MAVS通过促进p53线粒体定位参与肿瘤发生的分子机制研究

The p53 tumor suppressor protein induces apoptosis in response to genotoxic and environmental stresses. Recent studies have revealed the existence of a transcription independent mitochondrial p53 apoptotic pathway; however, the mechanism that regulates its translocation to the mitochondria has been unknown. In this study, we show that the innate immune pathway adaptor MAVS forms a complex with p53 under apoptotic stress that directs p53 translocation to the mitochondria and the subsequent initiation of the mitochondrial apoptosis pathway. Loss of MAVS expression abrogated p53 translocation to the mitochondria and inhibited apoptosis. Furthermore, analysis of GES database 3141 and 17536 revealed that subjects of low MAVS expression correlated with poor overall survial. Taken together, we would like to explore the interaction of MAVS with p53 and their biological significance, the importance of MAVS in tumorgenisis and diagnosis and the usefulness as a therapeutic target could be uncovered through the correlation study between MAVS and p53 protein expression from a large cohort of subjects with breast cancer containing detailed follow-up informations.

作为维护基因组稳定性最重要的肿瘤抑制基因，p53通过激活p21和Bax的表达诱导细胞周期阻滞和细胞凋亡。研究证实凋亡压力下p53的线粒体定位对于细胞凋亡的激活至关重要，但负责调控p53线粒体定位的分子目前尚不十分清楚。我们前期研究发现先天免疫信号转导途径重要接头蛋白MAVS与p53发生相互作用，在凋亡诱导下，二者在线粒体部位的相互作用逐渐增强。MAVS敲低细胞的p53在凋亡压力下定位到线粒体的能力显著减弱，而且MAVS敲除细胞对凋亡诱导药物的杀伤不敏感。已发表数据库分析结果显示MAVS低表达的肿瘤病人预后较差。以上结果提示我们：MAVS很有可能通过调控p53介导的细胞凋亡参与肿瘤的发生与发展。因此，本项目拟进一步研究MAVS通过调控p53线粒体定位参与细胞凋亡的分子机制，并结合临床标本对MAVS表达水平与肿瘤分级、肿瘤耐药以及预后相关性进行分析，为MAVS在肿瘤发生中的作用提供重要线索。