in IC.DP cells; that v-Abl TK activation, probably via upregulation of Bcl-XL, prevents loss of Psim and blocks the release of cytochrome c from mitochondria; and that neither of these mitochondrial events is sufficient for commitment to apoptosis.
Chen
Q
Q
School of Biological Sciences and the Department of Medicine, Victoria University of Manchester, Manchester, UK.
Takeyama
N
N
Brady
G
G
Watson
A J
AJ
Dive
C
C
D000818:Animals; D017209:Apoptosis; D001773:Blood Cells / Q000378:metabolism*; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D003114:Colony-Forming Units Assay; D003574:Cytochrome c Group / Q000378:metabolism*; D003600:Cytosol / Q000378:metabolism; D004789:Enzyme Activation / Q000187:drug effects; D007377:Interleukin-3 / Q000494:pharmacology / Q000502:physiology; D008407:Mast Cells / Q000166:cytology / Q000378:metabolism; D008564:Membrane Potentials / Q000502:physiology; D051379:Mice; D008928:Mitochondria / Q000378:metabolism / Q000502:physiology*; D016374:Oncogene Proteins v-abl / Q000378:metabolism; D013696:Temperature; D013997:Time Factors
D003574:Cytochrome c Group; D007377:Interleukin-3; D016374:Oncogene Proteins v-abl