中心体蛋白pericentrin核质穿梭与致癌相关性研究

The large coiled-coil centrosomal protein pericentrin was reported to provide a structural scaffold at centrosomes for numerous structural and functional proteins. The correct localization and interaction of pericentrin and its binding proteins contribute to a diversity of fundamental cellular processes. Recent study found that pericentrin is abmormally overexpressed in a series of cancers, such as prostate cancer and lymphoma, leading to severe centrosome and spindle defects and genomic instability, however, the molecular mechanism is still unclear. We found that pericentrin is not only a centrosomal protein, but also a nucleocytoplasmic shuttling protein, indicating that pericentrin may play a crucial role in nucleus. We also found that the localization and function of pericentrin at centrosomes is regulated by the nuclear export receptor Crm1. In order to elucidate the relationship between the nucleocytoplasmic shuttling of pericentrin and its function in cell cycle regulation during tumorigenesis, first, we try to know how pericentrin regulates the processes of gene transcription, DNA damage repair, apoptosis and proliferation after entering the nucleus; second, we want to know how pericentrin regulates the structure and function of centrosomes through interaction with Crm1/RanGTP in cytoplasm; third, we hope to find the expression and subcellular localization differences of pericentrin and its binding proteins between in tumor cells and in normal cells in clinical. Our study might contribute to future clinical therapy and anticancer drug design.

Pericentrin是存在于中心粒外基质的中心体结构蛋白，通过募集与定位多种中心体蛋白来调控微管的组织与成核，对维持中心体、纺锤体结构完整，保证有丝分裂正常进行至关重要。Pericentrin在前列腺癌、淋巴瘤等多种肿瘤中表达量异常升高，并引起中心体与纺锤体结构异常及非整倍体细胞的产生，但其分子机制尚不清楚。我们在实验中发现，pericentrin不仅定位于中心体，还能进行核质穿梭运动，显示其在细胞核内具有一定的调控功能,而在细胞质中，pericentrin在中心体的定位及功能也受到出核转运受体Crm1的调控。为了阐明pericentrin的致癌机理，本课题拟利用已建立的成熟实验平台，从基础和临床两方面深入研究pericentrin核质穿梭对中心体结构与功能的影响，及对基因转录与细胞周期的调控作用，为临床治疗与可能的药物设计提供理论基础。

Pericentrin是存在于中心粒外基质的中心体结构蛋白，通过募集与定位多种中心体蛋白来调控微管的组织与成核，对维持中心体、纺锤体结构完整，保证有丝分裂正常进行至关重要。我们在实验中发现，pericentrin不仅定位于中心体，还能进行核质穿梭运动，显示其在细胞核内具有一定的调控功能,而在细胞质中，pericentrin在中心体的定位及功能也受到出核转运受体Crm1的调控。Crm1的过度表达或pericentrin的异常定位均能引起细胞的癌变。本项目通过对出核转运受体Crm1及受其调控的货物蛋白pericentrin的细胞功能学研究，并通过与福州大学的合作，对具有抑制出核转运及细胞周期的天然海洋药物Dicitrinone进行抗癌机制的研究，阐明Crm1及pericentrin可能的致癌机理，并揭示Dicitrinone通过抑制蛋白出核转运、调控pericentrin中心体定位以及调控细胞周期发挥抗癌活性的机理。我们的实验结果为通过靶向Crm1和pericentrin治疗肿瘤提供了可能的理论基础，也为Dicitrinone进一步的修饰改造以及可能的抗肿瘤临床应用研究提供了实验基础。.本项目至今为止共发表SCI文章5篇，中文核心期刊1篇，目前尚有2-3篇SCI文章正在整理中，将于今后陆续发表，此外，申请国家发明专利2项。各项指标基本达到或超过预期目标。