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J Biol Chem, Vol. 274, Issue 7, 3953-3961, February 12, 1999
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From the Cytolytic granule-mediated target cell killing is
effected in part through the synergistic action of the membrane-acting
protein perforin and serine proteases such as granzymes (Gr) A and B. In this study, we examine the subcellular distribution of granzymes in
the presence of perforin and the induction of apoptosis in mouse FDC-P1
myeloid and YAC-1 lymphoma cells that express the proto-oncogene
bcl2. Using confocal laser scanning microscopy to visualize
and quantitate subcellular transport of fluoresceinated granzyme, we
find that granzyme entry into the cytoplasm in the absence of perforin
is not impaired in the bcl2-expressing lines. However,
perforin-dependent enhancement of granzyme cellular uptake and, importantly, granzyme redistribution to the nucleus were strongly
inhibited in the bcl2-expressing lines, concomitant with greatly increased resistance to granzyme/perforin-induced cell death.
DNA fragmentation induced by granzyme/perforin was severely reduced in
the bcl2-expressing lines, implying that prevention of
granzyme nuclear translocation blocks the nuclear events of apoptosis.
The kinetics of GrB nuclear uptake and induction of apoptosis were
faster than for GrA, whereas YAC-1 cells showed greater resistance to
granzyme nuclear uptake and apoptosis than FDC-P1 cells. In all
cases, granzyme nuclear accumulation in the presence of perforin
correlated precisely with ensuing apoptosis. All results supported the
idea that GrA and GrB share a common, specific nuclear targeting
pathway that contributes significantly to the nuclear changes of apoptosis.
Nuclear Signaling Laboratory, Division for
Biochemistry and Molecular Biology, John Curtin School of Medical
Research, Canberra City, Australia, ¶ Cellular Cytotoxicity
Laboratory, The Austin Research Institute, Heidelberg, Australia, and
Department of Medicine, Northwestern University Medical School,
Evanston, Illinois 60201
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