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Blood, Vol. 93 No. 7 (April 1), 1999:
pp. 2353-2359
Subcellular Distribution and Redistribution of Bcl-2 Family Proteins in
Human Leukemia Cells Undergoing Apoptosis
Li Jia,
Marion G. Macey,
Yuzhi Yin,
Adrian C. Newland, and
Stephen
M. Kelsey
From the Department of Haematology, St Bartholomew's and the Royal
London School of Medicine and Dentistry, London, UK.
It has been suggested that the ratio of Bcl-2 family proapoptotic
proteins to antiapoptotic proteins determines the sensitivity of
leukemic cells to apoptosis. However, it is believed that Bcl-2 family
proteins exert their function on apoptosis only when they target to the
mitochondrial outer membrane. The vinblastine-resistant T-lymphoblastic
leukemic cell line CEM/VLB100 has increased sensitivity to
tumor necrosis factor- (TNF-)-induced cytochrome c
release, mitochondrial respiratory inhibition, and consequently
apoptosis, compared with parental CEM cells. However, there was no
difference between the two cell lines in the expression of Bcl-2 family
proteins Bcl-2, Bcl-XL, Bcl-XS, Bad, and Bax at
the whole cell level, as analyzed by Western blotting. Bcl-2 mainly
located to mitochondria and light membrane as a membrane-bound protein,
whereas Bcl-XL was located in both mitochondria and
cytosol. Similar levels of both Bcl-2 and Bcl-XL were
present in the resting mitochondria of the two cell lines. Although the
proapoptotic proteins Bcl-XS, Bad, and Bax were mainly
located in the cytosol, CEM/VLB100 mitochondria expressed
higher levels of these proapoptotic proteins. Subcellular redistribution of the Bcl-2 family proteins was detected in a cell-free
system by both Western blotting and flow cytometry after exposure to
TNF-. The levels of Bcl-2 family proteins were not altered at the
whole cell level by TNF-. However, after exposure to TNF-, Bax,
Bad, and Bcl-XS translocated from the cytosol to the
mitochondria of both cell lines. An increase in Bcl-2 levels was
observed in CEM mitochondria, which showed resistance to
TNF--induced cytochrome c release. By contrast, decreased
mitochondrial Bcl-2 was observed in CEM/VLB100 cells, which
released cytochrome c from the mitochondria and underwent
apoptosis as detected by fluorescence microscopy. We conclude that
mitochondrial levels of Bcl-2 family proteins may determine the
sensitivity of leukemic cells to apoptosis and that, furthermore, these
levels may change rapidly after exposure of cells to toxic stimuli.
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