Cytosolic FoxO1 is essential for the induction of autophagy and tumour suppressor activity
Cytosolic FoxO1 is essential for the induction of autophagy and tumour suppressor activity
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胞质 FoxO1 对于诱导自噬和肿瘤抑制活性至关重要
DOI：
10.1038/ncb2069
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发表时间：
2010-07-01
影响因子：
21.3
通讯作者：
Zhu, Wei-Guo
中科院分区：
文献类型：
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作者：
Zhao, Ying;Yang, Jing;Zhu, Wei-Guo
自噬的特点是将大量细胞质（包括受损的蛋白质和细胞器）隔离，并将货物运送到溶酶体进行降解。虽然自噬途径也与肿瘤抑制活性有关，但其机制尚不清楚。在这里，我们报告细胞质fox01，叉头O家族蛋白，是自噬的介质。内源性FoxO1是人类癌细胞在氧化应激或血清饥饿反应中自噬所必需的，但这一过程与FoxO1的转录活性无关。在应激反应中，FoxO1通过与sirtuin-2（一种NAD+依赖的组蛋白去乙酰化酶）解离而乙酰化，并与Atg7（一种e1样蛋白）结合，从而影响导致细胞死亡的自噬过程。在人类结肠肿瘤和异种移植小鼠模型中，fox01调节的细胞死亡与肿瘤抑制活性相关。我们的发现将fox01的抗肿瘤活性与自噬过程联系起来。
Autophagy is characterized by the sequestration of bulk cytoplasm, including damaged proteins and organelles, and delivery of the cargo to lysosomes for degradation. Although the autophagic pathway is also linked to tumour suppression activity, the mechanism is not yet clear. Here we report that cytosolic FoxO1, a forkhead O family protein, is a mediator of autophagy. Endogenous FoxO1 was required for autophagy in human cancer cell lines in response to oxidative stress or serum starvation, but this process was independent of the transcriptional activity of FoxO1. In response to stress, FoxO1 was acetylated by dissociation from sirtuin-2 (SIRT2), a NAD+-dependent histone deacetylase, and the acetylated FoxO1 bound to Atg7, an E1-like protein, to influence the autophagic process leading to cell death. This FoxO1-modulated cell death is associated with tumour suppressor activity in human colon tumours and a xenograft mouse model. Our finding links the anti-neoplastic activity of FoxO1 and the process of autophagy.