肿瘤细胞耐受能量代谢应激调控AUF1入核的机制研究

Gene expresion regulation is vital for cells in stress tolerance and regulation of mRNA stability is one of the most important aspect. We previously reported that AUF1, an mRNA stability regulator, plays an essential role in cancer cells under metabolic stress tolerance. Under metabolic stress, cancer cells enhance the mRNA stability of AUF1 targets by driving the cytoplasmic AUF1 to the nucleus in an unknown mechanism. Furthermore, we demonstrated that inactivation of AMPK almost blocked the nuclear translocation of AUF1, suggesting that AMPK pathway may mediates the nuclear translocation of AUF1 after glucose deprivation. To further elucidate the mechanism of AUF1 nuclear import after AMPK activation, we will first define the binding partners or complexes of AUF1 and then identify the key factors that mediates the nuclear translocation of AUF1. Finally, we will explore the mechanism underlying the AMPK activation-key factors-AUF1 nuclear import pathway by further bioinformatics analysis and experimental study. This study will elucidate the mechanism of AUF1 in cancer cells under metabolic stress and provide new insights into therapeutic targets for cancer therapy.

基因表达对于细胞耐受应激至关重要，其中mRNA稳定性调节是基因表达的重要调控层面。申请人的前期研究发现肿瘤细胞通过调控AUF1进核从而减少AUF1促进的靶mRNA降解，进而耐受能量代谢应激，然而AUF1进核的机制不明。我们发现抑制AMPK活化后，AUF1进核显著减少，提示AMPK通路可能介导葡萄糖剥夺情况下AUF1进核。为全面探索AMPK调控AUF1进核的分子机制，本项目拟寻找AMPK活化后参与AUF1进核的蛋白和/或蛋白复合体，并鉴定其中介导AUF1进核的关键因子，然后结合生物信息学分析和进一步的实验深入探索AMPK活化->关键因子->AUF1进核调控通路的分子机制，为阐明AUF1在肿瘤细胞耐受能量代谢应激过程中的作用机制、寻找新的肿瘤干预靶点奠定基础。

基因表达对于细胞耐受应激至关重要，其中mRNA稳定性调节是基因表达的重要调控层面。申请人的前期研究发现肿瘤细胞通过调控AUF1进核从而减少AUF1促进的靶mRNA降解，进而耐受能量代谢应激，然而AUF1进核的机制不明。为此，我们设计并完成了本项目研究，并取得以下结果：1）发现AMPK通路介导葡萄糖剥夺情况下AUF1进核；2）发现Transportin 1参与了葡萄糖剥夺后AUF1的入核过程。我们的研究成果加深了对细胞耐受能量缺乏的认识。本项目研究已发表SCI论文2篇，其中IF>5论文1篇，IF>3论文1篇，培养博士后2名、研究生5名，圆满完成原计划的研究目标和预期指标。