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首页> 外文期刊>Molecular and Cellular Biology >Hsp72 and Stress Kinase c-jun N-Terminal Kinase Regulate the Bid-Dependent Pathway in Tumor Necrosis Factor-Induced Apoptosis
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Hsp72 and Stress Kinase c-jun N-Terminal Kinase Regulate the Bid-Dependent Pathway in Tumor Necrosis Factor-Induced Apoptosis

机译：Hsp72和应激激酶c jun N终端激酶调节肿瘤坏死因子诱导的细胞凋亡的依赖于投标的途径。

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The major inducible heat shock protein Hsp72 has been shown to protect cells from certain apoptotic stimuli. Here we investigated the mechanism of Hsp72-mediated protection from tumor necrosis factor (TNF)-induced apoptosis of primary culture of IMR90 human fibroblasts. Hsp72 temporarily blocked apoptosis in response to TNF and permanently protected cells from heat shock. An Hsp72 mutant (Hsp72ΔEEVD) with a deletion of the four C-terminal amino acids, which are essential for the chaperone function, blocked TNF-induced apoptosis in a manner similar to that of normal Hsp72 but did not inhibit heat shock-induced death. Therefore, the chaperone activity of Hsp72 is dispensable for suppression of TNF-induced apoptosis but is required for protection from heat shock. In fibroblasts derived from Bid knockout mice, similar temporal inhibition of TNF-induced apoptosis was seen. In these cells neither normal Hsp72 nor Hsp72ΔEEVD conferred additional protection from apoptosis, suggesting that Hsp72 specifically affects Bid-dependent but not Bid-independent apoptotic pathways. Furthermore, both normal Hsp72 and ΔHsp72EEVD inhibited Bid activation and downstream events, including release of cytochrome c, activation of caspase 3, and cleavage of poly-ADP-ribose polymerase. Both Hsp72 and ΔHsp72EEVD blocked activation of the stress kinase c-jun N-terminal kinase (JNK) by TNF, and specific inhibition of JNK similarly temporarily blocked Bid activation and the downstream apoptotic events. These data strongly suggest that in TNF-induced apoptosis, Hsp72 specifically interferes with the Bid-dependent apoptotic pathway via inhibition of JNK.
机译：主要的诱导性热休克蛋白Hsp72已显示可保护细胞免受某些凋亡刺激。在这里，我们研究了Hsp72介导的保护机制，免受肿瘤坏死因子（TNF）诱导的IMR90人成纤维细胞原代培养细胞凋亡。 Hsp72暂时阻断对TNF的凋亡，并永久保护细胞免受热激。 Hsp72突变体（Hsp72ΔEEVD）缺失了伴侣功能所必需的四个C末端氨基酸，以类似于正常Hsp72的方式阻断了TNF诱导的凋亡，但没有抑制热休克诱导的死亡。因此，Hsp72的伴侣活性对于抑制TNF诱导的细胞凋亡是必不可少的，但对于防止热激则是必需的。在来自Bid基因敲除小鼠的成纤维细胞中，可以看到类似的时间抑制TNF诱导的细胞凋亡。在这些细胞中，正常的Hsp72和Hsp72ΔEEVD均未赋予细胞凋亡额外的保护作用，表明Hsp72特异性影响Bid依赖性但不依赖Bid的凋亡途径。此外，正常的Hsp72和ΔHsp72EEVD均抑制Bid激活和下游事件，包括细胞色素 c 的释放，胱天蛋白酶3的激活以及聚ADP-核糖聚合酶的裂解。 Hsp72和ΔHsp72EEVD均能阻止TNF激活应激激酶c-jun N末端激酶（JNK），而对JNK的特异性抑制同样会暂时阻止Bid激活和下游凋亡事件。这些数据强烈表明，在TNF诱导的细胞凋亡中，Hsp72通过抑制JNK特异性干扰Bid依赖性凋亡途径。

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