Ionizing radiation-induced, Bax-mediated cell death is dependent on activation of cysteine and serine proteases.
Ionizing radiation-induced, Bax-mediated cell death is dependent on activation of cysteine and serine proteases.
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发表时间：
1999-07
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通讯作者：
B. Gong;Q. Chen;B. Endlich;S. Mazumder;A. Almasan
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作者：
B. Gong;Q. Chen;B. Endlich;S. Mazumder;A. Almasan
BCL-2家族蛋白和白介素1-β转换酶/秀丽线虫细胞死亡基因-3(ICE/CED-3)家族蛋白(Caspase)是细胞凋亡的基本调节因子。然而，它们相互作用的确切机制尚不清楚。在本研究中，我们发现伽玛射线诱导的白血病细胞凋亡与多个caspase的激活和Bax的上调有关。特定的caspase抑制剂可抑制细胞膜的变化和caspase活性。同样，丝氨酸蛋白酶抑制剂z-Ala-Ala-Asp-CMK(AAD)和对甲苯磺酰赖氨酸氯甲基酮(TLCK)在体内也能阻止caspase的激活和聚ADP-核糖聚合酶的切割，但在体外对caspase的活性没有影响。TLCK还可通过抑制P53功能而阻止Bax的上调。Caspase和丝氨酸蛋白酶的抑制剂部分阻止了细胞死亡，这表明caspase参与了Bax介导的细胞死亡。我们提出了Bax介导的细胞死亡的信号事件的顺序，包括P53和Bax上调的上游和下游步骤。
Bcl-2 family proteins and interleukin-1-beta converting enzyme/Caenorhabditis elegans cell death gene-3 (ICE/CED-3) family proteases (caspases) represent the basic regulators of apoptosis. However, the precise mechanism by which they interact is unclear. In this study, we found that gamma-radiation-induced apoptosis of leukemia cells was associated with activation of multiple caspases and bax up-regulation. Membrane changes and caspase activities were suppressed by specific caspase inhibitors. Similarly, the serine protease inhibitors z-Ala-Ala-Asp-cmk (AAD) and tosyl-lysine chloromethyl ketone (TLCK) also prevented caspase activation and poly(ADP-ribose) polymerase cleavage in vivo but had no effect on caspase activity in vitro. TLCK also prevented bax up-regulation as a result of its inhibitory effect on p53 function. Inhibitors of caspases and serine proteases partially prevented cell death, suggesting a caspase involvement in Bax-mediated cell death. We propose an ordering of signaling events in Bax-mediated cell death, including steps upstream and downstream of p53 and bax up-regulation.