HSP90 regulates cell survival via inositol hexakisphosphate kinase-2
HSP90 regulates cell survival via inositol hexakisphosphate kinase-2
复制标题
DOI：
10.1073/pnas.0711168105
复制
发表时间：
2008-01-29
影响因子：
11.1
通讯作者：
Snyder, Solomon H.
中科院分区：
文献类型：
--
作者：
Chakraborty, Anutosh;Koldobskiy, Michael A.;Snyder, Solomon H.
热休克蛋白 (HSP) 是丰富的诱导性蛋白质，以其维持蛋白质构象和重新折叠受损蛋白质的能力而闻名。一些HSP，尤其是HSP90，具有抗细胞凋亡作用，是抗癌药物的靶标。肌醇六磷酸激酶-2 (IP6K2) 是产生肌醇焦磷酸 IP7 [二磷酸肌醇五磷酸 (5-PP-IP5)] 的酶家族之一，可介导细胞凋亡。 IP6K2 活性的增加使癌细胞对压力源变得敏感，而 IP6K2 的耗尽则阻止细胞死亡。我们现在证明 HSP90 在生理上结合 IP6K2 并抑制其催化活性。废除 HSP90-IP6K2 结合的药物和选择性突变会引发 IP6K2 激活，导致细胞死亡。因此，HSP90 的促生存作用反映了 IP6K2 的抑制作用，表明选择性阻断这种相互作用可以提供有效且更安全的化疗模式。
Heat-shock proteins (HSPs) are abundant, inducible proteins best known for their ability to maintain the conformation of proteins and to refold damaged proteins. Some HSPs, especially HSP90, can be antiapoptotic and the targets of anticancer drugs. Inositol hexakisphosphate kinase-2 (IP6K2), one of a family of enzymes generating the inositol pyrophosphate IP7 [diphosphoinositol pentakisphosphate (5-PP-IP5)], mediates apoptosis. Increased IP6K2 activity sensitizes cancer cells to stressors, whereas its depletion blocks cell death. We now show that HSP90 physiologically binds IP6K2 and inhibits its catalytic activity. Drugs and selective mutations that abolish HSP90-IP6K2 binding elicit activation of IP6K2, leading to cell death. Thus, the prosurvival actions of HSP90 reflect the inhibition of IP6K2, suggesting that selectively blocking this interaction could provide effective and safer modes of chemotherapy.