Bcl-2 and caspase inhibition cooperate to inhibit tumor necrosis factor-α-induced cell death in a Bcl-2 cleavage-independent fashion
Bcl-2 and caspase inhibition cooperate to inhibit tumor necrosis factor-α-induced cell death in a Bcl-2 cleavage-independent fashion
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DOI：
10.1074/jbc.274.26.18552
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发表时间：
1999-06-25
影响因子：
4.8
通讯作者：
Boise, LH
中科院分区：
文献类型：
--
作者：
Johnson, BW;Boise, LH
Bcl-2家族蛋白诱导或抑制凋亡的能力取决于细胞类型和凋亡刺激。我们已经在鼠pro-B细胞系FL5.12中显示Bcl-2不能抑制肿瘤坏死因子α（TNF α）诱导的细胞死亡，并且在此过程中被切割。对这一观察结果的一个潜在解释是胱天蛋白酶激活直接或间接抑制Bcl-2功能。已经表明Bcl-2的半胱天冬酶切割是其不能阻断某些细胞死亡的原因。与Bcl-2裂解是半胱天冬酶介导的事件一致，该裂解可被50 μ M CBZ-Val-Ala-Asp-氟甲基酮（zVAD-fetamine）所诱导。此外，Bcl-2可以以剂量依赖性方式与半胱天冬酶抑制剂zVAD-favor合作，以阻断TNF α诱导的细胞死亡。Bcl-2的过表达导致抑制TNF α诱导的细胞凋亡所需的zVAD-β的量减少10倍。然而，切割缺陷型突变体（D31 A和D34 A）在响应TNF α诱导的细胞死亡时相对于野生型Bcl-2没有显示出增强的活力，并且还显示出与zVAD-β相同的协同性。这些结果表明，Bcl-2裂解是不重要的抑制TNF α诱导的细胞死亡，但不排除参与后承诺阶段的细胞凋亡。
The ability of proteins of the Bcl-2 family to either induce or inhibit apoptosis is dependent on both cell type and the apoptotic stimulus. We have shown in the murine pro-B cell line FL5.12 that Bcl-2 is incapable of inhibiting tumor necrosis factor alpha (TNF alpha)-induced cell death and is cleaved during this process. One potential explanation for this observation is that caspase activation directly or indirectly inhibits Bcl-2 function. It has been suggested that caspase cleavage of Bcl-2 is responsible for its inability to block certain cell deaths. Consistent with Bcl-2 cleavage being a caspase-mediated event, this cleavage is inhibitable by 50 mu M CBZ-Val-Ala-Asp-fluoromethylketone (zVAD-fmk). Furthermore, Bcl-2 can cooperate with the caspase inhibitor zVAD-fmk in a dose-dependent manner to block TNF alpha-induced cell death. Overexpression of Bcl-2 results in a 10-fold decrease in the amount of zVAD-fmk required to inhibit TNF alpha-induced apoptosis. However, cleavage-defective mutants (D31A and D34A) show no enhanced viability relative to wild-type Bcl-2 in response to TNF alpha-induced cell death and also show the same cooperativity with zVAD-fmk. These results suggest that Bcl-2 cleavage is not important for the inhibition of TNF alpha-induced cell death but do not preclude an involvement in a post-commitment phase of apoptosis.