SR蛋白通过Wnt信号调控肿瘤细胞增殖的机制研究

Uncontrollable proliferation distingushes tumor against normal cells.The Wnt signaling, due to over-accumulation of its key transducer beta-catenin in many type of cancers, has been considered as one major pathway driving tumorigenic cell proliferation. It is believed that beta-catenin over-accumulation is largely due to its defected degradation, via mutations in APC/Axin or beta-catenin itself. However, the regulation of beta-catenin protein synthesis might be equally important, yet, is less studied. Here we have identified a group of SR proteins (Serine/arginine-rich splicing factor) that may participate in controlling beta-catenin protein translation. Over-expression of some SR proteins has been reported in several type of cancers. We therefore propose that in these SR protein-high tumor cells, beta-catenin might be accumulated due to enhanced translation. We plan to investigate this mechanism at molecular level.

不受控的细胞增殖是肿瘤细胞区别于正常细胞的关键性状，而Wnt信号通路，因其信号转导关键因子beta-catenin蛋白在多种肿瘤细胞中异常积累，是驱动肿瘤细胞增殖的重要信号通路之一。目前认为，导致beta-catenin蛋白异常积累的机制主要是其降解受损，表现为beta-catenin蛋白自身降解信号的突变或其降解复合体关键成分APC/Axin等的突变，而beta-catenin蛋白的合成调控却几乎没有研究。我们在前期研究中鉴定到一组SR蛋白（Serine/arginine-rich splicing factor）可能参与肿瘤细胞中beta-catenin蛋白的翻译调控。在肿瘤细胞中SR蛋白有比较广泛的表达上调，我们认为，在这些SR蛋白高表达的肿瘤细胞中，beta-catenin蛋白的翻译得以加强，因而导致其蛋白过度积累。我们希望通过该项目的研究，揭示这种调控的分子机制。

不受控的细胞增殖是肿瘤细胞区别于正常细胞的关键性状，而Wnt 信号通路，因其信号转导关键因子beta-catenin 蛋白在多种肿瘤细胞中异常积累，是驱动肿瘤细胞增殖的重要信号通路之一。与已知的多种调控beta-catenin蛋白稳定性的因子不同，我们发现在肿瘤细胞中高表达的一类SR蛋白可以通过增强蛋白合成来提升细胞中beta-catenin的量，进而导致细胞转化。揭示了一种新的通过Wnt/beta-catenin信号促进肿瘤发生发展的机制。在此基础上，我们还围绕Wnt信号与EGF信号的相互关系，研究了小G蛋白Rac1的GEF，Tiam1对EGFR 信号以及化疗药物诱导的DNA损伤信号的响应，揭示了细胞控制Tiam1蛋白稳定性的两种机制以及可能影响着两种机制的外界和内在因素。这些研究结果加深了人们对肿瘤发生发展以及治疗相关的基础理论的理解。

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