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, 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.

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。

分化疗法被认为是治疗急性髓性白血病 (AML) 的一个非常有前景的治疗策略，但是由于对分化障碍这一过程具体机制的认识匮乏，导致靶向介导AML细胞分化过程仍然受到极大的挑战。本项目研究发现，在AML细胞被诱导分化的过程中，细胞周期依赖性蛋白CDK2被KLHL6泛素化进而进入泛素蛋白酶体通路发生特异性降解。并且，沉默CDK2可以非常有效的促进AML细胞系和原代AML细胞发生分化。同时，采用小分子抑制剂抑制CDK2激酶活性可以将AML细胞从分化障碍中释放，提示我们CDK2可以作为一个潜在的分化治疗靶点。进一步研究发现，CDK2的分化调控机制是通过直接靶向PRDX2蛋白介导的ROS累积发挥效应的。最后，下调CDK2不仅可以通过诱导AML细胞分化抑制肿瘤生长，而且可以延长AML模型NOD/SCID小鼠的生存时间。因此，我们首次发现了CDK2对分化的阻断功能，而进一步提示抑制CDK2可以作为分化治疗AML疾病的有效策略。