CASPASE-DEPENDENT APOPTOSIS OF COS-7 CELLS INDUCED BY BAX OVEREXPRESSION - DIFFERENTIAL-EFFECTS OF BCL-2 AND BCL-X(L) ON BAX-INDUCED CASPASE ACTIVATION AND APOPTOSIS
C. Kitanaka et al., CASPASE-DEPENDENT APOPTOSIS OF COS-7 CELLS INDUCED BY BAX OVEREXPRESSION - DIFFERENTIAL-EFFECTS OF BCL-2 AND BCL-X(L) ON BAX-INDUCED CASPASE ACTIVATION AND APOPTOSIS, Oncogene, 15(15), 1997, pp. 1763-1772
Bcl-2 family proteins and ICE/CED-3 family proteases (caspases) are re
garded as the basic regulators of apoptotic cell death. They are evolu
tionarily conserved and implicated in a variety of apoptosis. However,
the precise mechanism by which these two families interact to regulat
e cell death is not yet known. In this study, we found that the overex
pression of the Bcl-2 family member Bar induced apoptotic cell death i
n COS-7 cells through the activation of CPP32 (caspase-3)-like proteas
es that cleaved the DEVD tetrapeptide. This apoptotic cell death was s
uppressed by the viral proteins CrmA and p35, as well as by the chemic
ally synthesized caspase inhibitors Z-Asp-CH2-DCB and zVAD-fmk. We als
o found that the Bax-induced apoptosis of COS-7 cells was suppressed b
y Bcl-x(L) and Bcl-2, though both Bcl-x(L) and Bcl-2 similarly prevent
ed etoposide-induced apoptosis in COS-7 cells, In addition, Bcl-x(L) i
nhibited the activation of caspase-3-like proteases accompanying Bax-i
nduced COS-7 cell death but Bcl-2 did not. These results indicate that
the caspase activation is essential for Bax-induced apoptosis, and th
at the ability of Bcl-2 and Bcl-x, to prevent the Bax-induced caspase
activation and apoptosis in COS-7 cells could be differentially regula
ted. Our results also suggest that Bcl-2 family proteins function upst
ream of caspase activation and control apoptosis through the regulatio
n of caspase activity.