Novel p53 target genes involved in cross talk between oncogenic signals and p53 pathways.

p53和Akt是调节肿瘤发生的关键参与者，具有相反的作用：当p53反式激活靶基因以发挥其作为肿瘤抑制因子的功能时，Akt磷酸化其底物并转导下游生存信号。此外，p53和Akt相互负调节以平衡细胞内的存活和死亡信号。我们现在确定PHLDA3为p53靶基因，其编码仅PH结构域蛋白。我们发现PHLDA3与Akt的PH结构域竞争膜脂质结合，从而抑制Akt易位到细胞膜和活化。在原发性肺癌和胰腺癌中经常观察到PHLDA3基因位点的缺失，提示PHLDA3在肿瘤抑制中的作用。此外，我们发现p53在密码子72处的癌症易感性多态性影响由Mdm 2和Ras调控的致癌信号通路。总的来说，我们的结果揭示了p53和致癌信号通路之间的新的协调模式。

p53 and Akt are critical players regulating tumorigenesis with opposite effects : While p53 transactivates target genes to exert its function as a tumor suppressor, Akt phosphorylates its substrates and transduces downstream survival signals. In addition, p53 and Akt negatively regulate each other to balance survival and death signals within a cell. We now identify PHLDA3 as a p53 target gene, which encodes a PH domain only protein. We find that PHLDA3 competes with the PH domain of Akt for binding of membrane lipids, thereby inhibiting Akt translocation to the cellular membrane and activation. Loss of the PHLDA3 genomic locus was frequently observed in primary lung and pancreatic cancers, suggesting a role of PHLDA3 in tumor suppression.In addition, we have found that cancer susceptibility polymorphism of p53 at codon 72 affects oncogenic signaling pathways regulated by Mdm2 and Ras.Collectively, our results reveal a new mode of coordination between p53 and oncogenic signalling pathways.