The overexpression of Bax produces cell death upon induction of the mitochondrial permeability transition

被引:525
作者
Pastorino, JG [1 ]
Chen, ST [1 ]
Tafani, M [1 ]
Snyder, JW [1 ]
Farber, JL [1 ]
机构
[1] Thomas Jefferson Univ, Dept Pathol & Cell Biol, Philadelphia, PA 19107 USA
关键词
D O I
10.1074/jbc.273.13.7770
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Stably transfected Jurkat T cells were produced in which Bax expression is inducible by muristerone A. The cell death resulting from induction of the overexpression of Bax was prevented by inhibition of the mitochondrial permeability transition (MPT) with cyclosporin A (CyA) in combination with the phospholipase A(2) inhibitor aristolochic acid (ArA). The caspase-3 inhibitor Z-Asp-Glu-Val aspartic acid fluoromethylketone (Z-DEVD-FMK) had no effect on the loss of viability. The MPT was measured as the CyA plus ArA-preventable loss of the mitochondrial membrane potential (Delta Psi(m)). The MPT was accompanied by the release of cytochrome c from the mitochondria, caspase-3 activation in the cytosol, cleavage of the nuclear enzyme poly(ADP-ribose)polymerase (PARP), and DNA fragmentation, all of which were inhibited by CyA plus ArA, Z-DEVD-FMK had no effect on the loss of Delta Psi(m) and the redistribution of cytochrome c but did prevent caspase-3 activation, PARP cleavage, and DNA fragmentation. It is concluded that Bax induces the MPT, a critical event in the loss of cell viability. In addition to the cell death, the MPT mediates other typical manifestations of apoptosis in this model, namely release of cytochrome c, caspase activation with PARP cleavage, and DNA fragmentation.
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页码:7770 / 7775
页数:6
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