Pleckstrin homology-like domain family A member 3 is one of three relatively small, similar proteins that share a common pleckstrin homology domain. Expression of PHLDA3 and the related PHLDA1 occurs in several fetal and adult tissues, in contrast to the more restricted expression of PHLDA2 seen in mouse tissues. PHLDA3 is one of several proteins induced following treatment of tumor cells with cisplatin, an anti-cancer drug that cross-links DNA and promotes apoptosis through activation of the tumor suppressor p53. Additional evidence that PHLDA3 is involved in promoting apoptosis through p53 came from a study examining the opposing effects of p53 and Akt in tumor development. Tumor suppressor p53 binds the PHLDA3 promoter to induce transcription. Induced overexpression of PHLDA3 increases apoptosis while deletion of PHLDA3 results in increased Akt activity and a reduction in p53-mediated apoptosis. PHLDA3 appears to compete with the PH domain of Akt, preventing Akt activation and promotion of Akt-induced cell survival pathways.
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