Heat shock protein 90 regulates phosphatidylinositol 3-kinase-related protein kinase family proteins together with the RUVBL1/2 and Tel2-containing co-factor complex
Heat shock protein 90 regulates phosphatidylinositol 3-kinase-related protein kinase family proteins together with the RUVBL1/2 and Tel2-containing co-factor complex
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DOI：
10.1111/j.1349-7006.2011.02112.x
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发表时间：
2012-01-01
期刊：
影响因子：
5.7
通讯作者：
Ohno, Shigeo
中科院分区：
文献类型：
--
作者：
Izumi, Natsuko;Yamashita, Akio;Ohno, Shigeo
热休克蛋白90（Heat shock protein 90，Hsp 90）是一种保守的分子伴侣蛋白，它与一系列重要的信号转导蛋白（包括几种致癌蛋白）密切相关，是一种很有前途的抗肿瘤治疗靶点。Hsp 90抑制也使癌细胞对DNA损伤敏感。然而，其潜在机制尚未完全了解。在这里，我们提供的证据表明，热休克蛋白90是磷脂酰肌醇3-激酶相关的蛋白激酶（PIKK）家族蛋白，包括DNA损伤的应激反应的中央调节器的一般调节。Hsp 90的抑制导致所有PIKK的减少并抑制PIKK介导的信号传导。此外，Hsp 90与RUVBL 1/2复合物和Tel 2复合物形成复合物，这两种复合物均与所有PIKK相互作用并控制其丰度和功能。这些结果表明，Hsp 90可以与RUVBL 1/2复合物和Tel 2复合物形成多种复合物，并在PIKK的调节中发挥作用，为Hsp 90抑制抗癌治疗的有效性提供了额外的理论基础，包括对DNA损伤的敏化。（Cancer Sci 2012; 103：50-57）
Heat shock protein 90 (Hsp90), a conserved molecular chaperone for a specific set of proteins critical for signal transduction including several oncogenic proteins, has been recognized as a promising target for anticancer therapy. Hsp90 inhibition also sensitizes cancer cells to DNA damage. However, the underlying mechanisms are not fully understood. Here, we provide evidence that Hsp90 is a general regulator of phosphatidylinositol 3-kinase-related protein kinase (PIKK) family proteins, central regulators of stress responses including DNA damage. Inhibition of Hsp90 causes a reduction of all PIKK and suppresses PIKK-mediated signaling. In addition, Hsp90 forms complexes with RUVBL1/2 complex and Tel2 complex, both of which have been shown to interact with all PIKK and control their abundance and functions. These results suggest that Hsp90 can form multiple complexes with the RUVBL1/2 complex and Tel2 complex and function in the regulation of PIKK, providing additional rationale for the effectiveness of Hsp90 inhibition for anticancer therapy, including sensitization to DNA damage. (Cancer Sci 2012; 103: 50-57)