实体肿瘤经常处于葡萄糖不足引起的代谢应激。野生型p53在代谢应激时发挥保护作用，这与多数肿瘤p53缺失或突变，但在代谢应激时存活的现象矛盾，提示存在其他p53非依赖性机制。最近我们发现BAG3增加p53缺失细胞在代谢应激时的存活。代谢应激在多个GSK3b潜在磷酸化位点增加BAG3磷酸化水平，并且GSK3b活性与BAG3磷酸化水平密切相关。另外，我们发现葡萄糖充足时BAG3与p53蛋白直接互作并促进其降解，代谢应激时BAG3与SESN2 mRNA结合而稳定其表达，GSK3b活性在该“开关切换”中发挥关键作用。SESN2在营养物质匮乏时保护细胞，因此我们推测GSK3b介导BAG3磷酸化促进SESN2表达而参与代谢应激时保护性应答。多数肿瘤存在p53突变或缺失和BAG3表达增加，本项目解析BAG3在肿瘤细胞适应葡萄糖不足而生存的分子机制，这对于理解肿瘤发生发展并靶向治疗极其重要。

Metabolic stress induced by glucose insufficiency often occurs during initiation and progression of solid tumor. It has been reported that wild type p53 plays a critical role in maintaining cell survival during metabolic stress. P53 was lost or mutated in large amounts of tumors, while most tumor cells maintain survival during metabolic stress. These apparently paradoxical phenomena indicate that some other protective factors might protect tumors from metabolic stress independent of p53. Recently, we found that BAG3 overexpression protected tumor cells with loss of p53 from glucose insufficiency, indicating that BAG3 might be one of p53-independent protective mechanisms during metabolic stress. We found that BAG3 expression was unaltered by metabolic stress induced by glucose insufficiency, while its phosphorylation was increased. We identified that BAG3 phosphorylation was increased at 5 sites: T285, S289, S377, S381, and S385. These sites conformed with consensus sequence for phosphorylation mediated by GSK3b. We confirmed that inhibition of GSK3b decreased the protective role of BAG3 in metabolic stress. In addition, we demonstrated that BAG3 interacted with both p53 protein and SESN2 mRNA.GSK3b might be responsible for the switch as metabolic stress and GSK3b activator decreased interaction between BAG3 and p53 protein, while increased interaction between BAG3 and SESN2 mRNA. Since SESN2 plays a protective role under insufficiency of nutrients via suppressing protein biosynthesis and promoting autophagy, we suspected that GSK3b mediated phosphorylation of BAG3 might protect cells from metabolic stress independent of p53 via binding with SESN2 mRNA and increasing its expression at the post transcriptional level. As p53 is lost or mutated while BAG3 is upregulated in most of tumors, the current project aims to investigate the potential role of BAG3 in tumor cell survival under metabolic stress induced by nutrient insufficiency, as well as its underlying mechanisms. The current project might enhance our understanding on how tumor cells survive under metabolic stress, as well as provide potential targets for prevention or treatment of tumors.