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
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
复制标题
DOI：
10.1038/sj.onc.1201349
复制
发表时间：
1997-10-09
期刊：
影响因子：
8
通讯作者：
Kuchino, Y
中科院分区：
文献类型：
--
作者：
Kitanaka, C;Namiki, T;Kuchino, Y
Bcl-2家族蛋白和ICE/CED-3家族蛋白酶（半胱天冬酶）被认为是凋亡性细胞死亡的基本调节剂。它们在进化上是保守的，并与多种细胞凋亡有关。然而，这两个家族相互作用调节细胞死亡的确切机制尚不清楚。在这项研究中，我们发现Bcl-2家族成员Bax的过度表达通过激活切割DEVD四肽的CPP 32（caspase-3）样蛋白酶诱导COS-7细胞凋亡。这种凋亡性细胞死亡受到病毒蛋白CrmA和p35以及化学合成的半胱天冬酶抑制剂Z-Asp-CH 2-DCB和zVAD-favorite的抑制。Bcl-x（L）和Bcl-2均能抑制足叶乙甙诱导的COS-7细胞凋亡，而Bcl-x（L）和Bcl-2对足叶乙甙诱导的COS-7细胞凋亡有抑制作用。此外，Bcl-x（L）能抑制caspase-3样蛋白酶的激活，而Bcl-2则无此作用。这些结果表明，caspase的激活是必不可少的顺铂诱导的细胞凋亡，Bcl-2和Bcl-x，以防止顺铂诱导的caspase激活和细胞凋亡的COS-7细胞中的能力可以被差异调节。我们的研究结果还表明，Bcl-2家族蛋白的功能上游的caspase激活和控制凋亡通过调节caspase活性。
Bcl-2 family proteins and ICE/CED-3 family proteases (caspases) are regarded as the basic regulators of apoptotic cell death. They are evolutionarily conserved and implicated in a variety of apoptosis. However, the precise mechanism by which these two families interact to regulate cell death is not yet known. In this study, we found that the overexpression of the Bcl-2 family member Bax induced apoptotic cell death in COS-7 cells through the activation of CPP32 (caspase-3)-like proteases that cleaved the DEVD tetrapeptide. This apoptotic cell death was suppressed by the viral proteins CrmA and p35, as well as by the chemically synthesized caspase inhibitors Z-Asp-CH2-DCB and zVAD-fmk. We also found that the Bax-induced apoptosis of COS-7 cells was suppressed by Bcl-x(L) and Bcl-2, though both Bcl-x(L) and Bcl-2 similarly prevented etoposide-induced apoptosis in COS-7 cells, In addition, Bcl-x(L) inhibited the activation of caspase-3-like proteases accompanying Bax-induced COS-7 cell death but Bcl-2 did not. These results indicate that the caspase activation is essential for Bax-induced apoptosis, and that the ability of Bcl-2 and Bcl-x, to prevent the Bax-induced caspase activation and apoptosis in COS-7 cells could be differentially regulated. Our results also suggest that Bcl-2 family proteins function upstream of caspase activation and control apoptosis through the regulation of caspase activity.