MAT1活性切割片段pM9对髓性白血病细胞治疗作用及机制研究

MAT1, an assembly factor and targeting subunit of both cyclin-dependent kinase-activating kinase (CAK) and general transcription factor IIH kinase, is a critical protein that regulates cell cycle and transcription during all-trans retinoic acid induced granulocytic differentiation of myeloid leukemia. Previous studies show that MAT1 protein is highly expressed in leukemic cells, whereas MAT1 cleavage accompanies retinoic acid-induced granulocytic differentiation of leukemic myeloblasts. Our study has identified pM9 as the functional fragment from MAT1 cleavage during granulocytic differentiation of myeloid leukemia, and wish to further elucidate its effect on CAK activity and RARalpha phosphorylation in the attempt to clarify its molecular mechanism. In addition, the structural basis of pM9 will provide support for the finding of small peptides that function as CAK antagonists. Our study not only focus on the importance of MAT1 cleavage during granulocytic differentiation of leukemia, but also provide novel insight into MAT1 cleavage-induced CAK suppression and advance the development of anti-leukemic small molecules targeting CAK activity.

MAT1蛋白是细胞周期蛋白依赖性激酶活化蛋白激酶（CAK）和通用转录因子IIH激酶的组成部分，参与调控细胞周期和转录，是全反式维甲酸对髓性白血病细胞发挥治疗作用的关键蛋白之一。前期研究中已证实MAT1在白血病细胞中持续高表达，而MAT1的切割参与调控了全反式维甲酸的生物活性。本项目将进一步确证pM9作为MAT1的活性切割片段，对CAK活性和维甲酸受体RARa磷酸化的影响，阐明pM9介导的RARa磷酸化水平与髓性白血病细胞粒性分化的相关性及其调控机制，并以pM9为基础进一步寻找具有拮抗CAK活性的小分子肽段，为寻找可模拟该片段的小分子化合物提供理论依据。本项目不仅将发现MAT1切割方式对白血病分化调控的生物学意义，还可基于MAT1切割片段抑制CAK活性的独特方式，寻找全新机制的治疗髓性白血病候选药物，为CAK作为白血病治疗的潜在靶点提供理论依据和新思路，有很强的理论创新和临床应用价值。

MAT1蛋白是细胞周期蛋白依赖性激酶活化蛋白激酶（CAK）和通用转录因子IIH激酶的组成部分，参与调控细胞周期和转录，是全反式维甲酸对髓性白血病细胞发挥治疗作用的关键蛋白之一。本项目证实MAT1在白血病细胞中持续高表达，而MAT1的切割参与调控了全反式维甲酸的生物活性，进一步研究发现pM9作为MAT1的活性切割片段，对CAK活性和维甲酸受体RARa磷酸化具有明显的影响，并阐明了pM9介导的RARa磷酸化水平与髓性白血病细胞粒性分化的相关性及其调控机制，并以pM9为基础寻找发现了具有拮抗CAK活性的小分子肽段，为寻找可模拟该片段的小分子化合物提供理论依据。本项目不仅阐明了MAT1切割方式对白血病分化调控的生物学意义，还为CAK作为白血病治疗的潜在靶点提供理论依据和新思路。本项目发表相关SCI论文3篇，授权发明专利4项，获得自然科学奖励2次，编写英文专著1本，培养研究生7名，超额完成预期目标。