A. Bruel et al., ALTERED SENSITIVITY TO RETINOID-INDUCED APOPTOSIS ASSOCIATED WITH CHANGES IN THE SUBCELLULAR-DISTRIBUTION OF BCL-2, Experimental cell research, 233(2), 1997, pp. 281-287
In the acute promyelocytic leukemia cell line NB4, Bcl-2 downregulatio
n occurred as a late event of retinoid-induced differentiation. In the
maturation-resistant NB4-R1 subclone, retinoids failed to downregulat
e Bcl-2 even in the situation of apoptosis massively induced by pan-ag
onists and RXR-selective agonists. We observed that NB4 and NB4-R1 cel
ls differed with respect to the intracellular localization of Bcl-2 wh
ich showed a perinuclear localization in NB4-R1 cells, while Bar was b
roadly expressed in the cytoplasm and to only a minor extent in the pe
rinuclear area. Therefore, the distinct intracellular localization of
Bcl-2 and Bar was in general nonoverlaping. Bcl-2 remained massively e
xpressed until cell disruption. Bar was not significantly upregulated
in cells committed to death. However, Bar localization changed from a
diffuse pattern to concentrate in few specific cytoplasmic area at a s
tage preceding the formation of apoptotic bodies. A human Bcl-2 transg
ene was transiently overexpressed in NB4-R1 cells which showed increas
ed resistance to apoptosis induced by retinoids. Stably transfected cl
ones of NB4-R1 cells showed an increased expression of Bcl-2 and a mar
ked resistance to apoptosis. Interestingly, the overexpression of Bcl-
2 restored a pattern of uniform Bcl-2 labeling in the cytoplasm and, r
emarkably, the colocalization of Bcl-2 with Bar. This work demonstrate
s that the ability of retinoid-induced cells to undergo apoptosis depe
nds on the level of expression and the functional interaction between
Bcl-2 and Bar. (C) 1997 Academic Press.