Hsp70 exerts its anti-apoptotic function downstream of caspase-3-like proteases
Hsp70 exerts its anti-apoptotic function downstream of caspase-3-like proteases
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DOI：
10.1093/emboj/17.21.6124
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发表时间：
1998-11-02
期刊：
影响因子：
11.4
通讯作者：
Egeblad, M
中科院分区：
文献类型：
--
作者：
Jäättelä, M;Wissing, D;Egeblad, M
热休克蛋白70（Hsp 70）是一种有效的细胞凋亡抑制剂。为了研究其作用机制，我们建立了Hsp 70水平改变的肿瘤细胞系。在用肿瘤坏死因子、星形孢菌素和阿霉素治疗后，获得的细胞中Hsp 70的表达水平与它们的存活率良好相关。令人惊讶的是，存活的Hsp 70表达告诉响应于凋亡刺激的应激活化蛋白激酶的激活，产生自由基，线粒体跨膜电位的早期破坏，从线粒体释放细胞色素c和激活半胱天冬酶-3样蛋白酶的方式基本上类似于死亡的细胞与低Hsp 70水平。然而，热休克蛋白70抑制晚期半胱天冬酶依赖的事件，如激活胞浆磷脂酶A（2）和核形态的变化，此外，热休克蛋白70赋予显着的保护作用，防止细胞死亡诱导的半胱天冬酶-3的强制表达。因此，Hsp 70在死亡信号通路中比任何已知的抗凋亡蛋白更晚地拯救细胞免于凋亡，使其成为治疗干预的诱人靶点。
The major heat shock protein, Hsp70, is an effective inhibitor of apoptosis, To study its mechanism of action, we created tumor cell lines with altered Hsp70 levels. The expression levels of Hsp70 in the cells obtained correlated well with their survival following treatments with tumor necrosis factor, staurosporine and doxorubicin. Surprisingly, the surviving Hsp70-expressing tells responded to the apoptotic stimuli by activation of stress-activated protein kinases, generation of free radicals, early disruption of mitochondrial transmembrane potential, release of cytochrome c from mitochondria and activation of caspase-3-like proteases in a manner essentially similar to that of the dying cells with low Hsp70 levels. However, Hsp70 inhibited late caspase-dependent events such as activation of cytosolic phospholipase A(2) and changes in nuclear morphology, Furthermore, Hsp70 conferred significant protection against cell death induced by enforced expression of caspase-3. Thus, Hsp70 rescues cells from apoptosis later in the death signaling pathway than any known anti-apoptotic protein, making it a tempting target for therapeutic interventions.