pVHL磷酸化修饰及对其抑癌功能的影响

项目名称： pVHL磷酸化修饰及对其抑癌功能的影响

项目编号： No.31270829

项目类型： 面上项目

立项/批准年度： 2013

项目学科： 生物科学

项目作者： 方靖

作者单位： 中国科学院上海生命科学研究院

项目金额： 80万元

中文摘要： pVHL是抑癌蛋白，它结合低氧诱导因子HIFα介导其泛素化降解。HIFα是转录因子，在肿瘤生长过程中发挥重要作用。炎症与肿瘤密切相关，但炎症促进肿瘤的机制仍不清楚。我们发现炎症因子IL-1β抑制pVHL与HIFα的结合，导致HIFα表达升高。进一步研究显示IL-1β可能诱导pVHL发生磷酸化，阻止了pVHL和HIFα的结合。质谱和免疫沉淀结果表明IRAK4 (IL-1 receptor associated kinae 4) 与pVHL结合，IRAK4是IL-1/IL-1R下游激酶，结果提示IRAK4可能是pVHL的激酶。据此，我们提出假设：IL-1β诱导pVHL磷酸化导致其抑制HIFα的功能丧失。本申请是在前期基础上继续IL-1β诱导pVHL磷酸化研究，阐明分子机制，揭示pVHL磷酸化对其抑癌功能的影响。该研究有助于了解炎性因子对pVHL/HIFα的调控作用以及炎症在肿瘤中的作用机制。

中文关键词： VHL；低氧诱导因子1alpha；磷酸化；肿瘤；

英文摘要： pVHL, product of von Hippel Lindau tumor suppressor gene, binds to hypoxia-inducible facotr α (HIFα) and mediates HIFα ubiquitination and proteasomal degradation. HIFα is a transcription factor and plays an important role in tumorigenesis. Inflammation is closely associated with cancer. However, the mechanisms that inflammation promotes cancer remain largely unknown. We found that the pro-inflammatory factor IL-1β prevented pVHL from binding to HIFα, leading to HIFα accumulation. Further experimental results suggested that IL-1β induced phosphorylation of pVHL which blocked the pVHL-HIFα interaction. Mass spectrum analysis and immunoprecipitation experiments showed that the Interleukin-1 receptor associated kinase 4 (IRAK4) bound to pVHL. The results suggest that IRAK4, a major kinase downstream of IL-1/IL-1R, might be the kinase that modifies pVHL. Here, we propose that IL-1β induces phosphorylation of pVHL and compromises pVHL's function against HIFα. The aim of this project is to continue the study of pVHL phosphorylation by IL-1β, to uncover the molecular mechanisms underlain and to clarify the effects of the phosphorylation on pVHL's function. This study will help understand the regulation of pVHL/HIFα by pro-inflammatory factors and the mechanisms that inflammation promotes cancer.

英文关键词： VHL；HIF-1alpha；phosphorylation；cancer；