1. Cytosolic FoxO1 is essential for the induction of autophagy and tumour suppressor activity
- Author
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Li Yu, Shan Wang, Wenjuan Liao, Jingnan Feng, Jing Yang, Donglai Wang, Xiangyu Liu, Hui Zhang, Wei-Guo Zhu, and Ying Zhao
- Subjects
Sequestosome-1 Protein ,endocrine system ,Programmed cell death ,Blotting, Western ,Mice, Nude ,FOXO1 ,Ubiquitin-Activating Enzymes ,Biology ,BAG3 ,SIRT2 ,digestive system ,Autophagy-Related Protein 7 ,Mice ,Cytosol ,Sirtuin 2 ,Cell Line, Tumor ,Autophagy ,Animals ,Humans ,Adaptor Proteins, Signal Transducing ,Forkhead Box Protein O1 ,nutritional and metabolic diseases ,food and beverages ,Acetylation ,Forkhead Transcription Factors ,Cell Biology ,Hydrogen Peroxide ,Actins ,Cell biology ,Cancer research ,RNA Interference ,Histone deacetylase ,Microtubule-Associated Proteins ,hormones, hormone substitutes, and hormone antagonists ,HeLa Cells ,Protein Binding - Abstract
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.
- Published
- 2010