Disruption of Hsp90 function results in degradation of the death domain kinase, receptor-interacting protein (RIP), and blockage of tumor necrosis factor-induced nuclear factor-κB activation
Disruption of Hsp90 function results in degradation of the death domain kinase, receptor-interacting protein (RIP), and blockage of tumor necrosis factor-induced nuclear factor-κB activation
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DOI：
10.1074/jbc.275.14.10519
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发表时间：
2000-04-07
影响因子：
4.8
通讯作者：
Liu, ZG
中科院分区：
文献类型：
--
作者：
Lewis, J;Devin, A;Liu, ZG
死亡结构域激酶，受体相互作用蛋白（RIP），是肿瘤坏死因子受体1（TNFR 1）复合物的主要成分之一，在肿瘤坏死因子（TNF）介导的核因子κ B（NF-κ B）活化中起重要作用。NF-κ B的活化保护细胞免受TNF诱导的凋亡。热休克蛋白（Hsps）是一种分子伴侣，它赋予蛋白质稳定性，并有助于在热休克和其他应激后恢复蛋白质的天然折叠。最丰富的热休克蛋白，热休克蛋白90，也参与调节稳定性和功能的细胞信号分子的数量。在这里，我们报告说，RTP是一种新的热休克蛋白90相关的激酶，其特异性抑制剂，格尔德霉素（GA），破坏热休克蛋白90的功能，选择性地导致RIP降解和随后的抑制肿瘤坏死因子介导的I κ B激酶和NP-κ B激活。MG-132，一种特异性蛋白酶体抑制剂，废除GA诱导的RIP降解，但未能恢复TNF对I κ B激酶的激活，这可能是因为，在GA和MG-132的存在下，RIP在洗涤剂不溶性亚细胞组分中积累。最重要的是，RIP的降解使细胞对TNF诱导的凋亡敏感。这些数据表明，Hsp 90通过调节RIP的稳定性和溶解性在TNF介导的NF-κ B活化中起重要作用。因此，GA对NF-κ B活化的抑制可能是该药物抗肿瘤活性的关键组分。
The death domain kinase, receptor interacting protein (RIP), is one of the major components of the tumor necrosis factor receptor 1 (TNFR1) complex and plays an essential role in tumor necrosis factor (TNF)-mediated nuclear factor kappa B (NF-kappa B) activation. The activation of NF-kappa B protects cells against TNF-induced apoptosis. Heat-shock proteins (Hsps) are chaperone molecules that confer protein stability and help to restore protein native folding following heat shock and other stresses. The most abundant Hsp, Hsp90, is also involved in regulating the stability and function of a number of cell-signaling molecules. Here we report that RTP is a novel Hsp90-associated kinase and that disruption of Hsp90 function by its specific inhibitor, geldanamycin (GA), selectively causes RIP degradation and the subsequent inhibition of TNF-mediated I kappa B kinase and NP-kappa B activation. MG-132, a specific proteasome inhibitor, abrogated GA-induced degradation of RIP but failed to restore the activation of I kappa B kinase by TNF, perhaps because, in the presence of GA and MG-132, RIP accumulated in a detergent-insoluble subcellular fraction. Most importantly, the degradation of RIP sensitizes cells to TNF-induced apoptosis. These data indicate that Hsp90 plays an important role in TNF-mediated NF-kappa B activation by modulating the stability and solubility of RIP. Thus, inhibition of NF-kappa B activation by GA may be a critical component of the anti-tumor activity of this drug.