SIPA1在乳腺癌细胞中质核转运机制及其调控基因表达的功能研究

The appropriate subcellular localization of proteins is critical as it provides eligible physiological context for their function. Aberrant localization of proteins contributes to the pathogenesis of many human diseases, such as metabolic, cardiovascular and neurodegenerative diseases, as well as cancer. SIPA1 (signal-induced proliferation-associated protein 1) is a GTPase activation protein that can catalyze the hydrolysis of Rap1 bound GTP to GDP. Our previous study demonstrates that SIPA1 is mainly localized in nucleus of highly invasive breast cancer cells, and it could promote integrin β1 gene transcription as well as cell invasion and metastasis. But how SIPA1 translocated to cell nucleus in the presence of extracellular stimuli and regulate gene expression is largely unknown. In this proposal, we are going to find new sequence determining the transporting of SIPA1 from cytoplasm to nucleus, and important proteins participating in SIPA1's translocation and regulation of gene expression, as well as the exact interaction pattern between them. Finally, we will also develop clinical application to distinguish the nuclear SIPA1 from all SIPA1 in cell, as well as potential reagents to interfere the function of nuclear SIPA1, which will certainly support for its application in translational medicine in the future.

蛋白质亚细胞定位是其发挥正常功能的基本保证。蛋白质胞内转运的异常可引起代谢类、心血管类、神经退行性乃至肿瘤等疾病。SIPA1是Rap1负调控因子，促进Rap1 GTPase水解活性。已报道SIPA1主要分布于细胞质中，申请人研究发现SIPA1在高转移性乳腺癌细胞核内大量积累，作用于Integrin基因，激活相关信号通路蛋白的表达与活化，促进癌细胞浸润和转移。SIPA1如何入核以及是否是新的转录因子调节肿瘤细胞基因表达尚不清楚。本项目将确定SIPA1蛋白结构中决定其入核的关键结构区域，明确SIPA1入核过程中的关键胞外刺激信号、胞内相关信号转导通路，筛查调控其入核关键蛋白及协助SIPA1共同调控基因表达的关键蛋白，确定受SIPA1调控的靶基因，并在此基础上研发SIPA1核定位检测技术和SIPA1核质定位干预方法，为肿瘤的临床准确诊断和治疗奠定理论和方法学基础。

蛋白质亚细胞定位是其发挥正常功能的基本保证。蛋白质胞内转运的异常可引起代谢类、心血管类、神经退行性乃至肿瘤等疾病。SIPA1是Rap1负调控因子，促进Rap1 GTPase水解活性。已报道SIPA1主要分布于细胞质中，申请人研究发现SIPA1在高转移性乳腺癌细胞核内大量积累，作用于Integrin基因，激活相关信号通路蛋白的表达与活化，促进癌细胞浸润和转移。SIPA1如何入核以及是否是新的转录因子调节肿瘤细胞基因表达尚不清楚。本项目将确定SIPA1蛋白结构中决定其入核的关键结构区域，明确SIPA1入核过程中的关键胞外刺激信号、胞内相关信号转导通路，筛查调控其入核关键蛋白及协助SIPA1共同调控基因表达的关键蛋白，确定受SIPA1调控的靶基因，并在此基础上研发SIPA1核定位检测技术和SIPA1核质定位干预方法，为肿瘤的临床准确诊断和治疗奠定理论和方法学基础。