肿瘤相关蛋白出核转运与肿瘤生物学进程密切相关，包括增殖、侵袭转移、治疗抵抗等。伏隔核1（NAC1）是我们及合作团队研究发现的一个新的促癌因子，但均偏重于核分布NAC1的生物功能学研究。我们前期实验发现NAC1还具有类似核输出信号典型序列参与其出核转运，并且阻滞其出核转运可显著抑制肿瘤细胞侵袭能力，提示出核NAC1与肿瘤细胞侵袭转移等恶性特征有着密切联系。但出核NAC1促进肿瘤细胞侵袭转移的内在机制和生物学意义不明。本研究拟在前期工作基础上，从泛素连接酶Cullin3物理性结合底物识别BTB类蛋白NAC1形成泛素连接酶复合物出发，研究Cullin3通过NAC1识别特异性抑癌蛋白底物RGS2并介导其泛素化降解，从而促进肿瘤细胞侵袭转移的作用机制。进一步通过干预NAC1出核转运评估其作为抑制肿瘤细胞侵袭转移新靶点的可能性和重要意义。

Nuclear export of tumor-related proteins is closely associated with various tumor biological processes, including proliferation, invasion, metastasis and therapeutic resistance. In our preliminary study, we found that nuclear NAC1, a new putative oncogene uncovered by us and our collaborators, has a nuclear export signal (NES) at the N terminus (aa 17-28) that contributes to NAC1 nuclear-cytoplasmic shuttling,and hampering NAC1 export decreases the invasiveness of tumor cells, suggesting that nuclear exported NAC1 plays a vital role in malignant phenotypes, particularly in invasion and metastasis. In this proposal, we propose to investigate the molecular mechanism underlying how nuclear exported NAC1 contributes to invasion, metastasis and its implication in cancer biology and treatment. We will investigate the molecular interaction between NAC1 and Cullin3 and determine whether Cullin3 interacts with RGS2, a tumor suppressor, through NAC1, to ubiquitinate and degrade RGS2 in tumor cells. We will further explore the potential of nuclear exported NAC1 as a novel target for cancer treatment.