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

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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.