p53是迄今发现最为重要的肿瘤抑制因子，申请者前期采用Mdm2缺失突变的细胞模型，通过诱导p53活化，证明內源性p53能增强细胞中Akt的磷酸化水平并进一步利用Mdm2 微阵列芯片分析技术发现了p53新的靶基因Rap2B，进而提出科学假说：正常生理条件下，內源性p53的活化可以通过其靶基因Rap2B促进Akt的磷酸化和活化，进而参与p53-MDM2负反馈通路的调节。 本课题通过细胞及分子水平研究p53促进Akt的磷酸化和活化的分子机制，以揭示p53是否通过其特异性效应靶基因Rap2B介导Akt的磷酸化，并阐明其生物学意义及在肿瘤发生发展中的作用，为肿瘤的临床治疗及抗肿瘤靶点的筛选提供理论依据和指导。

p53 is a well-known tumor suppressor and plays critical roles in the suppression of the development of human cancer. During our studies with MEF harboring the p53ER fusion protein with three Mdm2 alleles, we observed differential p53 transactivation and further proved that the endogenous p53 could increase the phosphorylation level of Akt. Subsequently, we performed a microarray experiment screening for novel p53 candidate target genes and identified Rap2B as a robust p53 target gene by analyzing the microarray database. Therefore, we proposed the scientific hypothesis: the endogenous p53 could increase the phosphorylation and activation of Akt via its target gene Rap2B, which further involved in the regulation of p53-MDM2 feedback. In this project, at cellular and molecular level, we will investigate the molecular mechanism underlying the phosphorylation and activation of Akt induced by p53 and whether the phosphorylation and activation of Akt induced by p53 was mediated through Rap2B. We expect our research will elucidate the biological significance of this phenomenon and its role in tumor development, and will offer theoretical basis for potential anti-cancer target screening and clinical cancer therapeutic intervention.

p53是迄今发现最为重要的肿瘤抑制因子，我们采用Mdm2缺失突变的细胞模型，通过诱导p53活化，证明內源性p53能增强细胞中Akt的磷酸化水平，本课题在细胞及分子水平证明了p53及rap2b可以促进Akt的磷酸化，而p53特异性效应靶基因Rap2B可以促进细胞迁移，同时我们还发现rap家族另一蛋白rap2a为p53的靶基因，p53能直接调控Rap2a的转录，Rap2a的促肿瘤细胞迁移可能与PI3K/Akt信号通路的激活有关。