PH Domain-Only Protein PHLDA3 Is a p53-Regulated Repressor of Akt
PH Domain-Only Protein PHLDA3 Is a p53-Regulated Repressor of Akt
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DOI：
10.1016/j.cell.2008.12.002
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发表时间：
2009-02-06
期刊：
影响因子：
64.5
通讯作者：
Taya, Yoichi
中科院分区：
文献类型：
--
作者：
Kawase, Tatsuya;Ohki, Rieko;Taya, Yoichi
P53和Akt是调控肿瘤发生的关键分子，但作用相反：当P53反式激活靶基因以发挥其肿瘤抑制功能时，Akt将其底物磷酸化并转导下游的生存信号。此外，P53和Akt相互负向调节以平衡细胞内的生存和死亡信号。我们现在确定PHLDA3是一个P53靶基因，它编码一个仅有PH结构域的蛋白。我们发现PHLDA3与Akt的PH结构域竞争结合膜脂，从而抑制Akt向细胞膜的转位和激活。内源性PHLDA3消融后Akt活性增强，P53依赖性细胞凋亡减少。我们还证明了PHLDA3对非锚定细胞生长的抑制作用。PHLDA3基因缺失在原发性肺癌中经常被观察到，提示PHLDA3在肿瘤抑制中起作用。我们的结果揭示了P53和Akt通路之间的一种新的协调模式。
p53 and Akt are critical players regulating tumorigenesis with opposite effects: whereas 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 that 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. Ablation of endogenous PHLDA3 results in enhanced Akt activity and decrease of p53-dependent apoptosis. We also demonstrate the suppression of anchorage-independent cell growth by PHLDA3. Loss of the PHLDA3 genomic locus was frequently observed in primary lung cancers, suggesting a role of PHLDA3 in tumor suppression. Our results reveal a new mode of coordination between the p53 and Akt pathways.