蛋白磷酸酶PP2A缺陷导致肿瘤发生的分子机制以及动物模型研究

Protein phosphatase 2A (PP2A) is a major phosphatase, expressed ubiquitously in eukaryotic cells, and was found a raised level in multiple solid tumors, correlating with malignancy. As a tumor suppressor, pp2a disguise itself with its broad spectrum of substrates and subtypes. Although some mechanisms were offered to explain its contribution in control of cell cycle and tumor suppression, its role in cell life is still unclear. To further understand the role of PP2A in mitosis and tumorigenesis, we study the molecular mechanism of tumor suppressor PP2A at both cell level and mice model level. We found that PP2A could regulate the mitotic progress and proliferative ability through kinesin protein EG5 dephosphorylation. We also generate PP2A Aβ knockout mice to study the relationship between EG5 status (protein level and phosphorylation level) and tumorigenesis, which help understanding how PP2A defect induced tumorigenesis. This study will fill the gap of PP2A Aβ Knockout mice, and offer a well mice model for studying the molecular mechanism of tumor suppressor PP2A.

蛋白磷酸酶PP2A是真核细胞内广泛分布的几个主要磷酸酶之一，并且在多种肿瘤中表达异常。PP2A亚型众多，底物范围广泛使它的分子机制非常复杂。尽管已经有一些机制解释PP2A在细胞周期中的作用以及抑癌机理，但是仍有很多不清楚的地方。为了更好的了解PP2A在细胞有丝分裂和肿瘤发生中的作用，我们分别从细胞水平和转基因小鼠水平研究PP2A的抑癌机制。本项目的前期研究发现PP2A通过调节EG5磷酸化水平参与调节细胞有丝分裂周期的进程，进而影响细胞增殖能力。同时我们通过转基因技术，对小鼠进行了PP2A的基因敲除，研究Pp2aAβ敲除小鼠组织中EG5蛋白质水平以及磷酸化状态与肿瘤发生的关系，进一步探索PP2A缺陷诱导小鼠肿瘤发生的机制。本项目填补了PP2AAβ基因敲除小鼠的空白，为研究抑癌基因PP2A在抑制肿瘤发生中的作用提供了很好的动物模型，期望能够从分子和动物水平共同验证抑癌基因PP2A的抑癌机制。