CDK2泛素化降解介导白血病细胞分化的非细胞周期依赖的机制研究

CDK2为细胞周期调控蛋白，但近年来包括Nature Genetics在内的诸多权威期刊报道CDK2具有更广泛的非细胞周期调控的生物学功能。我们前期研究发现CDK2蛋白水平的下调可诱导肿瘤细胞走向分化，该作用与CDK2调控细胞周期无关，而是其直接参与了细胞分化的调控，相关研究尚未见文献报道。本项目将在此基础上，进一步研究肿瘤细胞分化过程中泛素-蛋白酶体通路下调CDK2蛋白的分子机制，发现CDK2参与诱导肿瘤细胞分化的关键节点和调控网络，并利用已获得的具有明显诱导分化作用的CDK2结合抑制剂，研究CDK2作为诱导肿瘤细胞分化作用靶点的可能性。通过这些研究，不仅将阐明CDK2参与肿瘤细胞分化调控的分子机制，发现CDK2的新生物学功能，而且将为研究全新的分化诱导剂提供新靶点和理论依据，力求突破分化治疗相关药物品种少、机制单一的瓶颈，为发展具有自主知识产权的新型肿瘤分化诱导剂奠定理论基础。

CDK2, one of the cell cycle regulators, is recently reported to have wide cell cycle-independent biological functions by most authoritative journals (such as Nature Genetics). Our previous research has demonstrated that CDK2 deficiency will induce differentiation of leukemia cells, which is independent of its cell cycle function. Thus, we will further investigate the role of CDK2 and its ubiquitin-proteasome system dependent degradation in the differentiation process of leukemia cells, and find the key factor and signal network for CDK2 regulation. Moreover, we will evaluate the possibility of CDK2 to be a novel therapeutic target by using small molecular CDK2 binding inhibitors which can induce differentiation of leukemia cells. Taken together, these researches not only can clarify the mechanism involved in CDK2 induced cell differentiation, reveal the novel biological functions of CDK2, but also provide a new therapeutic target for differentiation therapeutic strategy, and in the hope to advance the development of differentiation drugs.