CRM1是真核生物中重要的核输出蛋白，其介导的跨核运输是细胞中最重要的核-质运输途径之一。在肿瘤细胞中，CRM1活性及表达水平异常升高，导致多种肿瘤抑制因子过量的转运出核，从而无法发挥抗肿瘤作用。申请人已发表的研究发现杆状病毒蛋白Ac34在昆虫细胞中能有效抑制依赖CRM1的出核途径。进一步的研究表明哺乳动物细胞中CRM1的功能也受到Ac34的抑制。据此，本项目将阐明Ac34在哺乳动物细胞中抑制CRM1通路的分子机制，并确定Ac34上调控CRM1通路的关键活性位点与区域；进而验证Ac34在肿瘤细胞中抑制肿瘤抑制因子出核的能力，并明确Ac34的抗肿瘤效果；在此基础上，设计合成基于Ac34最小功能区域的小分子多肽，检测其抗肿瘤效果。本项目的开展将发现昆虫病毒蛋白抑制哺乳动物CRM1通路的具体机制，同时也有望为基于CRM1的抗肿瘤药物研发提供新的思路与理论基础。

As an important nuclear export protein in eukaryotes, CRM1 mediates cross-nuclear transport, which is one of the most important nuclear-cytoplasm transport pathways in cells. In tumor cells, the activity and expression levels of CRM1 are abnormally elevated, resulting in a variety of tumors suppressors excessively transport out of the nucleus, and subsequently losing their anti-tumor capacities. Our published data has found that baculovirus Ac34 is able to effectively inhibit CRM1-dependent nuclear export pathway in insect cells, and further study showed that the functions of CRM1 are also suppressed by Ac34 in mammalian cells. Based on this, we will elucidate the molecular mechanism of suppressing CRM1 pathway by Ac34 in mammalian cells, and further identify the key active sites and regions of Ac34 involving in the inhibition of CRM1. Further study will focus on the ability of suppressing tumor suppressors export nuclear by Ac34 in tumor cells and the anti-tumor effect of Ac34. And then we will design and synthesize small molecule polypeptides according to the smallest functional region of Ac34, and further examine their anti-tumor effect. The study will benefit for unfolding specific mechanism in that insect viral proteins inhibit mammalian CRM1 pathways and be expected to provide novel insights and theoretical basis for the development of novel anti-tumor drugs targeting CRM1.