BCR-ABL delays apoptosis upstream of procaspase-3 activation.
The p210(bcr-abl) protein was shown to inhibit apoptosis induced by DNA damaging agents. Apoptotic DNA fragmentation is delayed in the bcr-abl+ K562 and KCL-22 compared with the bcr-abl- U937 and HL-60 cell lines when treated with etoposide concentrations that induce similar DNA damage in the four cell lines. By the use of a cell-free system, we show that nuclei from untreated cells that express p210(bcr-abl) remain sensitive to apoptotic DNA fragmentation induced by triton-soluble extracts from p210(bcr-abl-) cells treated with etoposide. In the four tested cell lines, apoptotic DNA fragmentation is associated with a decreased expression of procaspase-3 (CPP32/Yama/apopain) and its cleavage into a p17 active fragment, whereas the long isoform of procaspase-2 (ICH-1L) remains unchanged and the poly(adenosine diphosphate-ribose)polymerase protein is cleaved. These events are delayed in bcr-abl+ compared with bcr-abl- cell lines. The role of p210(bcr-abl) in this delay is confirmed by comparing the effect of etoposide on the granulocyte-macrophage colony-stimulating factor (GM-CSF)-dependent UT7 cells and the bcr-abl-transfected GM-CSF-independent UT7/9 clone. We conclude that the cytosolic pathway that leads to apoptotic DNA fragmentation in etoposide-treated leukemic cells is delayed upstream of procaspase-3-mediated events in bcr-abl+ cell lines.
Dubrez
L
L
Department of Biology and Therapy of Cancer, INSERM CJF 94-08, Faculty of Medicine, Dijon, and INSERM U 362, IGR, Villejuif, France.
Eymin
B
B
Sordet
O
O
Droin
N
N
Turhan
A G
AG
Solary
E
E
D017209:Apoptosis / Q000502:physiology*; D053148:Caspase 3; D020169:Caspases; D003546:Cysteine Endopeptidases / Q000502:physiology*; D004249:DNA Damage; D004789:Enzyme Activation; D004792:Enzyme Precursors / Q000502:physiology; D016044:Fusion Proteins, bcr-abl / Q000502:physiology*; D018922:HL-60 Cells; D006801:Humans; D015398:Signal Transduction / Q000502:physiology*
D004792:Enzyme Precursors; D016044:Fusion Proteins, bcr-abl; C505407:CASP3 protein, human; D053148:Caspase 3; D020169:Caspases; D003546:Cysteine Endopeptidases