The Hippo pathway promotes cell survival in response to chemical stress
The Hippo pathway promotes cell survival in response to chemical stress
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DOI：
10.1038/cdd.2015.10
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发表时间：
2015-09-01
影响因子：
12.4
通讯作者：
King-Jones, K.
中科院分区：
文献类型：
--
作者：
Di Cara, F.;Maile, T. M.;King-Jones, K.
细胞应激防御机制已经进化到维持稳态，以应对各种环境挑战。压力信号传导途径会激活多种细胞程序，从激活生存途径到细胞受到无法修复的损伤时启动细胞死亡。为了识别应激反应途径中的新参与者，我们使用咖啡因作为外源性应激诱导剂进行了细胞培养 RNA 干扰 (RNAi) 筛选，因为这种化合物是一种公认的解毒反应途径诱导剂。具体来说，我们研究了当果蝇激酶和磷酸酶通过 RNAi 耗尽时咖啡因如何影响细胞存活。使用这种方法，我们鉴定并验证了 10 种激酶和 4 种磷酸酶，它们对于细胞培养物和活果蝇中咖啡因诱导的应激下的细胞生存至关重要。值得注意的是，我们的筛选丰富了 Hippo 通路成分，表明该通路调节细胞应激反应。事实上，我们证明 Hippo 途径可以有效抑制应激诱导的细胞死亡。此外，我们证明 Hippo 激活对于抑制促凋亡程序是必要的，该程序是由转录共激活因子 Yki 与转录因子 p53 响应一系列应激刺激的相互作用而触发的。因此，我们的体外和体内功能丧失数据表明，Hippo 信号传导参与了响应化学应激的细胞生存信号的转导。
Cellular stress defense mechanisms have evolved to maintain homeostasis in response to a broad variety of environmental challenges. Stress signaling pathways activate multiple cellular programs that range from the activation of survival pathways to the initiation of cell death when cells are damaged beyond repair. To identify novel players acting in stress response pathways, we conducted a cell culture RNA interference (RNAi) screen using caffeine as a xenobiotic stress-inducing agent, as this compound is a well-established inducer of detoxification response pathways. Specifically, we examined how caffeine affects cell survival when Drosophila kinases and phosphatases were depleted via RNAi. Using this approach, we identified and validated 10 kinases and 4 phosphatases that are essential for cell survival under caffeine-induced stress both in cell culture and living flies. Remarkably, our screen yielded an enrichment of Hippo pathway components, indicating that this pathway regulates cellular stress responses. Indeed, we show that the Hippo pathway acts as a potent repressor of stress-induced cell death. Further, we demonstrate that Hippo activation is necessary to inhibit a pro-apoptotic program triggered by the interaction of the transcriptional co-activator Yki with the transcription factor p53 in response to a range of stress stimuli. Our in vitro and in vivo loss-of-function data therefore implicate Hippo signaling in the transduction of cellular survival signals in response to chemical stress.